Plaque psoriasis

 

Overview

 

Psoriasis encompasses a group of related immune‐mediated inflammatory skin diseases that affect up to 3% of the population. The commonest presentation of psoriasis is plaque psoriasis. Psoriasis is associated with co‐morbidities including obesity, diabetes, vascular disease, depression and inflammatory bowel disease, which contribute to the considerable morbidity and mortality.

A spectrum of treatments is available. Patients with mild disease are usually treated with topical corticosteroids and vitamin D derivatives. Other topical therapies include tar-based preparations, anthralin, calcineurin inhibitors and tazarotene. In patients with more widespread disease, traditional approaches such as photo (chemo) therapy (UVB or PUVA), methotrexate, cyclosporine, or acitretin may be required. Alternatively, targeted immunomodulators (“biologic” therapies) that are highly specific (e.g. targeting TNF-α, IL-12/23, IL-17) are increasingly being used, albeit at a greater cost than conventional approaches.

Because psoriasis is a chronic disease, it requires a long-term treatment strategy, which takes into account potential medication side effects and individual needs. Treatment strategies are often divided into a clearing phase and a maintenance phase.

 

 

 

 

 

Salient features

 

·    Psoriasis is a chronic, immune-mediated disorder that results from a polygenic predisposition combined with environmental triggers, e.g. trauma, infections, medications, psychological stress

 

·    The underlying pathophysiology involves various classes of T cells and their interactions with dendritic cells and cells involved in innate immunity, including neutrophils and keratinocytes

 

·    Identification of susceptibility genes has pointed to a major role for the innate and adaptive immune systems as well as altered epidermal differentiation

 

·    Sharply demarcated, scaly, erythematous plaques characterize the most common form of psoriasis; occasionally, sterile pustules are seen

 

·    The most common sites of involvement are the scalp, elbows and knees, followed by the nails, hands, feet and trunk (including the intergluteal fold)

 

·    Typical histologic findings include acanthosis with elongated rete ridges, hypogranulosis, hyper- and parakeratosis, dilated blood vessels, and a perivascular infiltrate of lymphocytes with neutrophils singly or within aggregates in the epidermis

 

·    Psoriatic arthritis is the major associated systemic manifestation and the most common presentation is asymmetric oligoarthritis of the small joints of the hands and feet; other comorbidities include depression, metabolic syndrome, and cardiovascular disease in patients with moderate to severe disease

 

·    Topical therapy is used to treat limited disease, whereas phototherapy, methotrexate, cyclosporine and targeted immuno-modulators (“biologic” therapies) that target key immune effector cells and cytokines lead to significant clinical improvement of moderate to severe psoriasis

 

Introduction

A common, chronic, disfiguring, inflammatory and proliferative condition of the skin, associated with systemic manifestations in many organ systems, in which both genetic and environmental play a critical role in the etiology and pathogenesis. The most characteristic lesions consist of red (salmon pink), scaly (large adherent silvery centrally attached scales), sharply demarcated, indurated plaques, present particularly over extensor surfaces and scalp. Various environmental triggering factors, e.g. trauma, infections or medications, may elicit disease in predisposed individuals. The disease is life-long and its course is unpredictable but is usually chronic with exacerbations and remissions that are emotionally and physically debilitating.

Psoriasis is a systemic disease process in which up to 20–30% of patients has or will develop psoriatic arthritis. In addition, in patients with moderate to severe psoriasis, there is an increased relative risk for metabolic syndrome and atherosclerotic cardiovascular disease.

 

Provisional working classification of psoriasis

Clinical forms of psoriasis (based on morphology or natural history)

·        Plaque psoriasis (psoriasis vulgaris)

·        Acute guttate psoriasis

·        ‘Unstable’ psoriasis

·        Erythrodermic psoriasis

·        Pustular psoriasis

·        Atypical forms of psoriasis

Other specified forms of psoriasis (based on age or precipitants)

·        Linear and segmental psoriasis

·        Psoriasis in childhood and old age

·        Photo aggravated psoriasis

·        Drug‐induced or exacerbated psoriasis

·        HIV‐induced or exacerbated psoriasis

Psoriasis affecting specific sites

·        Scalp psoriasis

·        Follicular psoriasis

·        Seborrheic psoriasis (sebopsoriasis)

·        Flexural psoriasis (inverse psoriasis)

·        Genital psoriasis

·        Non‐pustular palmoplantar psoriasis

·        Nail psoriasis

·        Mucosal lesions

·        Ocular lesions

 

 

PSORIASIS, PLAQUE

 

Epidemiological aspects

 

Incidence and prevalence

 

1-3 per cent of world’s populations have psoriasis.

 

Age of onset

Psoriasis can first appear at any age, but two peaks age of onset: one at 20–30 years and a second peak at 50–60 years. In approximately 75% of patients, the onset is before the age of 40 years. Although the age of onset is earlier in women than in men, the natural history is similar – chronic with intermittent remissions. Plaque psoriasis is the most frequent form of the disease in children, followed by guttate psoriasis.

Sex

 

Males and females are equally affected by psoriasis vulgaris.

 

 

Genetic epidemiology

Based on population data, lifetime risks of psoriasis is 28 % if one parent is affected, 65% if both parents are affected, and 6% if one sibling affected, compared to 4% when no parent or sibling is affected. Genomic imprinting may explain why psoriatic fathers are more likely to pass on the disease to their children than are psoriatic mothers. HLA-Cw6 is strongly linked to the age of onset of psoriasis. This finding led Henseler and Christophers to propose two different forms of psoriasis exist: type 1 psoriasis, with age of onset before 40 years, is hereditary with a positive family history, strongly HLA associated (particularly HLA-Cw6), and more likely to be severe and type II psoriasis, with age of onset after 40 years, is sporadic with no family history, lacking HLA associated, and usually mild.

Guttate psoriasis is almost invariably HLA associated and thought to be closely linked pathogenetically to type 1 plaque psoriasis.

 

 

 

 

Environmental risk (Precipitating) factors

Triggering factors, both external (directly interacting with the skin) and systemic, can elicit psoriasis in genetically predisposed individuals. These factors not only initiate the disease process but also cause exacerbation of pre-existing disease.

 

 

The interplay between innate and adaptive immune cells in the pathogenesis of Psoriasis

 

Psoriasis can be triggered by several factors, including genetic variants, infection, wound, obesity, stress, and drugs. Early upstream events in psoriasis involve the innate immune activation of skin resident keratinocytes or fibroblasts or recruited plasmacytoid dendritic cells (pDCs) or neutrophils. Cytokines derived from these innate immune cells promote myeloid dendritic cell maturation, with consequent Th17 T cell development and the beginning of the adaptive immune phase. T cell infiltrate promotes inflammatory amplification of innate immune cells, leading to the formation of an autoimmune self-amplifying loop that drives pathogenic hyper proliferation of keratinocytes and manifestations of psoriasis.

 

External triggering factors

 

Trauma - Koebner and reverse Koebner phenomena

Psoriasis is one of several conditions in which various types of trauma may elicit the disease in previously uninvolved skin (Koebner reaction). A wide range of injurious local stimuli, including physical, chemical, electrical, surgical, infective and inflammatory insults, has been recognized to elicit psoriatic lesions. The lag time between the trauma and the appearance of skin lesions is usually 2–6 weeks. Clearing of existing psoriasis following injury has been observed and termed the reverse Koebner reaction. The Koebner reaction is often thought to be more frequent in actively spreading, severe psoriasis. The Koebner phenomenon suggests that psoriasis is a systemic disease that can be triggered locally in the skin.

Trauma can initiate innate immune activation with subsequent specific immune activation and keratinocyte hyper proliferation and angiogenesis. Up to 25% of patients report the development of psoriasis in sites of skin trauma and this is commoner in patients who are HLA‐C:06:02 positive.

 

 

Systemic triggering factors

 

Infection

 

Acute guttate psoriasis is strongly associated with preceding or concurrent streptococcal infection, particularly of the throat (tonsillitis). There is evidence that streptococcal infection may be important in chronic plaque psoriasis also. Oligoclonal expansion of T cells occurs in the tonsils in response to streptococcal colonization, and the same T‐cell repertoire is found in the peripheral blood and skin of patients with guttate psoriasis. It has been proposed that psoriasis is an autoimmune disease that is fueled by persistent intracellular streptococcal infection. Streptococci are facultative intracellular bacteria and are not eliminated by standard antibiotic therapy, which may explain the lack of efficacy of antibiotics in treating guttate psoriasis. Tonsillectomy appears to be effective in some patients because there is a reduction in skin homing T cells.

Further, acute episodes of guttate psoriasis are much more common in individuals with a family history of plaque psoriasis and one-third of cases of guttate psoriasis progress to the chronic plaque form.

Drugs

 

Drugs may be associated with the precipitation or exacerbation of psoriasis. A drug can affect the patient with psoriasis in several ways: (1) exacerbation of pre-existing psoriasis; (2) induction of lesions of psoriasis in clinically normal skin in a person with psoriasis; (3) precipitation of psoriasis de novo; and (4) development of treatment resistance. In addition, in sites of involvement by other cutaneous drug reactions (e.g. exanthematous), psoriatic lesions may appear secondary to the Koebner phenomenon, and plaques may develop at sites of injections of interferon. The clinical manifestations of drug-induced psoriasis span the spectrum of psoriasis, from limited or generalized plaques to erythroderma and pustulosis of the palms and soles. Nail changes and scalp involvement may also be seen.

 

There are many drugs reported to be responsible for the onset or exacerbation of psoriasis. Chief amongst are lithium salts, synthetic antimalarials, interferon α and TNF‐α inhibitors. Given the known co‐morbidities of psoriasis, β‐blockers, ACE inhibitors and NSAIDS are widely prescribed in patients with psoriasis and yet, in most, do not appear to have a major detrimental effect.

Lesions of drug-induced psoriasis usually regress within weeks to a few months of discontinuing the inciting drug. However, psoriasiform eruptions, including palmoplantar pustulosis, may be more persistent in patients receiving TNF-α inhibitor.

 

Histologic findings are not always characteristic. They may suggest psoriasis or be more compatible with a lichenoid drug eruption.

 

Sunlight

 

Although sunlight is generally beneficial, in 5–20% of patients psoriasis may be provoked by strong sunlight and cause summer exacerbations in exposed skin.

 

Some of these patients gave a history of polymorphic light eruption (PLE) with psoriasis appearing as a Koebner phenomenon within PLE lesions. Recent work has indicated that severely photosensitive psoriasis is predominantly female, distinct from PLE, and strongly associated with HLA-Cw6, family history and very early age of onset. Photo-chemotherapy (PUVA) can be helpful in these patients.

 

Metabolic factors

 

The early onset of psoriasis in women, with a peak around puberty, changes during pregnancy and provocation of psoriasis by high dose estrogen therapy potentially indicates a role for hormonal factors in the disease.

 

Hypocalcemia following accidental parathyroidectomy has been reported to be a triggering factor for generalized pustular psoriasis. If psoriasis changes in pregnancy, it is more likely to improve than worsen and about 50% of the patients may show improvement in pregnancy, while in the postpartum period it is more likely to deteriorate. However, pregnant women may develop pustular psoriasis, also referred to as impetigo herpetiformis, sometimes in association with hypocalcemia.

 

Psychogenic stress

Emotional upset is a well-established systemic triggering factor in psoriasis, with a heightened cortisol response to stress having been demonstrated in affected patients. It has been associated with initial presentations of the disease and up to 80% of psoriasis patients report that psychological distress results in flares of their pre-existing disease. Moderate to severe psoriasis is associated with increased levels of depression, anxiety and worry compared to the general population.

 

Alcohol consumption, smoking and obesity

 

Obesity, increased alcohol consumption, and smoking have all been associated with psoriasis.

 

It has long been suspected that both cigarettes and alcohol have a detrimental effect on psoriasis. Alcohol may exacerbate pre-existing disease but does not appear to induce psoriasis. This effect seems greater in men than in women. Psoriasis appears to be more prevalent (15%) in patients with alcoholic liver disease. Heavy drinkers tend to have more extensive and inflamed disease. Excess drinking is undoubtedly also a consequence of the disease and leads to treatment resistance and reduced therapeutic compliance. Abstinence has been reported to induce remission.

 

In one analysis, smoking appeared to have a role in the onset of psoriasis, while obesity appeared to be a consequence of psoriasis.

 

Cigarette smoking is increased amongst patients with plaque psoriasis compared to the normal population, particularly in women. Patients who smoke are at increased risk of developing psoriasis, of having more severe disease and of developing psoriatic arthritis. Smoking has multiple immunological effects that may contribute to the initiation and persistence of psoriasis. There is a particularly strong association between cigarette smoking and palmoplantar pustulosis in women. Some studies have found that the prevalence of psoriasis in a population of individuals who stop smoking or who lose weight eventually reverts to background levels.

 

 

HIV and acquired immune deficiency syndrome

 

The association between severe psoriasis, psoriatic arthropathy and human immunodeficiency virus (HIV) infection is well recognized.

 

Pathogenesis

 

The cardinal features of lesional psoriatic skin are: (i) epidermal hyper- proliferation with loss of differentiation; (ii) increased angiogenesis within the dermis leading to dilatation and proliferation of dermal blood vessels and (iii) a marked dermal and epidermal accumulation of inflammatory cells, particularly neutrophils and T lymphocytes.

 

Epidermal proliferation

 

Normal basal keratinocytes proliferate, differentiate and ascend through the layers of the epidermis before undergoing senescence and entering the keratin layer. The epidermis of psoriasis replicates too quickly. Keratinocytes proliferate out of control, and an excessive number of germinative cells enter the cell cycle as consequence of an increase in the proliferating cell compartment in the basal and supra-basal levels of the epidermis with subsequent rapid progression through the epidermal layers and decreased differentiation. The growth fraction of epidermal basal cells is greatly increased to almost 100% compared with 30% in normal skin. This ‘out of control’ proliferation is rather like a car going too fast because the accelerator is stuck, and cannot be stopped by putting a foot on the brake. The epidermal turnover time is greatly shortened, to less than 10 days compared with 30 to 60 days in normal skin. This epidermal hyperproliferation accounts for many of the metabolic abnormalities associated with psoriasis. It is not confined to obvious plaques: similar but less marked changes also occur in the apparently normal skin of psoriatics.

Vascular changes

 

Vertical dermal capillary loops in lesional skin are dilated, elongated and twisted. It has been demonstrated that epidermal keratinocytes are the primary source of angiogenic activity. These cells produce an array of soluble mediators with angiogenic activity including vascular endothelial growth factor (VEGF). It is over-expressed in psoriatic epidermis as are its receptors on lesional psoriatic microvasculature.

 

In addition to vascular growth, dermal capillaries contribute to the inflammatory process actively through surface expression of molecules involved in leukocyte homing, induced by inflammatory mediators such as histamine, neuropeptides, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). Importantly, E selectin is induced and intercellular adhesion molecule-1 (ICAM- 1) up-regulated on dermal vessels in lesional tissue, thus providing a mechanism for skin homing T lymphocytes to accumulate within lesional dermis and epidermis.

 

Immunology and inflammation

 

It is increasingly clear that the innate immune system, which provides an early response against harm to the host, is dysregulated in psoriasis. Further, in psoriatic stratum corneum, there is an abundance of antimicrobial peptides such as defensins and cathelicidins, which have the capacity to activate innate immunity.

 

Innate immune mechanisms in turn lead to antigen driven T cell expansion and activation. A subset of T cell, thought to play a key role in autoimmunity, termed Th17, and is the primary pathogenic subset. Evidence includes genetic association with IL-23 being a key cytokine in generation of Th17 cells, abundance of IL-23 in psoriatic tissue.

Based on the above information, a pathogenic model has been suggested in which aberrations in the stratum corneum trigger activation of innate immune mechanisms, which in turn lead to recruitment and activation of Th17 cells, which provide effector cytokines leading to epidermal hyper proliferation and a proinflammatory state.

 

 

Pathogenesis of psoriasis – Exposure to microbial or mechanical injury damage associated molecular patterns/ pathogen associated molecular patterns leads to activation of antigen presenting cells like macrophages and dermal dendritic cells; failure to maintain skin barrier due to late cornified envelope proteins 3C/3B deletion leads to continuous exposure to such antigens. Interaction of APC and T cells leads to activation of Th1 and Th17 cells mediated by IL-23. Liberation of IL-17 and IL-22 by Th17 cells, and tumor necrosis factor-α and IFN-γ by Th1 cells further perpetuates the keratinocyte injury creating a vicious positive feedback cycle.

 

Genetic and environmental factors act in conjunction to produce immune dysregulation in the presence of a defective skin barrier. Interaction of damage associated molecular patterns (DAMP) and the pathogen associated molecular patterns (PAMP) with their receptors, such as TLR and NOD like receptors, causes the activation of keratinocytes and the epidermal innate immune system and thus, increased secretion of antimicrobial proteins. This interaction between DAMP/PAMP with TLR/NOD like receptors is also followed by liberation of inflammatory cytokines such as TNF-α, IL-8 and IL-1β, all of which are potent chemo attractants. In patients who carry the psoriasis susceptibility genes, such as HLA-C*06, LCE3B/LCE3C-del or defensin genes, exposure to PAMP leads to a heightened inflammatory response and defective skin barrier repair with increased expression of keratins 6 and 17, and the LCE3 family. Aberrant skin repair allows a sustained exposure to PAMPs which are engulfed by Langerhans cells and dendritic cells.

 

Immunopathogenesis

The underlying pathophysiology involves T cells and their interactions with dendritic cells and cells involved in innate immunity, including keratinocytes.

 

Immunopathogenesis of psoriasis 

The occurrence of triggering environmental factors in genetically predisposed individuals, carrying susceptibility alleles of psoriasis-associated genes, results in disease development. During the initiation phase, stressed keratinocytes can release self DNA and RNA, which form complexes with the cathelicidin LL37 that then induce interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs; recruited into the skin via fibroblast-released chemerin), thereby activating dermal DCs (dDCs). Keratinocyte-derived interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) also contribute to the activation of dDCs. Activated dDCs then migrate to the skin-draining lymph nodes to present an as-yet-unknown antigen (either of self or of microbial origin) to naive T cells and (via secretion of different types of cytokines by DCs) promote their differentiation into T helper 1 (Th1), Th17 and Th22 cells. Th1 cells (expressing cutaneous lymphocyte antigen [CLA], CXC-chemokine receptor 3 [CXCR3] and CC-chemokine receptor 4 [CCR4]), Th17 cells (expressing CLA, CCR4 and CCR6) and Th22 cells (expressing CCR4 and CCR10) migrate via lymphatic and blood vessels into psoriatic dermis, attracted by the keratinocyte-derived chemokines CCL20, CXCL9–11 and CCL17; this ultimately leads to the formation of a psoriatic plaque. Th1 cells release IFN-γ and TNF-α, which amplify the inflammatory cascade, acting on keratinocytes and dDCs. Th17 cells secrete IL-17A and IL-17F (and also IFN-γ and IL-22), which stimulate keratinocyte proliferation and the release of β-defensin 1/2, S100A7/8/9 and the neutrophil-recruiting chemokines CXCL1, CXCL3, CXCL5 and CXCL8. Neutrophils (N) infiltrate the stratum corneum and produce reactive oxygen species (ROS) and α-defensin with antimicrobial activity, as well as CXCL8, IL-6 and CCL20. Th22 cells secrete IL-22, which induces further release of keratinocyte-derived T cell-recruiting chemokines. Moreover, inflammatory DCs (iDCs) produce IL-23, nitric oxide (NO) radicals and TNF-α, while natural killer T (NKT) cells release TNF-α and IFN-γ. Keratinocytes also release vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietin (Ang), thereby promoting neoangiogenesis. Macrophage (M)-derived chemokine CCL19 promotes clustering of Th cells expressing chemokine receptor CCR7 with DC in the proximity of blood vessels, with further T-cell activation. At the dermal–epidermal junction, memory CD8⁺ cytotoxic T cells (Tc1) expressing very-late antigen-1 (VLA-1) bind to collagen IV, allowing entry into the epidermis and contributing to disease pathogenesis by releasing both Th1 and Th17 cytokines. Cross-talk between keratinocytes, producing TNF-α, IL-1β and transforming growth factor-β (TGF-β), and fibroblasts, which in turn release keratinocyte growth factor (KGF), epidermal growth factor (EGF) and TGF-β, and possibly Th22 cells releasing FGFs, contribute to tissue reorganization and deposition of extracellular matrix (e.g. collagen, proteoglycans).

 

Histopathology

 

The main changes are the following.

1 Parakeratosis (nuclei retained in the horny layer).

2 Irregular thickening of the epidermis over the rete ridges, but thinning over dermal papillae. Bleeding may occur when scale is scratched off (Auspitz’s sign).

3 Epidermal polymorphonuclear leucocyte infiltrates and micro-abscesses (described originally by Munro).

4 Dilated and tortuous capillary loops in the dermal papillae.

5 T-lymphocyte infiltrate in upper dermis.

 

Typical histologic findings include acanthosis with uniform elongated rete ridges, thinning of the suprapapillary plate, hypogranulosis, hyper- and parakeratosis, dilated and tortuous capillary loops in the dermal papillae and a perivascular infiltrate of lymphocytes with neutrophils singly or within aggregates in the epidermis.

 

Initial lesion

In the initial lesion, i.e. a smooth surface pinhead-sized papule, the histopathologic features are not yet diagnostic with a preponderance of dermal changes. A superficial perivascular infiltrate of lymphocytes and macrophages is seen in the dermis along with papillary edema and a dilation of capillaries appears to precede epidermal changes in early developing lesions. In acute eruptive guttate lesions, mast cell degranulation is a constant feature.

There is mild epidermal acanthosis without parakeratosis. Macrophages and lymphocytes appear in the lower half of the epidermis and some spongiosis of the epidermis is seen at these sites. Per a large body of evidence, neutrophils are not yet detected in this early phase.

 

Active lesion

 

A fully developed guttate lesion or the marginal zone of an enlarging psoriatic plaque is designated as an “active lesion”. The histopathologic findings in an active lesion are diagnostic for psoriasis.

In the papillary dermis, the capillaries are increased in number and length and they have a dilated tortuous appearance. Marked edema is seen, especially at the tops of the papillae. There is a mixed perivascular infiltrate of lymphocytes, macrophages and neutrophils, and lymphocytes and neutrophils have migrated into the epidermis.

The epidermis is acanthotic with rete ridges of even length with focal accumulations of neutrophils and lymphocytes. There is spongiosis in the malpighian layer. Above these foci, the granular layer is absent and the stratum corneum still contains flattened nuclei (parakeratosis). The accumulation of neutrophils within a spongiotic malpighian layer to form the characteristic “spongiform pustules of Kogoj” and the accumulation of neutrophil remnants in the stratum corneum, surrounded by parakeratosis, as a “microabscess of Munro” are the two findings that are pathognomonic for psoriasis and AGEP.

 

Stable lesion

 

In the papillary dermis, the capillaries are elongated and tortuous, extending upward into elongated club-shaped dermal papillae and almost touch the undersurface of the thinning suprapapillary epidermis; only a small suprapapillary plate of epidermal cells covers the tip of these dermal papillae and are surrounded by a mixed mononuclear and neutrophil infiltrate, as well as extravasated erythrocytes. Invasion of the epidermis with leukocytes takes place particularly in the suprapapillary region. This micromorphology explains the “Auspitz” phenomenon.

The hyperproliferation of the epidermis now has reached its characteristic pattern. The rete ridges are elongated and have a squared-off appearance. Some rete ridges coalesce at the base. In some lesions, micropustules of Kogoj and microabscesses of Munro may be seen.

 

Clinical features

History

 

Pruritus is often the dominant symptom and, although not as severe as in atopic eczema, is experienced by the majority of patients. Skin tightness and burning are frequent in unstable, erythrodermic or pustular psoriasis and pain may be experienced in areas of fissure formation, particularly in palmoplantar or flexural disease. Shedding of scale can be a significant symptom, for instance in scalp psoriasis, and contributes to feelings of embarrassment.

The first manifestation of psoriasis may develop at any age and in general those with earlier onset disease are more likely to have a family history of psoriasis. The course of the disease including the frequency of relapses and remissions varies greatly between individuals. Exacerbating factors should be enquired after, and responses to previous treatments noted. It is important to ask concerning the involvement by psoriasis of specific sites that may not be volunteered by the patient, for instance the ano‐genital region. A detailed medical history should be taken including symptoms of common co‐morbidities, particularly of articular symptoms.

 

Presentation

Plaque psoriasis is the most common type of psoriasis, accounting for about 80–90% of all cases and is characterized by a relatively symmetric distribution of sharply demarcated erythematous papules and plaques with micaceous scales. The degree of body surface area involvement can vary, from limited to extensive. The scalp, elbows, knees and presacrum are sites of predilection, as are the hands and feet. The genitalia are involved in up to 45% of patients. Plaques may persist for months to years at the same locations. Although the course of this disease is chronic, periods of complete remission do occur and remissions of 5 years have been reported in approximately 15% of patients.

 

At any one point in time, different variants may coexist in a particular individual, but the skin lesions all share the same important hallmarks: erythema, thickening and scale. The color of the plaques, a full rich red (sometimes referred to as ‘salmon pink’), has a particular depth of hue not normally seen in eczema or lichen simplex. This quality of color is of particular diagnostic value in lesions on the palms, soles and scalp. In fair‐skinned individuals, the color is less rich and almost magenta pink. In dark‐skinned races, the quality of the color is lost. On the legs, a bluish tint is often present, but this differs from the violaceous hue of lichen planus. The lesions are well defined, with a sharply delineated edge. When they merge, annular and gyrate figures may be produced. This definition is of special diagnostic value on the scalp and penis, when other evidence of psoriasis is absent, and in the flexures. The epidermal thickening characteristic of the psoriatic process causes the lesions to be raised from the adjoining skin, and easily palpable. There may be any number of lesions or only a single one. When multiple, lesions are usually monomorphic and distributed relatively symmetrically. They vary in diameter from one to several centimeters and are oval or irregular in shape. Large plaques form by their coalescence and are commonly seen on the legs and sacral region. When plaques occur across the line of joint movement, fissuring may occur.  In addition to their highly characteristic sharp demarcation, psoriatic lesions are sometimes surrounded by a pale blanching ring, which is referred to as Woronoff's ring. Linear and geometric configurations may arise at the sites of trauma as an isomorphic (Koebner) phenomenon. Erythema may persist at the site of a previously treated plaque for many months. Post inflammatory hypo pigmentation or hyper pigmentation is also both frequent and occasionally lentigines may persist following clearance of a plaque.

Most psoriasis lesions are surmounted by silvery white scales, which vary considerably in thickness. The amount of scaling may be minimal in partially treated disease, and in the flexures. When scaling is not evident it can often be induced by light scratching, a useful sign in diagnostically uncertain lesions.

The classic findings of erythema, thickening and scale are reflections of the histologic findings of elongated dilated capillaries that are close to the skin surface, epidermal acanthosis plus cellular infiltrates, and abnormal keratinization, respectively. If the superficial silvery white scales are removed via curettage (grattage method), a characteristic coherence is observed, as if one has scratched on a wax candle (“signe de la tache de bougie”). Subsequently, a smooth, glossy red surface membrane is seen, which will also come off as a whole. If the latter is removed, where the thin suprapapillary epidermis is torn off, then a wet surface is seen with characteristic pinpoint bleeding. This finding, called Auspitz sign is the clinical reflection of elongated vessels in the dermal papillae together with thinning of the suprapapillary epidermis.

 

 

During exacerbations, psoriatic lesions often itch. Pinpoint papules surrounding existing psoriatic plaques indicate that the patient is in an unstable phase of the disease. In addition, expanding psoriatic lesions are characterized by an active edge with a more intense erythema. Inflamed lesions may be slightly tender. The involution of a lesion usually starts in its center, resulting in annular psoriatic lesions.

 

Because the percentage of body surface area involved does not reflect the severity of the individual lesions with respect to erythema, induration and scaling, the Psoriasis Area and Severity Index (PASI) was formulated. This is a single calculated score that is based on the body surface area involved (in each of four anatomic areas – head, upper extremities, trunk and lower extremities) and clinical grading of lesional erythema, induration and scaling. The PASI is a cumbersome calculation and is more commonly utilized for clinical trials than for the routine management of patients with psoriasis.

 

CALCULATION OF THE PSORIASIS AREA AND SEVERITY INDEX-PASI
Severity of psoriatic lesions
[0, none; 1, slight; 2, moderate; 3, severe; 4, very severe]
	Head	Trunk	Upper limbs	Lower limbs
Erythema	0 to 4	0 to 4	0 to 4	0 to 4
Induration	0 to 4	0 to 4	0 to 4	0 to 4
Scaling	0 to 4	0 to 4	0 to 4	0 to 4
Total score =	Sum of the above	Sum of the above	Sum of the above	Sum of the above
Area of psoriatic involvement
[0, none; 1, <10%; 2, 10 to <30%; 3, 30 to <50%; 4, 50 to <70%; 5, 70 to <90%; 6, 90–100%]
Degree of involvement =	0 to 6	0 to 6	0 to 6	0 to 6
Multiply  ×	×	×	×	×
Correction factor for area of involvement =	0.10	0.30	0.20	0.40
×  ×	A	B	C	D
A + B + C + D = total PASI

The PASI ranges from 0 to 72

 

Psoriasis affecting specific sites

 

Scalp psoriasis

The scalp is one of the most common sites for plaque psoriasis and may be the first and only site affected.  The whole scalp may be diffusely involved, or multiple discrete plaques of varying size may be seen, in contrast to the less well-defined areas of involvement in seborrheic dermatitis. At times, however, it is not possible to distinguish seborrheic dermatitis from psoriasis, and the two disorders may coexist. Very thick plaques can develop, especially at the occiput. Plaques tend to be restricted to hair‐bearing areas, extending a short distance beyond the hairline and around the ears. A morphological entity consisting of plaques of asbestos-like scaling, firmly adherent to the scalp and for some distance to the scalp hairs has been termed pityriasis (tinea) amiantacea. It is most common in children and young adults, and is best regarded as a non-specific reaction pattern. Although pityriasis amiantacea can also be seen in patients with other scaling scalp conditions such as seborrheic dermatitis, secondarily infected atopic dermatitis and tinea capitis, psoriasis is the most common cause. It may be an early manifestation occurring before the other stigmata of psoriasis. Hair loss, sometimes cicatricial, is seen in pityriasis amiantacea. Otherwise, common scalp psoriasis is not a frequent cause of alopecia, although it may occur.

 

Follicular psoriasis

 

Psoriasis around hair follicle openings on the trunk and limbs – follicular psoriasis – may occur as an isolated phenomenon, or in association with plaque psoriasis. The lesions are smaller than the typical lesions of guttate psoriasis and may be either grouped or diffuse. In children it may be confused with pityriasis rubra pilaris (PRP).

 

Seborrhoeic psoriasis (sebopsoriasis)

 

There is no reason why a genetically constituted psoriatic should not develop seborrheic dermatitis. Plaques of thin sharply demarcated erythema with variable scale may occur in the typical distribution of seborrheic dermatitis such as scalp, hairline, medial eyebrows, paranasal areas, external ears, presternal and interscapular area having features of both diseases.

It may occur as an isolated phenomenon, or in association with plaque psoriasis.  When it arises as an isolated phenomenon, it is difficult to distinguish from seborrheic dermatitis, and may represent a koebnerization of psoriasis within this entity. Involvement of the face other than in a seborrheic distribution is uncommon in adults, but it occurs in widespread psoriasis elsewhere on the skin.

 

Flexural psoriasis (inverse psoriasis)

Flexural lesions are more common in older adults than children and are characterized by shiny, pink to red, sharply demarcated thin plaques. Although the lesions are themselves anhidrotic, the effect of hyperhidrosis of the surrounding skin, maceration and friction alter the appearance of the psoriasis, which retains its characteristic color but scaling is greatly reduced or absent. The surface has a glazed hue and fissuring at the depth of the fold is common.  The most common sites of involvement are the axillae, inguinal crease, umbilicus, intergluteal cleft, submammary region and retroauricular folds. Flexural areas are involved in association with plaque psoriasis elsewhere on the skin or less frequently, lesions remain confined to flexural sites, known as “inverse” psoriasis. Inverse psoriasis may occur as a primary disorder or as a Koebner phenomenon to localized dermatophyte, candidal or bacterial infections or seborrheic intertriginous dermatoses that can trigger flexural psoriasis. Failure to respond to antibacterial or antifungal preparations should arouse suspicion. Involvement of the napkin area (psoriatic napkin eruption) may be the first presentation of psoriasis in infancy.

 

Genital psoriasis

 

The genital skin is often involved in individuals with inverse psoriasis, less frequently in those with plaque psoriasis and may be the only manifestation of psoriasis.

Skin of the scrotum and penile shaft may be affected by psoriasis but the glans penis is the most frequently affected part. In circumcised men, lesions on the glans are similar in appearance to plaques at other sites. In the uncircumcised, the plaques lack scale but the color and well‐defined edge are usually distinctive.

The most common vulval presentation is a symmetrical, erythematous, non‐scaly, well‐demarcated thin plaque affecting the labia majora with marked pruritus.

 

Non‐pustular palmoplantar psoriasis

 

On the palms and soles, psoriasis may present as typical scaly plaques on which a fine silvery scale can be evoked by scratching; as less well‐defined plaques resembling lichen simplex or hyperkeratotic eczema; or as a pustulosis. It is often difficult to distinguish between psoriasis and eczema, with which it may sometimes appear to alternate. A sharply defined edge at the wrist, forearm or palm and absence of vesiculation are helpful. On the dorsal surface, the knuckles frequently show a dull‐red thickening of the skin. Elsewhere on the hands and feet, psoriasis retains its typical character. There may be a relationship to trauma or occupational irritants.

 

Nail psoriasis

Nail involvement has been reported in about 40% of psoriatic patients. The fingernails are more often affected than the toenails. This is seen in association with all types of psoriasis of the skin, and patients with nail involvement appear to have an increased incidence of psoriatic arthropathy. There is no sex predilection, but patients over 40 years of age are affected twice as often as those under 20 years. Nail disease is more likely to be severe if psoriasis is early onset and familial.

Psoriasis may affect any part of the nail unit, including the nail matrix, nail bed and hyponychium. Nail pitting is the best known and possibly the most frequent psoriatic nail abnormality. Small parakeratotic foci in the proximal portion of the nail matrix results in loss of parakeratotic cells from the surface of the nail plate, leaving a variable number of tiny, punched-out depressions on the nail plate surface. This is a process analogous to the shedding of psoriatic skin scale. Pitting is the most frequently seen in fingernails; individual pits being uniform in size at about 1 mm diameter and sometimes arranged longitudinally. They emerge from under the cuticle and grow out with the nail. Leukonychia and loss of transparency (less common findings) are due to involvement of the mid portion of the matrix. If the whole nail matrix is involved, a whitish, crumbly, poorly adherent “nail” is seen. Psoriasis of the nail bed may cause localized separation of the nail plate. Cellular debris and serum accumulate in this space. The brown-yellow color observed through the nail plate looks like a spot of oil called “oil spot” or “oil drop” phenomenon (Salmon patches) which is highly specific for psoriasis. Splinter hemorrhages are the result of increased capillary fragility, and subungual hyperkeratosis and distal onycholysis are due to parakeratosis of the distal nail bed.

 

Mucosal lesions

Migratory annular erythematous lesions with hydrated white scale (annulus migrans) have been observed in patients with acrodermatitis continua of Hallopeau and generalized pustular psoriasis. The most common location is the tongue, and the clinical (and histologic) appearance is similar to geographic tongue.

 

Ocular lesions

 

Psoriasis may affect ocular structures directly, or by associated immunological phenomena. Direct involvement of the eyelid margins may cause blepharitis and its consequences, which are the most frequent ocular complications of psoriasis. A chronic non‐specific conjunctivitis and xerosis are also common in psoriasis. Uveitis is an important immunologically mediated complication seen in patients with more extensive psoriasis. It is more strongly associated with psoriatic arthritis.

 

Clinical variants (based on morphology or natural history)

 

Acute guttate psoriasis

 

Guttate psoriasis is more commonly seen in children and adolescents. More than 30% of psoriatic patients have their first episode before age 20; in many instances, an episode of guttate psoriasis is the first indication of the patient’s propensity for the disease. Streptococcal pharyngitis caused by group A streptococci or a viral upper respiratory tract infection may precede the eruption by 1 or 2 weeks. In over half of the patients, an elevated antistreptolysin O, anti-DNase B or streptozyme titer is found, indicating a recent streptococcal infection. Throat cultures should be taken to rule out streptococcal infection. A guttate flare may also occur in adults with plaque psoriasis.

This describes the sudden onset of a shower of bright red, drop shaped discrete small scaly papules and plaques.  In the early stages, there may be little scaling and the color is not specific. The lesions are from 2 mm to 1 cm in diameter, round or slightly oval. Lesions increase in diameter with time. They are scattered more or less evenly over the body, particularly on the trunk and proximal part of the limbs, rarely on the palms and soles. It may also affect face, ears and scalp. The lesions on the face are often sparse, difficult to see and disappear quickly. Although guttate lesions are normally profuse, there are occasionally no more than half a dozen present on the body. Pruritus is variable. The diagnosis is made mainly on the nature of the scaling, the general distribution and evidence for preceding infection. Lesions usually resolve spontaneously over about 3 months; it responds more readily to treatment than does chronic plaque psoriasis. A minority of patients with acute guttate psoriasis subsequently develops plaque psoriasis. A guttate flare may also occur in adults with plaque psoriasis and is more common in patients whose psoriasis had its onset in childhood.

 

Unstable’ psoriasis (syn. active psoriasis, eruptive inflammatory psoriasis)

 

In contrast to the lesions in plaque psoriasis which are static for prolonged periods, in some individuals and in some phases of the disease there is more marked activity in the form of enlargement of plaques that can become more intensely erythematous, and the development of many new smaller plaques. Patients may complain of more pain or pruritus within the plaques. The Koebner phenomenon is thought to be more frequent in this phase of the disease. The immediate outcome is unpredictable; the lesions may return to the inactive state, or progress to localized pustular or erythrodermic psoriasis. Recognized precipitants include withdrawal of systemic or potent topical corticosteroids, treatment with irritants such as tar or dithranol, acute infection, hypocalcemia and severe emotional upset.

 

Erythrodermic psoriasis

 

Erythrodermic psoriasis, in which most or the entire body surface is affected by psoriasis, is uncommon, occurring in 1–2% of patients but psoriasis has been found to be the underlying cause in about 25% of cases of erythroderma. Erythroderma in psoriasis may be chronic, due to the gradual extension of plaque psoriasis, or acute as part of the spectrum of ‘unstable’ psoriasis. In the chronic form, the individual may be systemically well, the clinical characteristics of psoriasis are retained and there are usually some areas of uninvolved skin. Mild topical treatments are well tolerated and the overall prognosis is good.

The acute form is often precipitated by environmental or therapeutic triggers including systemic illness, alcoholism, antimalarials, irritating topical treatments, ultraviolet radiation or by withdrawal of systemic corticosteroids, ciclosporin or methotrexate. The patient may be febrile and systemically ill. Dependent edema is common. Itching is often severe. The entire skin may be affected and the clinical characteristics of psoriasis are often lost. Untreated, the course is prolonged, relapses are frequent and there is an appreciable mortality. Complications are those of acute skin failure, including sepsis, temperature dysregulation (hypothermia or hyperthermia), hypoalbuminemia, anemia, and hypervolemia and high output cardiac failure.

Metabolic complications of erythroderma

Persistent, universal inflammation of the skin may have important consequences for thermoregulation, hemodynamics, intestinal absorption, protein, water and other metabolism. Under normal environmental conditions, radiant and convective heat loss from the body surface is increased, occasionally leading to dangerous hypothermia. An increase in metabolic activity provides compensatory increases in body heat production, but at the expense of tissue catabolism and muscle wasting if prolonged. At the same time, the psoriatic or erythrodermic skin is hypohidrotic or anhidrotic, because of intraepidermal occlusion of the sweat duct. There is attendant risk of hyperthermia in very high ambient temperatures. Skin blood flow, blood volume and cardiac output may all be increased, and if these changes persist, they may lead to failure of a cardiovascular system already compromised by hypertension, myocardial or valvular heart disease, or anemia (particularly in old people). A healthy cardiovascular system will tolerate the increased metabolic demand for years. Malabsorption (dermatogenic enteropathy) may occur, reverting as the psoriasis remits. The principal loss in the profuse scaling of exfoliative psoriasis is of protein (keratin) but some iron is also lost. In fulminating psoriasis, further protein loss may be attributable to enteropathy, as well as leakage from the circulation into the skin. Eventually, hypoalbuminemia may contribute to the edema caused by the skin inflammation itself, or cardiac failure. Mild anemia is prone to develop, because of a combination of iron loss and possibly impaired absorption and utilization of iron. Serum and red cell folate and serum B12 may also be low. The barrier efficiency of the skin in psoriatic erythroderma is impaired, the chief effect being increased transepidermal water loss. The urine output tends to drop and, if water intake is inadequate for any reason, dehydration results.

Although there are many causes of erythroderma, clues to the diagnosis of psoriatic erythroderma include previous plaques in classic locations, characteristic nail changes, and central facial sparing.

                                   

Atypical forms of psoriasis

 

Rupioid, elephantine and ostraceous psoriasis are plaques associated with gross hyperkeratosis. Rupioid psoriasis refers to limpet‐like cone‐shaped lesions. The term elephantine psoriasis is very persistent, thickly scaling, large plaques that occur on the back, limbs, hips or elsewhere. Ostraceous psoriasis refers to a ring‐like hyperkeratotic lesion with a concave surface, resembling an oyster shell.

 

Psoriasis in childhood and old age

Psoriasis in children

 

Psoriasis in children is more common in girls than boys and it significantly associated with several co‐morbidities including obesity and diabetes.

All of the clinical variants of psoriasis described in adults are recognized in childhood. The napkin area is frequently the first site affected; under the age of 2 years, napkin psoriasis with or without disseminated lesions is the most frequent form, presenting with well‐defined erythema devoid of scale.

Guttate psoriasis is more frequent in children than adults, particularly under the age of 12 years. In older children, plaque psoriasis is the most frequent presentation, and the face and ano‐genital sites appear to be affected more frequently than in adults. The disease often first appears in the scalp, where it may present as pityriasis amiantacea. Other flexural forms also occur. The disease may mimic chronic blepharitis or perleche, usually unilaterally, with a small plaque of psoriasis on one eyelid extending to the lid margin, or on the cheek at the angle of the mouth. An indolent pustular acrodermatitis, sometimes of only one digit, usually eventually proves to be psoriatic. More extensive, chronic lesions of the hands and feet may occur with persistent dryness, hyperkeratosis and fissuring. Pitting of the fingernails may be the only manifestation for months or even years. Follicular psoriasis occurs on the extensor prominences of elbows and knees. Erythrodermic, pustular psoriasis and psoriatic arthritis are rare in childhood.

Psoriasis in elderly

In older age groups, psoriasis that starts for the first time after the age of 65 years tends to be less extensive than early‐onset disease. There is less often a family history of psoriasis. Plaque psoriasis involving the scalp is the commonest phenotype. Inverse psoriasis and erythrodermic psoriasis may be more common than in early‐onset disease whereas guttate and generalized pustular psoriasis are rare.

 

HIV‐induced or exacerbated psoriasis

 

The association between severe psoriasis, psoriatic arthropathy and HIV infection is well recognized. Psoriasis may be the first presentation of HIV infection, as may the deterioration in previously stable disease. Plaque psoriasis is the most frequent phenotype, with a predilection for the scalp and palmoplantar skin. Sebopsoriasis, rupioid psoriasis and psoriatic erythroderma are also common, as are mixed patterns. Psoriasis tends to be more prevalent in the later stages of HIV‐related immune dysfunction, but may occur earlier. The mechanism of worsening of psoriasis in HIV infection is unclear and represents a paradox, given that helper T cells are the major target of HIV. Suggested explanations include HIV‐induced reduction in regulatory T cells, an increased number of memory CD8+ T cells, effects of HIV on dendritic cell populations, HIV proteins acting as super antigens or shared genetic variants between psoriasis and HIV responder status. One suggestion is that HIV affects peripheral blood helper T cells and affects to a lesser degree cutaneous resident memory T cells which are pathogenic in psoriasis. Psoriasis tends to improve with a reduced viral load, especially on treatment with highly active antiretroviral therapy.

 

Differential diagnosis

In seborrheic dermatitis, the lesions are lighter in color, less well defined and covered with a dull or branny scale. Eczema at times develops a psoriasiform appearance, especially on the legs. Hyperkeratotic eczema of the palms is a common cause of misdiagnosis. Color, scratch‐evoked scaling and well‐defined margins are suggestive of psoriasis, and nail changes may be diagnostic. Lichen planus could give rise to difficulty when the two diseases alternate or coexist, especially when present as hypertrophic lesions on the legs, as penile lesions and on the palms. The violaceous color, Wickham's striae and the presence of oral changes are usually decisive. Lichen simplex can resemble psoriasis closely, particularly on the scalp and near the elbow. The intensified skin markings, rather ill‐defined edge and the marked itching are characteristic, and the point of the elbow tends to be avoided. Candidiasis shows a glistening deep red color resembling psoriasis, particularly in the flexures, but scaling tends to be confined to the edge, and small satellite pustules and papules are usually evident outside the main area. Tinea cruris has a well‐defined, often polycyclic edge, but Trichophyton rubrum infections, especially of the palm, may cause difficulty. If corticosteroids have been applied, scaling may be absent and the diagnosis must be made by microscopy and culture of skin scrapings.

 

Complications and co‐morbidities

 

Patients with psoriasis experience increased morbidity and mortality from a range of systemic diseases, affecting most major organ systems.

 

Immune‐mediated inflammatory diseases

 

Psoriatic arthritis is the most frequent inflammatory disease associated with psoriasis. Inflammatory bowel disease (IBD) such as crohn disease and ulcerative colitis, and psoriasis share an association with sacroiliitis and HLA-B27 positivity. The risks of other immune‐mediated diseases are autoimmune thyroid disease and type 1 diabetes.

 

Psychological distress

 

Psoriasis is associated with significant psychological distress. Excessive alcohol consumption is found more commonly in men with severe psoriasis, and could be a consequence of stress caused by severe skin disease.

 

Cancer

 

The incidence of non‐melanoma skin cancer is more common in psoriasis patients compared with the general population. It has been shown that psoriatic patients who have had >200 PUVA treatments are at increased risk for the development of skin cancers, especially squamous cell carcinomas (SCCs)  and basal cell carcinoma, and this may be compounded by immunosuppressive treatments, including ciclosporin, methotrexate, TNF‐α inhibitors and possibly high‐dose UVB.

 

Association with internal diseases (including comorbidities)

In patients with moderate to severe psoriasis, there is an increased relative risk for atherosclerotic cardiovascular disease and metabolic syndrome.

Cardiovascular disease

 

Cardiovascular diseases, e.g. myocardial infarctions, peripheral arterial disease, cerebrovascular accidents, are more common in patients with severe psoriasis. The latter is associated with a threefold increased risk for myocardial infarction and a 3.5–4.4-year reduction in life expectancy. This is largely due to an increased risk for having metabolic syndrome. Patients with severe psoriasis die at a younger age than unaffected people and cardiovascular disease accounts for the majority of this excess mortality. In patients with psoriasis, serum levels of C-reactive protein (CRP) have been reported to be elevated (as compared to healthy controls), and elevated CRP levels represent a risk factor for the development of cardiovascular disease. It has also been shown that TNF-α and IL-6 can target adipocytes and induce dyslipidemia. Recently, evidence has been accumulating that treatment with methotrexate and/or TNF-α inhibitors may reduce the risk of atherosclerotic cardiovascular disease. Patients with psoriasis may also be at increased risk for the development of venous thromboembolism.

The increased vascular risk also relates to behaviors (such as cigarette smoking, which is more frequent amongst those with psoriasis).

 

Metabolic syndrome

 

The metabolic syndrome (truncal obesity, hyperlipidemia, hypertension and insulin resistance) is significantly elevated in patients with psoriasis mainly in those having more extensive disease.  The strongest of these associations is with obesity, which can be seen in childhood psoriasis, and tends to predate the onset of psoriasis. Obesity in adults appears to be a risk factor for the development of psoriasis. Patients who are obese (BMI >30) have more severe psoriasis than lean patients. Obesity may decrease treatment responsiveness and is one of the risk factors for the development of premature cardiovascular disease. Psoriasis severity is associated with insulin resistance and medications that target insulin resistance may be effective in psoriasis and also weight loss in obese patients with psoriasis improve psoriasis severity.

 

Hepatobiliary disease

Death rates due to liver disease have been reported to be significantly elevated in patients with severe psoriasis. Non-alcoholic steatohepatitis, characterized by fatty infiltration, periportal inflammation and focal necrosis, is more commonly observed in patients with psoriasis. In patients with psoriasis, non-alcoholic fatty liver disease is correlated with the presence of obesity, hyperlipidemia, the metabolic syndrome, an AST: ALT ratio >1, and psoriatic arthritis. Chronic administration of methotrexate is associated with a significant risk for hepatic damage in patients with psoriasis, whereas similar methotrexate dosages in patients with rheumatoid arthritis do not pose such hepatotoxic potential, possibly because of genetic predisposition, increased alcohol consumption by psoriasis patients, and a higher incidence of non-alcoholic fatty liver disease. Neutrophilic cholangitis is a recognized cause of liver dysfunction in patients with generalized pustular psoriasis and occasionally in plaque psoriasis.

 

Others

 

There are rare reports of acute respiratory distress syndrome complicating erythrodermic or generalized pustular psoriasis. Psoriasis is also associated with an increased risk of hyperuricemia and gout.

 

Disease course and prognosis

 

This remains as unpredictable as it was 150 years ago. ‘Psoriasis is at all times and under all forms a very troublesome and, often, an intractable disease, but it is rarely dangerous to life. It is impossible to say, in any particular case, how long the disease will last, whether a relapse will occur, or for what period of time the patient will remain free from psoriasis. Relapse is the rule, however completely the lesions have been treated and by whatever method. Guttate attacks carry a better prognosis and have longer remissions after treatment. At the other extreme, erythrodermic and pustular forms carry an appreciable mortality and arthropathic forms a considerable morbidity. Early onset and a family history of the disease appear to worsen the prognosis. It is now known that severe plaque psoriasis will also appreciably shorten life expectancy by an average of 4–6 years. There is little doubt that even severe cases can be maintained in prolonged remission by the use of systemic therapies, including the biologics.

 

Investigations

 

The diagnosis of psoriasis is usually clinical. A skin biopsy of lesional skin may occasionally be helpful in atypical cases.

 

Management

 

The diagnosis of psoriasis is usually based on clinical features. In the few cases in which clinical history and examination are not diagnostic, biopsy is indicated to establish the correct diagnosis. The majority of psoriasis cases fall into three major categories: guttate, erythrodermic/pustular, and chronic plaque, of which the latter is by far the most common. Guttate psoriasis is often a self-limited disease with spontaneous resolution within 6-12 weeks. In mild cases of guttate psoriasis, treatment may not be needed, but with widespread disease, UVB phototherapy in association with topical therapy is very effective. Erythrodermic/pustular psoriasis is often associated with systemic symptoms and necessitates treatment with fast-acting systemic medications. The most commonly used drug for erythrodermic and pustular psoriasis is acetretin. In occasional cases of pustular psoriasis, systemic steroids may be indicated (asterisk). Dotted arrows indicate that guttate, erythrodermic and pustular forms often evolve into chronic plaque psoriasis. Therapeutic choices for chronic plaque psoriasis are typically based on the extent of the disease. Among the main treatment regimens (topical treatment, phototherapy, day treatment centers, and systemic treatments), first and second line modalities are indicated by the solid and dashes lines respectively. Individuals with conditions that limit their activities, including painful palmoplanter involvement and psoriatic arthritis, may require more potent treatments irrespective of the extent of affected body surface area. Likewise, psychological issues and impact on quality of life should be taken into consideration. Within each treatment regimen, first-line and second-line choices are grouped. Cyclosporine A is not considered a first-line long-term systemic treatment because of its side effects, but short term treatment can be helpful for induction of remission. If patients have incomplete response to or are unable to tolerate individual first-line systemic medications, combination regimens, rotational treatments, or use of biological therapies should be considered.

 

General

Treatment of psoriasis should be individualized. Care of the psoriatic patient needs to focus not only on the skin, but also on the co-morbidities that exist or might develop. To date, no treatment has been shown to cure this disease and alters its natural history, so counseling of the patient and family members regarding its natural history and management strategies is recommended.

Some treatments are better suited for rapid clearing; others are better suited to be maintenance treatment. The optimum management involves the sequential use of therapeutic agents involving three steps, namely, the clearing phase (induction of remission), the transitional phase, and the maintenance phase  (maintenance of remission). In inducing remission, 75% reduction in PASI from baseline (PASI 75) has been widely adopted as a minimum response criterion for severe plaque psoriasis in clinical trials. With the availability of higher efficacy treatments, this standard is rising to PASI 90. 

 

Determining degree of inflammation

The most common form of psoriasis is the localized chronic plaque disease involving the skin and scalp. It must be determined whether the plaque is inflamed before instituting therapy. Red, sore plaques can be irritated by tar, calcipotriol, and anthralin. Irritation can induce further activity. Inflammation should be suppressed with topical steroids and/or antibiotics before initiation of other treatments.

Determining the end of treatment

The plaque is effectively treated when induration has disappeared. Residual erythema, hypo pigmentation, or brown hyper pigmentation is common when the plaque clears; patients frequently mistake the residual color for disease and continue treatment. If the plaque cannot be felt by drawing the finger over the skin surface, treatment may be stopped.

Duration of remission

Among topical monotherapy, tazarotene induce longer remissions than calcipotriene and corticosteroids; among systemic agents, longer remissions occur with acitretin than cyclosporine or methotrexate, but compared with the remission rate of phototherapeutic modalities, the remission rates are much less.

 

Topical treatment

 

Topical therapies are the mainstay of treatment for psoriasis of limited extent. The main groups of topical therapies are emollients, corticosteroids, vitamin D and its analogues, coal tar and retinoids

Topical corticosteroids

 

Maximal quantities: 50 g/week of a super potent corticosteroid; 100 g/week of a potent corticosteroid.

 

INDICATIONS AND CONTRAINDICATIONS FOR TOPICAL CORTICOSTEROIDS

Indications

·       Mild to moderate psoriasis: first-line treatment as monotherapy or in combination   ·       Severe psoriasis: often in combination with a vitamin D3 analogue, a topical retinoid, anthralin or tar; also as an adjunct to systemic therapy or photo(chemo)therapy   ·       Monotherapy for flexural and facial psoriasis (usually mild strength)   ·       Recalcitrant plaques often require occlusion (plastic, hydrocolloid)

Contraindications

·       Bacterial, viral, and mycotic infections   ·       Atrophy of the skin   ·       Allergic contact dermatitis due to corticosteroids or constituents of the formulation   ·       Pregnancy or lactation*

 

* Can consider limited use of mild- to moderate-strength corticosteroids.

 

Corticosteroids are anti-inflammatory, ant proliferative, immunosuppressive, and vasoconstrictive. Lower potency corticosteroids are used for limited periods of time on the face, neck, flexures, genitalia, areas with thin skin, and in infants and are also used in unstable, erythrodermic and generalized pustular psoriasis. In other areas and in adults, mid- or high-potency agents are used. Patients with thick, chronic plaques such as the palms and soles require treatment with the highest potency corticosteroids, such as clobetasol. For clobetasol and halobetasol, maximal weekly use should be 50 gm or less. Newer formulations of corticosteroids, particularly foams, are easier to apply than traditional creams or ointments and can be used for scalp, truncal or limb psoriasis. Once-daily application has been shown to be as effective as twice-daily application, and long-term remissions may be maintained by applications on alternate days.

Topical steroids give fast but temporary relief. They are most useful for reducing inflammation and controlling itching. Initially, when the patient is introduced to topical steroids, the results are most gratifying. However, tachyphylaxis, or tolerance, occurs, and the medication becomes less effective with continued use. Patients remember the initial response and continue topical steroids in anticipation of continued effectiveness. Long-term use of topical steroids results in atrophy and telangiectasia. Topical steroids are useful for treating inflamed and intertriginous plaques.

A group I through V steroid applied one to four times a day in a cream or ointment base is required for best results. Group V topical steroids applied once or twice a day should be used in the intertriginous areas and on the face. Some plaques resolve completely, but most remain only partially reduced with continued application. Continual application for more than 3 weeks should be discouraged. Remissions are usually brief and the plaques may return shortly after treatment is terminated. Topical steroid creams applied under an occlusive plastic dressing promote more rapid clearing, but remissions are not extended.

At least 80% of patients treated with high-potency topical corticosteroids experience clearance. In fact, the maximum improvement is usually achieved within 2 weeks. With maintenance therapy consisting of 12 weeks of intermittent applications of betamethasone dipropionate ointment (restricted to weekends), 74% of patients remained in remission. Unfortunately, no efficacy data are available on prolonged treatment for more than 3 months. As tachyphylaxis and/or rebound can occur fairly rapidly, i.e. within a few days to weeks, intermittent treatment schedules (e.g. once every 2 or 3 days or on weekends) are advised for more prolonged treatment courses. Combination topical therapy can take advantage of the rapid effect of topical corticosteroids as well as the prolonged benefits of topical vitamin D₃ analogues. Potent topical corticosteroids tend not to induce a lasting remission, unlike tar which has the potential to do so.

Intralesional steroids

Intralesional injection of small resistant plaques with triamcinolone acetonide (Kenalog 5 to 10 mg/ml) almost invariably clears the lesion, for instance on the backs of the hands and knuckles and accords long-term remission. Atrophy may occur with the 10 mg/ml concentration.

 

Vitamin D₃ analogues

 

Vitamin D₃ analogues should be avoided or limited in patients with abnormalities in bone or calcium metabolism (e.g. sarcoidosis) or renal insufficiency; they are pregnancy category C. If used in conjunction with phototherapy, need to apply after UV irradiation or at least several hours prior, because they may reduce UV penetration into the skin.

 

 

	Calcipotriene/calcipotriol	Calcitriol	Tacalcitol
Concentration	50 mcg/g	3 mcg/g	2 mcg/g; 4 mcg/g
Formulations	Ointment, cream, lotion, solution, foam	Ointment	Ointment, lotion
Frequency	BID	BID	BID; daily
Maximum weekly amount*	100 g	200 g	70 g; 70 g†
Chemical structure	26,27-cyclo-vitamin D3 22,23 double bond Transposition of the 25-OH to the 24 position	1α,25-dihydroxy vitamin D (active natural vitamin D3)	1α,24-dihydroxy vitamin D3
Inactivating enzymes	22,23-reductase; 24-oxido-reductase	24-hydroxylase	25-hydroxylase

 

* To avoid hypercalcemia.

† Maximum weekly amount for 8 weeks of treatment.

 

When the epidermis is hyper proliferative, vitamin D₃ inhibits epidermal proliferation, and it induces normal differentiation by binding with vitamin D receptor; it also acts on the immunocytes, shifting the Th1 cytokine profile of plaques towards Th2. Vitamin D₃ analogues also inhibits several neutrophil functions. Due to their therapeutic efficacy and limited toxicity, calcipotriene (calcipotriol) and other vitamin D₃ analogues have become a first-line therapy for psoriasis.

The naturally occurring active metabolite of vitamin D₃, calcitriol, and synthetic analogues calcipotriol and tacalcitol are all effective when applied topically in psoriasis. The most widely prescribed analogue in current use, calcipotriol (50 μg/g) ointment, has been reported to be at least as effective as 0.1% betamethasone valerate ointment in plaque psoriasis. Vitamin D and its analogues all have the potential to affect systemic calcium homeostasis with hypercalciuria and hypercalcemia. It is prudent to restrict the amount of calcipotriol (50 μg/g) ointment to less than 100 g per week, and to monitor serum and urinary calcium levels should these doses be exceeded. Hypercalcemia is reported with excessive quantities of calcipotriene applied over large surface areas.

Calcipotriene monotherapy has been shown to result in a ~60% reduction of PASI after 8 weeks of treatment, but practical use in psoriasis patients usually involves combination therapy with topical corticosteroids is commonly employed, both during the clearing phase as well as intermittently during long-term treatment. Calcipotriene is not as effective as group I corticosteroids, but regimens using calcipotriene and group I corticosteroids are superior over either agent alone. Most patients now use the following regimen: Calcipotriene is applied in the morning and a group I corticosteroid is applied in the evening for 2 weeks. Then a maintenance regimen is begun using group I corticosteroids twice daily on weekends and calcipotriene twice daily on weekdays.  Application of calcipotriene twice a day is much more effective than once a day application. Based on this observation, a stable ointment formulation of calcipotriol 50 μg/g and betamethasone dipropionate 0.5 mg/g has been licensed for therapy. This combination shows superior efficacy to either calcipotriol or betamethasone alone with better clearance and faster onset of action. When calcipotriene and betamethasone dipropionate are combined, a ~70% reduction in PASI has been observed (ointment formulation) as has clearing/minimal disease in ~70% of patients with scalp psoriasis (gel formulation). Calcipotriene treatment can produce a mild irritant contact dermatitis at the site of application. The face and intertriginous areas are prone to this side effect.

They are effective and safe and well tolerated for the short- and long-term treatment of psoriasis. Tachyphylaxis (tolerance) does not occur with calcipotriene. Calcipotriene solution is also available for scalp psoriasis.

Calcitriol is a new ointment formulation. It has similar properties to calcipotriene used in the same manner. It is limited to 200 gm/week and is a pregnancy category C drug. Use with caution in patients receiving medications known to increase serum calcium levels, such as thiazide diuretics. Caution should also be exercised in patients receiving calcium supplements or high doses of vitamin D. Transient local skin irritation may occur, but calcitriol 3 μg/g ointment is better tolerated than calcipotriol ointment for treatment of the face and flexures.

Tacalcitol 4 μg/g ointment applied once daily is effective for the treatment of plaque psoriasis but is probably less effective than calcipotriol 50 μg/g ointments.

Calcipotriol and tacalcitol have been combined with other therapies. Calcipotriol ointment enhances the efficacy of PUVA and UVB phototherapy. As UVA partly inactivates calcipotriol and UVB is absorbed by calcipotriol, it is recommended that calcipotriol is not applied immediately prior to phototherapy exposures. Calcipotriol 50 μg/g ointment used in combination with methotrexate enables lower cumulative doses of methotrexate to be used.

 

Topical calcineurin inhibitors

 

The topical calcineurin inhibitors tacrolimus and pimecrolimus were initially developed for the treatment of atopic eczema in childhood. They are useful for thinner skin areas such as the face, neck, flexures and genitalia and may be effective under occlusion for psoriatic plaques at other sites. Their advantage is that unlike topical corticosteroids they are selective, unlikely to be absorbed systemically and do not produce skin atrophy making them more suitable for long‐term use. The most common side effect is burning and itching that reduces with ongoing usage and can be reduced by not applying immediately after bathing. This side effect is worse with tacrolimus. Both are pregnancy category C, are found in human milk, and are not recommended for nursing mothers.

 

Topical retinoids

 

All-trans-retinoic acid and 13-cis-retinoic acid, although effective in the treatment of acne, are not effective for psoriasis. However, topical tazarotene, an acetylene retinoid that selectively binds retinoic acid receptor (RAR)-β and RAR-γ, can be used to treat psoriasis. Tazarotene has been shown to decrease epidermal proliferation and it inhibits psoriasis-associated differentiation (e.g. transglutaminase expression, K16 expression). It is available as cream  formulations and is applied once or twice daily.

 

In view of its modest efficacy as monotherapy, it is usually prescribed as a second-line therapy. Irritation of the skin with burning, pruritus, and erythema can limit the use of tazarotene. For this reason, combination therapy with topical corticosteroids is useful. The maximal area that can be treated with tazarotene is 10–20% of the body surface, and safety data are available for up to 1 year of treatment.

 

INDICATIONS AND CONTRAINDICATIONS FOR TOPICAL TAZAROTENE

Indications

·       Mild to moderate psoriasis: second-line treatment as monotherapy or in combination

Contraindications

·       Unstable plaque psoriasis in a phase of progression   ·       Erythrodermic psoriasis   ·       Allergic contact dermatitis to tazarotene or constituents of the formulation   ·       Pregnancy or lactation

 

 

Additional topical treatments

If the psoriatic plaques have thick scale, this needs to be reduced to enhance penetration of topical medications and ultraviolet (UV) light. Options include salt-water baths, topical salicylic acid and oral retinoids. Salicylic acid 5–10% has a substantial keratolytic effect and, in the case of scalp psoriasis, salicylic acid can be formulated in an oil or ointment base. Application of salicylic acid to localized areas can be done daily, but, for more widespread areas, two to three times per week is preferred. This is to prevent systemic intoxication, especially in infants or those with reduced renal function.

Coal tar

Coal tar has a range of anti-inflammatory actions and is effective as an antipruritic. Coal tar suppresses DNA synthesis. Although crude coal tar may be the most effective tar available for the treatment of psoriasis, a distilled product, liquor carbonis detergens (LCD), is also used. In view of its mutagenic potential, tar is contraindicated in pregnant or lactating women.

The Goeckerman regimen consists of the combination of crude coal tar along with ultraviolet light. It is very effective treatment for patients with severe psoriasis. Many formulations of coal tar are available over-the-counter.

Coal tar formulations are often poorly tolerated because of staining of clothes and tar odor. Newer preparations are more cosmetically acceptable. They may be applied daily for extended periods of time. The response is unpredictable but many patients are gratified with this safe, inexpensive treatment.

Nonmedicated topical moisturizers

Nonmedicated topical moisturizers may be effective treatment. They are applied one to three times daily. Patients who are not satisfied with irritating, expensive prescription topical medications often turn to use of just topical moisturizers with a gratifying effect.

 

Treatment of scalp psoriasis

The scalp is difficult to treat because hair interferes with the application of medicine and shields the skin from ultraviolet light. Symptoms of tenderness and itching vary considerably. The goal is to provide symptomatic and cosmetic relief. It is unnecessary and impractical to attempt to keep the scalp constantly clear.

 

Removing scale

Scale must be removed first to facilitate penetration of medicine. Superficial scale can be removed with shampoos that contain tar and salicylic acid. Thicker scale is removed by applying 10% liquor carbonis detergens (LCD) in Nivea oil to the scalp and washing 6 to 8 hours later with a shampoo. Combing during the shampoo helps dislodge scale.

 

LCD (10%), a tar extract of crude oil tar, is mixed with Nivea oil by the pharmacist. The unpleasant mixture is liberally massaged into the scalp at bedtime and washed out each morning. Warming the mixture before application enhances scale penetration. A shower cap protects pillows and also encourages scale penetration. An impressive amount of scale is removed in the first few days. Nightly applications are continued until the scalp is acceptably clear.

 

Mild-to-moderate scalp involvement

When used at least every other day, tar shampoos may be effective in controlling moderate scaling. Few drops of corticosteroid solutions can cover a wide area. Steroid gels (e.g. clobetasol gel), which have a keratolytic base and penetrate hair, are effective for localized plaques. Fluocinolone acetonide 0.01% oil (peanut oil) is an effective topical steroid that can be applied to the entire scalp and occluded with a shower cap. The scalp is dampened before application. The oil base penetrates and loosens scale. Treatment is repeated each night for 1 to 3 weeks until itching and erythema are controlled.

Clobetasol foam is available in 50-gm container. The foam becomes a liquid upon contact with the skin. This formulation is effective and pleasant, and easily penetrates through hair. Temporary stinging may occur during application.

Small plaques are effectively treated with intralesional steroid injections of triamcinolone acetonide (Kenalog 10 mg/ml). Remissions following use of intralesional steroids are much longer than those following topical steroids.

Ketoconazole cream is sometimes useful. Oral ketoconazole (400 mg daily) may be effective in some cases but the possibility of drug toxicity limits its usefulness.

 

Treatment of diffuse and thick scalp psoriasis

Calcipotriene 0.005% and betamethasone dipropionate 0.064% lotion is a topical suspension for the treatment of moderate-to-severe psoriasis of the scalp in adults. Apply the suspension to affected areas once daily for 2 weeks or until cleared. Treatment may be continued for up to 8 weeks. The maximum weekly dose should not exceed 100 gm. Patients should shake the bottle before using the product.

 

For patients who fail topical measures, systemic immunosuppressive agents (eg. methotrexate, cyclosporine) or biological agents may be administered.

 

Treatment of inverse/intertriginous psoriasis and genital psoriasis

Inverse psoriasis can involve the axillae; inframammary areas; abdominal, inguinal, and gluteal folds; groin; genitalia; perineum; and perirectal area. It is erythematous, less indurated, and well demarcated thin plaques with minimal scale. Genital psoriasis can be distressing. Penetration of medications is facilitated with moist opposing skin surfaces. The risk of atrophy by potent topical corticosteroids is increased. These areas respond to weaker topical steroids and calcineurin inhibitors (topical tacrolimus and topical pimecrolimus). Inflammation in these areas is often misinterpreted as a yeast infection.

 

 

Phototherapy

Photo (chemo) therapy

Photo (chemo) therapy represents a mainstay in the treatment of moderate to severe psoriasis. Phototherapy with narrowband ultraviolet B (UVB) and photo-chemotherapy with ultraviolet A (UVA) following ingestion of or topical application of a psoralen are classic treatment options. Monochromatic 308 nm light from an excimer laser or equivalent source can be used to target individual psoriatic plaques.

 

Narrow‐band UVB

 

Phototherapy with narrow‐band UVB is the recommended first line therapy for most patients with moderate to severe psoriasis. NB‐UVB has been combined with numerous therapies with apparent success, including methotrexate, acitretin and biological therapies. NB‐UVB should be avoided in patients who are taking ciclosporin due to concerns regarding accelerated cutaneous carcinogenesis.

NB‐UVB treatment should be given three times weekly. Thrice‐weekly NB‐UVB has been shown to clear psoriasis more quickly than twice‐weekly NB‐UVB.

NB‐UVB can cause erythema and pruritus in the acute setting and rarely blisters can develop in the resolving plaques. NB‐UVB may be less carcinogenic than PUVA, leading some authors to suggest that it can be used in patients who have reached the maximum number of lifetime PUVA treatments. Due to concerns regarding increased risk of SCC, the scrotum and genital skin should be protected from irradiation.

NB‐UVB causes cutaneous immunomodulation by inducing apoptosis of T cells and reduces epidermal hyper proliferation.

Narrow‐band UVB is a highly effective, remission‐inducing therapy in psoriasis with a long safety record. It continues to play a significant role in psoriasis management.

 

PUVA photo chemotherapy

 

PUVA is the acronym used for the combination of psoralens and long‐wave ultraviolet radiation (UVA 320–400 nm). Psoralens bind to DNA and when activated by UVA cause permanent DNA damage with resulting cell death. This reduces keratinocyte hyper proliferation, decreases antigen‐presenting cells in the dermis, reduces angiogenesis, and causes T‐cell apoptosis with associated clearance and remission of psoriasis. The psoralens that are commonly used are 8‐methoxypsoralen (8‐MOP), 5‐methoxypsoralen (5‐MOP) and trioxypsoralen (T‐MOP). Psoralens are used either topically or orally in combination with UVA.

Oral PUVA therapy is given in dermatology center according to dosing protocols. 8‐MOP is usually given at a dose of 0.6 mg/kg 2 h before UVA therapy. PUVA is usually given as a twice‐weekly treatment and the average number of treatments to clearance is 18. Twice‐weekly PUVA is as effective as three times weekly PUVA. The scrotum and genital skin are more sensitive to the development of PUVA‐induced skin cancers and should be protected from irradiation.

This modality is highly efficacious in treating psoriasis with reported clearance rates of over 90%. The average duration of remission (the time taken for 50% of a patient's psoriasis to return) is approximately 6 months.

PUVA can cause both acute and chronic side effects; these include erythema, maximal at 72–96 h, and blistering that is usually dose and skin photo type dependent. PUVA may also cause neurogenic pruritus (PUVA itch), commoner in fairer skin types and usually dose related. Patients describe a crawling under the skin that affects both psoriasis and normal looking skin. If treatment continues PUVA itch usually persists. PUVA is associated with an increased incidence of non‐melanoma skin cancer. This is true for both basal cell carcinoma and SCC. Immunosuppression with ciclosporin also appears to increase this risk. The relative risk of cutaneous SCC starts to increase after 250 treatments in a lifetime. The British Photo dermatology Group therefore recommends that a patient should not receive more than 200 treatments of PUVA. PUVA may be combined effectively with oral retinoids, so‐called re‐PUVA. This allows an overall dose reduction in UVA dose but remission times are typically shorter.

PUVA has been associated with cataract formation, so it is recommended that patients wear UVA protecting plastic‐lensed glasses on treatment days. Psoralens are teratogenic and patients should be advised about this risk even in patients undergoing topical or bath PUVA.

PUVA remains one of the mainstays of treatments for moderate to severe psoriasis but its use is declining, and has been largely replaced with NB‐UVB.

 

Systemic therapy

 

In general, systemic treatment is used for moderate-to-severe psoriasis, variably defined as patients with 10 % or more involvement of body surface area that is not responsive to topical therapy or phototherapy. The main systemic treatments in current clinical practice are methotrexate, cyclosporine and acitretin.

METHOTREXATE

 

Methotrexate is a folate antagonist that inhibits DNA synthesis by dihydrofolate reductase inhibition. Although initially thought to inhibit keratinocyte hyper proliferation, it appears to inhibit lymphocyte proliferation more profoundly (circulating and cutaneous) and is a likely explanation for its antipsoriatic activity.

MTX is a first-line systemic therapy for psoriasis as it is highly efficacious for severe disease and all clinical variants of psoriasis.  It is also used in localized severe psoriasis, generalized pustular psoriasis and erythroderma, although it’s relatively slow onset of action makes it less suitable for rapid control of severe disease. In chronic plaque psoriasis, initial improvement is observed between 1 and 7 weeks and maximum improvement can be expected after 8–12 weeks of treatment. Depending on the dosage schedule, the percentage of patients reaching PASI 75, i.e. a 75% reduction in the PASI score, ranges from 24% (low starting dose) to 60% (high starting dose) after 12–16 weeks of treatment.

MTX is administered weekly, usually as a single oral dose (but occasionally intramuscularly or subcutaneously) and less often every 12 hours for three doses per week; the maximum weekly dosage is usually 25 mg. Lower doses of methotrexate may be effective, particularly in the elderly, which may relate to reduced renal excretion in this age group. Potential side effects restrict its use to moderate to severe disease resistant to topical treatments and photo (chemo) therapy and/or situations in which these are contraindicated. The use of folic acid supplementation is needed during MTX administration as it reduces side effects, including gastrointestinal. 

Methotrexate therapy for psoriasis can cause a myriad of side effects including nausea, bone marrow suppression, mucositis and hepatotoxicity. The modern use of low‐dose once‐weekly methotrexate for psoriasis is associated with hepatic fibrosis in a minority of patients. Methotrexate hepatotoxicity nonetheless appears to be commoner in psoriasis patients than in those with rheumatoid arthritis. This may be due to increased risk factors for liver injury amongst psoriasis patients such as obesity, alcohol abuse and diabetes and the fact that higher therapeutic doses are generally used when treating psoriasis compared to rheumatoid arthritis. Standard liver function tests are insufficient to monitor patients for the development of hepatic fibrosis. In a significant minority of patients liver fibrosis can occur with normal liver enzymes. In the past, liver biopsies have been recommended in order to detect occult fibrosis but the use of the serum aminoterminal peptide of pro‐collagen III (PIIINP) as a biomarker of fibrosis has reduced the need for routine liver biopsies in these patients. Some studies in rheumatoid arthritis suggest that the use of concomitant folic acid may reduce abnormalities in liver enzymes. Pulmonary fibrosis has only been reported rarely in psoriasis patients treated with methotrexate. This contrasts with rheumatoid arthritis where pulmonary fibrosis induced by methotrexate is a significant concern. Guidelines do however recommend a chest X‐ray prior to starting methotrexate therapy. This is in order to screen for pre‐existent pulmonary pathology that may be exacerbated by methotrexate.

 

Indications

Methotrexate (MTX) has been used for more than 40 years to treat severe psoriasis. It induces remissions in the majority of treated patients and maintains remissions for long periods with continued therapy. It is relatively safe and well tolerated. Methotrexate is used alone or in combination with biologics. Safe use of methotrexate requires appropriate monitoring.

 

A.  Severe psoriasis

 

·       Chronic plaque psoriasis (>10–15% BSA or that affects certain areas of body so      that normal function and employment are prevented)

 

·       Pustular psoriasis (generalized or localized)

 

·       Erythrodermic psoriasis

 

·       Psoriatic arthritis (moderate to severe)

 

·       Severe nail psoriasis

 

B.  Psoriasis not responding to topical treatments, photo(chemo)therapy and/or   systemic retinoids

 

Contraindications

Absolute   ·       Severe anemia, leukopenia, and/or thrombocytopenia   ·       Significant liver function abnormalities, hepatitis (active and/or recent), severe fibrosis, cirrhosis, excessive alcohol intake   ·       Severe infections   ·       Concomitant medications that increase MTX levels, e.g. trimethoprim–sulfamethoxazole   ·       Significantly reduced pulmonary function   ·         Pregnancy or lactation   ·       Peptic ulcer (active)   ·       Hypersensitivity to MTX   ·       Unreliable patient     Relative   ·       Impaired kidney function (creatinine clearance <60 ml/min)†     ·       Currently planning to have children (male and female patients)‡   ·       Active infections   ·       Gastritis   ·       Pleural effusion or ascites†   ·       Concomitant hepatotoxic medications   ·       Immunodeficiency syndromes   ·       Concomitant radiation therapy   ·       Obesity (body mass index >30)   ·       Diabetes mellitus † Requires significant reduction in dosage.   ‡ Because of possible mutagenic risk and teratogenicity, discontinue MTX 3 months prior to attempts to conceive; continue contraception during these 3 months.

 

SIDE EFFECTS OF METHOTREXATE
Subjective symptoms	Hematopoietic†	Mucocutaneous
1.   Most frequent*,† 1.   Nausea 2.   Vomiting 3.   Abdominal pain 4.   Fatigue 5.   Headache 2.   Occasional 1.   Loss of libido 2.   Impaired memory	1.   Leukopenia‡ 2.   Thrombocytopenia 3.   Anemia	1.   Oral erosions† 2.   Alopecia 3.   Delayed phototoxicity 4.   Tenderness and/or necrosis of plaques due to overdose 5.   Rarely, urticaria, angioedema, vasculitis

 

Hepatic	Pulmonary	Fetal development
1.   Elevated LFT results 1.   Minor elevations of LFT results are common; if elevation exceeds 2× normal, must check more frequently; if exceeds 3× normal, consider dose reduction; if exceeds 5× normal, discontinue   Hepatitis† Cirrhosis§	Interstitial pneumonitis (acute-onset cough, dyspnea)	Birth defects: cranial and absence of digits
Carcinogenesis¶	Idiosyncratic reaction
1.   In rheumatoid arthritis patients, increased risk of lymphoma 2.   Risk factor for cutaneous SCC in PUVA-treated patients	1.   Early in course with full dosage 2.   Severe pneumonia 3.   Gastrointestinal hemorrhage 4.   Pancytopenia

 

Opportunistic infections	Additional/unusual
1.   Pneumocystis jiroveci pneumonia 2.   Cryptococcosis 3.   Disseminated histoplasmosis 4.   Disseminated herpes zoster	1.   Osteopathy (pain, osteoporosis, compression fractures) 2.   Ventricular cardiac arrhythmias 3.   Lowered seizure threshold

* Same day or 2–3 days following MTX administration; may respond to folic acid, dose reduction or antiemetic drug.

† May be reduced by folic acid (1–5 mg/day except on day MTX administered).

‡ Up to 10% of patients on oral regimens.

§ Up to 25% of patients receiving long-term therapy.

¶ No increased risk of malignancy was observed in large series of psoriasis patients.

 

Mechanism of Action

MTX suppresses psoriatic epidermal cell reproduction and has anti-inflammatory and immunomodulatory effects.

Dihydrofolate reductase (DHFR) converts dihydrofolate to tetrahydrofolate (fully reduced folic acid), which is a necessary cofactor in the synthesis of thymidylate and purine nucleotides, which, in turn, are required for DNA/RNA synthesis. MTX competitively inhibits DHFR, although this inhibition can be at least partially reduced by concomitant folic acid administration. MTX also exerts partially reversible inhibition downstream on thymidylate synthetase, inhibiting cell division during the S phase.

 

Although originally believed to suppress keratinocyte proliferation, it is more likely that MTX inhibits DNA synthesis in immunologically active cells. MTX decreases inflammation through other mechanisms as well. For example, by inhibiting aminoimidocarboxyamido-ribonucleotide transformylase, MTX increases local tissue concentrations of the potent anti-inflammatory mediator adenosine. By inhibiting methionine synthase, MTX reduces production of the proinflammatory mediator S-adenyl methionine. Methotrexate is immunosuppressive; use should be avoided in patients with active infections.

 

Dosages

MTX is administered as a once-weekly dose of up to 25 mg for dermatologic and rheumatologic diseases. Historically, MTX was administered in three doses over 24 hours (8 a.m. and 8 p.m. day 1, and 8 a.m. day 2). Dividing the dose can decrease minor gastrointestinal side effects in some patients and also have theoretical advantages for the divided dosing regimen from a cell cycle kinetics standpoint.  However, since the clinical result is the same, a single dose, which is easier and less confusing (for the patient and the pharmacist), is currently recommended. The patient should be admonished to adhere to the dosing schedule religiously, as more frequent dosing is much more likely to produce major hematologic complications and potentially an increased risk of liver fibrosis. Parenteral administration (intramuscular or subcutaneous) is available for patients who cannot tolerate oral MTX and has also been advocated by some clinicians for use in erythrodermic patients who may have decreased gastrointestinal absorption or when compliance is an issue.

 

Available in 2.5 mg tablets, therapy should begin with a test dose of 2.5–5 mg and repeat laboratory tests with a complete blood count (CBC) including differential and platelet count and LFT in approximately 7 days. This test dose practice is mandatory in any patient with a decreased calculated glomerular filtration rate or other significant risk factors for hematologic toxicity. Using a test dose also provides an additional safeguard against rare, idiosyncratic reactions to methotrexate.

Doses are usually started with lower initial levels to minimize side effects and adjusted to achieve clinical effectiveness. The usual weekly dose for psoriasis is 10–15 mg, although doses up to 25 mg per week are not uncommonly used, except in patients with renal insufficiency. Ordinarily, the dose should not exceed 25 mg weekly and, in view of the reduced bioavailability of oral MTX at higher doses, consideration should be given to switching to a subcutaneous route of administration if response remains poor. Reported schedules have been to start at lower dosages (e.g., 7.5 mg/week) and gradually increased, whereas others recommend starting at the anticipated target dosage (e.g., 15 mg/week).

The dose may be gradually increased by 2.5 to 5 mg every 2–4 weeks until satisfactory results are obtained with minimal toxicity. Once disease control has been attained for at least 1–2 months, the MTX can be tapered by 2.5 mg every 1–2 weeks to the lowest dose that still maintains disease control. It can take 4 to 8 weeks to see a response to changes in methotrexate dose. Some patients can be gradually weaned off therapy and restarted if the disease flares. The goal is to both decrease the total cumulative dose and improve tolerability.

 

 

MONITORING GUIDELINES FOR METHOTREXATE

 

 

Drug                        Initial screening           Follow-up monitoring   Special considerations

 

Methotrexate

CBC with PLT count CMP(BUN, creatinine, and LFTs) Pregnancy test for women of childbearing potential   Serologic tests for hepatitis A, B, C   HIV testing if indicated Liver biopsy is only indicated in high risk patients

1.   CBC with PLT and AST/ALT after initial 2.5–5 mg test dose 2.     3.   CBC with PLT and AST/ALT every week for 2–4 weeks and after each dose escalation, then monthly for 2–4 months, and then every 3–4 months, if stable 4.     5.   BUN and serum creatinine every 6–12 months 6.     7.   Serum markers and non-invasive imaging studies used to assess hepatic fibrosis

1.   Patients being considered for methotrexate therapy are divided into two groups based on their risk factors for liver injury. Per recent psoriasis treatment guidelines (2009), for patients without risk factors for hepatic fibrosis, liver biopsy is not indicated at baseline. For high-risk patients, liver biopsies are done baseline and then after every 1 g, and in those with grade IIIA liver biopsy changes, every 6 months or as recommended by a hepatologist 2.     3.   Consider creatinine clearance, especially in elderly patients

CMP: Comprehensive metabolic panel

Leukocyte and platelet counts are depressed maximally approximately 7 to 10 days after treatment. A drop in these counts below normal levels necessitates reducing or stopping therapy. Liver function tests (LFTs) are obtained at least 1 week after the last dose of the drug. MTX causes transient elevations in LFTs for 1 to 3 days after its administration, so a false-positive elevation might be seen if the patient is tested too soon.

Side Effects

Short-term side effects include nausea, anorexia, fatigue, oral ulcerations and stomatitis, mild leukopenia, thrombocytopenia, and macrocytic anemia. These are dose-related and rapidly reversible and related to renal and hematologic function. Switching among triple dosing, weekly oral dosing, and intramuscular dosing may decrease these reactions. 

The most important major side effects of MTX include pancytopenia, and hepatotoxicity. Pancytopenia typically develops early, compared to hepatic fibrosis and cirrhosis, which take years to develop. There is considerable debate regarding the risk of hepatotoxicity in psoriasis patients on long-term MTX, and recent studies have shown that methotrexate-associated fibrosis and cirrhosis may be less than initially reported. Compounding risk factors for developing hepatotoxicity from MTX are well established. Before prescribing MTX, references discussing this issue in detail should be reviewed and consultation with a hepatologist considered. For those without risk factors, consider liver biopsy in patients with cumulative doses of more than 3.5-4 gm of methotrexate and repeated liver biopsies after each subsequent 1.5-gm dosage, based on LFT results, risk factors (e.g., diabetes and obesity) or in consultation with a hepatologist.

 

 

RISK FACTORS FOR DEVELOPING HEPATIC TOXICITY FROM METHOTREXATE

·       Persistent abnormal liver function tests   ·       History of chronic liver disease including chronic hepatitis B or C viral infection   ·       Previous or concurrent excessive alcohol intake   ·       Family history of inheritable liver disease   ·       Diabetes mellitus   ·       Obesity   ·       Hyperlipidemia   ·       History of significant exposure to hepatotoxic drugs or chemicals   ·       Lack of folate supplementation

 

While the gold standard for detection of hepatic fibrosis remains liver biopsy, this invasive procedure harbors risks including subcapsular hemorrhage. A variety of serum markers and non-invasive imaging studies have been developed to try to detect hepatic fibrosis. Elevated levels of procollagen III aminopeptide (PIIINP) have been reported to be a serologic marker of fibrosis, but this assay does not specify which organ has fibrosis and it can be unreliable in patients with psoriatic arthritis or other inflammatory diseases.

 

Additional serologic assays for detecting hepatic fibrosis have been developed including: (1) FIBROSpect^® II – measures circulating levels of α₂-macroglobulin, tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid; and (2) FibroTest^®  – measures circulating levels of α₂-macroglobulin, haptoglobin, apolipoprotein A₁, γ-glutamyl transpeptidase, and total bilirubin. In both, the value of each serum marker is incorporated into a composite score. For the detection of moderate-to-severe fibrosis, these assays possess fairly good diagnostic accuracy, with a sensitivity of 47–77% and a specificity of 78–90%; however, they have been used primarily to evaluate patients with chronic hepatitis C viral infection. Imaging studies being investigated include: (1) ultrasound-based transient elastography (FibroScan^®) – a rapid, non-invasive measure of liver stiffness that is unreliable in obese patients; and (2) magnetic resonance elas­tography. Both the tests are not widely utilized and have limitations. In the future, it is likely that some combination of serologic assays plus imaging studies will allow selection of those patients on MTX most at risk for hepatic fibrosis in whom a liver biopsy can then be performed.

 

Photosensitivity may occur with MTX and patients should take appropriate sun precautions. Gastrointestinal intolerance is often abated with concomitant folic acid therapy. Other MTX-induced side effects include accelerated rheumatoid (cutaneous) nodulosis and reversible lymphoproliferative disorders.

 

 

METHOTREXATE (MTX) – COUNSELING FOR PATIENTS OF CHILDBEARING POTENTIAL

Women

·       Should not become pregnant while receiving MTX   ·       MTX can cause birth defects and abortions   ·       Must use highly effective means of contraception (e.g. OCPs; IUD; condom + spermicide)   ·       After discontinuing MTX, wait at least one ovulatory cycle before attempting to become pregnant

Men

·       May lead to low sperm counts   ·       Drug is present in semen   ·       Must use highly effective means of contraception (e.g. OCPs, IUD [female partner]; condom + spermicide)   ·       After discontinuing MTX, wait 3 months before attempting to have partner become pregnant

 

Use in Pregnancy and Lactation

MTX is an abortifacient and teratogen and should not be used during pregnancy. MTX can impair fertility by adversely affecting oogenesis and spermatogenesis, and by causing menstrual dysfunction: these effects are considered to be reversible on discontinuing treatment. It also has a mutagenic potential and thus it would seem prudent to advise both men and women to avoid conception whilst taking MTX and for up to 6 months thereafter; should pregnancy ensue before this time period, consider genetic counseling.

The American Academy of Pediatrics considers MTX to be contraindicated in breastfeeding owing to concerns of immune suppression, growth retardation, and carcinogenesis. Mothers receiving methotrexate should not breast-feed.

Drug Interactions

The interaction of MTX with other drugs can occur via a number of mechanisms:

·        Reduced absorption from gut: digoxin (absorption reduced by MTX), neomycin

·        Displacement from plasma proteins: NSAIDs (aspirin, diclofenac, ibuprofen, indometacin, ketoprofen, meloxicam and naproxen), sulphonamides

·        Added antifolate effect: nitrous oxide, trimethoprim, sulphonamides, dapsone, phenytoin, pyrimethamine

·        Diminished renal excretion: ciprofloxacin, NSAIDs, omeprazole, penicillins, probenecid, sulphonamides

·        Increased renal excretion: acetazolamide

·        Cumulative toxicity: tetracyclines, acitretin, clozapine, ciclosporin, cisplatin, leflunomide, alcohol

·        Other: theophylline (plasma levels increased by MTX)

 

Numerous medications may interact with methotrexate by a variety of mechanisms that can result in elevated drug levels, thereby increasing the risk for methotrexate toxicity.

After absorption, methotrexate binds to serum albumin, NSAIDs (aspirin, diclofenac, ibuprofen, indometacin, ketoprofen, meloxicam and naproxen), sulfonamides, phenytoin, and antibiotics including penicillin, minocycline, chloramphenicol, and trimethoprim may decrease the binding of methotrexate to albumin, leading to increased serum levels of methotrexate. Several other medications including colchicine, cyclosporin A (CsA), probenecid, NSAIDs, omeprazole, penicillins, ciprofloxacin and sulfonamides may lead to decreased renal tubular excretion leading to decreased renal elimination of methotrexate and increased serum levels. Trimethoprim, sulfonamides, and dapsone also inhibit the folate metabolic pathway and markedly increase the risk for pancytopenia with concomitant use. Acitretin has been used successfully in combination with methotrexate despite the potential for hepatotoxicity from both medications. Alcohol may cause synergistic liver damage in combination with MTX.

 Risk Factors for Hematologic Toxicity from Methotrexate

1.   Renal insufficiency

2.   Advanced age

3.   Lack of folate supplementation

4.   Methotrexate dosing errors (inadvertent daily dosing)

5.   Drug interactions: displacement of MTX from protein‐binding sites (particularly by NSAIDs or sulphonamides)

6.   Hypoalbuminemia

7.   Greater than moderate alcohol intake

Monitoring for Hepatotoxicity in Patients with No Risk Factors for Hepatotoxicity

1.   No baseline liver biopsy

2.   Monitor LFT results monthly for the first 6 mo and then every 1-3 mo thereafter

• For elevations <2-fold upper limit of normal: repeat in 2-4 wk
• For elevations >2-fold but <3-fold upper limit of normal: closely monitor,    repeat in 2-4 wk, and decrease dose as needed
• For persistent elevations in 5 of 9 AST levels during a 12-mo period or if there is a decline in the serum albumin level below the normal range with normal nutritional status, in a patient with well-controlled disease, a liver biopsy should be performed

3.   Consider liver biopsy after 3.5-4.0 gm total cumulative dosage

4.   Consider switching to another agent or discontinuing therapy after 3.5-4.0 gm total cumulative dosage

Monitoring for Hepatotoxicity in Patients with Risk Factors for Hepatotoxicity

1.   Consider the use of a different systemic agent.

2.   Consider delayed baseline liver biopsy (after 2-6 months of therapy to establish medication efficacy and tolerability).

3.   Perform repeated liver biopsies after approximately 1.5 gm of methotrexate.

 

Folate supplementation

Folate supplementation reduces hematologic, gastrointestinal, and hepatotoxic side effects without decreasing the efficacy. Options for folate supplementation include folic acid 1 mg daily or 5 mg once weekly except for the day of methotrexate dosing, reduces the frequency of side effects.

 

Lung toxicity

Methotrexate-induced lung injury can be sudden and severe. The presenting symptom is usually a new onset of cough and shortness of breath. It is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be retreated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome. The strongest predictors of lung injury are older age, diabetes, rheumatoid pleuropulmonary involvement, previous use of disease-modifying antirheumatic drugs, and hypoalbuminemia.

 

Recall of sunburn

Patients taking methotrexate with a previous history of sunburn or radiation burn may experience a flare-up of symptoms in the areas that had been burned. This reaction is distinct from true photosensitivity. Therefore patients on MTX should take appropriate sun precautions.

 

ACITRETIN

Acitretin is an oral retinoid and one of the safest systemic psoriasis therapies. It binds to retinoic acid receptors and reduces keratinocyte proliferation and also reduces Th17 cells with a concomitant increase in regulatory T cells. Acitretin is not immunosuppressant and therefore can be considered in clinical situations where other systemic medications are contraindicated, such as active malignancy.

 

INDICATIONS AND CONTRAINDICATIONS FOR ACITRETIN

Indications

·       Severe psoriasis that cannot be managed by topical treatments or photo(chemo)therapy   ·       Monotherapy is indicated for erythrodermic or pustular psoriasis   ·       Combination therapy is indicated for chronic plaque psoriasis

Contraindications

Absolute   ·       Severe liver dysfunction   ·       Severe kidney dysfunction (elimination reduced)   ·       Pregnancy or lactation   ·       Women of childbearing potential who cannot guarantee adequate contraception during and up to 3 years following discontinuation of acitretin   ·       Hyperlipidemia, especially hypertriglyceridemia, that cannot be controlled   ·       Excessive alcohol intake   ·       Unreliable patient   Relative   ·       Concomitant medications that interfere with retinoid bioavailability or whose metabolism is altered†   ·       Concomitant hepatotoxic drugs, e.g. methotrexate‡   ·       Poorly controlled diabetes mellitus   ·       History of pancreatitis   ·       Use of contact lenses   ·       Atherosclerosis

† Requires dose adjustment and careful monitoring, e.g. phenytoin competes for plasma protein binding.

‡ Reserved for treatment-resistant patients.

 

As monotherapy, acitretin is less effective for chronic plaque psoriasis. In one study, 23% of patients treated with 50 mg of acitretin daily for 8 weeks achieved ≥75% improvement in their PASI. Combination treatment with photo (chemo) therapy and/or vitamin D₃ analogues results in a substantial improvement in clinical response. Maximal therapeutic efficacy is reached after 2–3 months. Acitretin has been shown to be an effective maintenance therapy. As monotherapy, acitretin is highly effective in erythrodermic and pustular psoriasis. Its efficacy in nail psoriasis and psoriatic arthritis is only modest.

In patients with chronic plaque psoriasis, 0.5 mg/kg/day is the initial dosage, which can be increased depending upon the clinical response and side effects. For erythrodermic psoriasis, the initial dosage is 0.25 mg/kg/day, and in pustular psoriasis, the dose should be maximized, i.e. up to 1 mg/kg/day. In patients with chronic plaque psoriasis, mild cheilitis (just perceivable by the patient) is the goal, whereas in patients with pustular psoriasis, a dose that causes a clinically apparent but tolerable cheilitis is an endpoint.

Optimum dose range for monotherapy is 25-50 mg/day.

Lower doses of acitretin at 10 to 25 mg daily are usually effective when used in combination with phototherapy.  This results in faster and more complete responses to PUVA and to UVB.  Significantly lower ultraviolet doses are required when retinoids are added to a phototherapy regimen.

 

ACETRETIN – EVALUATION PRIOR TO AND DURING TREATMENT

Pre-acitretin screening

·       History to exclude contraindications   ·       Complete blood count   ·       Liver function tests (AST, ALT, γGT, alkaline phosphatase, bilirubin)   ·       Serum triglycerides, cholesterol, HDL   ·       Glucose   ·       Serum creatinine   ·       Pregnancy test   ·       Consider spinal X-ray (often initially performed during the first 3 months of therapy if long-term treatment is anticipated)

Evaluation during acitretin treatment

·       Monitor mucocutaneous side effects   ·       Serum triglycerides, cholesterol/HDL, and liver function tests (every month for the first 2 months then every 2–3 months)   ·       CBC and serum creatinine (elderly patients or patients with mild to moderate renal dysfunction) every 3 months   ·       Monitor for development of hyperostosis by history (twice yearly) and by X-ray of spine (e.g. once yearly or every other year in patients receiving long-term treatment)   ·       Pregnancy test (twice yearly throughout treatment)

 

Side effects

Mucocutaneous side effects, hepatotoxicity, and alterations in serum lipid profile are dose-dependent.

Acitretin is teratogenic. In the presence of ethanol, acitretin is esterified to etretinate. Etretinate persists in tissue for years. Therefore acitretin is not prescribed to women of child-bearing potential who may become pregnant within 3 years. In doses of 50 mg per day or higher, mucocutaneous side effects are common and include cheilitis, conjunctivitis, and hair loss, failure to develop normal nail plates, dry skin, and “sticky skin.” Periungual pyogenic granulomas can develop. Headache is a possible sign of pseudotumor cerebri. Elevation of serum lipid level, particularly triglycerides, can be prevented by concomitant administration of gemfibrozil or atorvastatin. Elevation of liver function tests can occur.

 

 

CYCLOSPORINE

Cyclosporine (CS) at dosages of 2.5 to 5.0 mg/kg/day administered to reliable, carefully selected patients who are closely monitored for both clinical and laboratory parameters produces fast and favorable results for severe plaque psoriasis. Cyclosporine is indicated for the treatment of severe, recalcitrant, plaque psoriasis in adults who are immunocompetent. Cyclosporine is also effective in treating pustular, erythrodermic, and nail psoriasis. Efficacy of cyclosporine has been demonstrated in all variants of psoriasis (including nail psoriasis), but less so for psoriatic arthropathy. In general, a reduction of the PASI of 60–70% can be reached within 4 weeks of treatment. During long-term treatment, there are no signs of tachyphylaxis.

Recommendations for Cyclosporine

1.   Indication: Adult, immunocompetent  patients with severe, recalcitrant psoriasis

1.   Severe is defined by the FDA as extensive or disabling plaque psoriasis

2.   Recalcitrant is defined by the FDA as those patients who have failed to respond to at least one systemic therapy or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated

3.   Some guidelines suggest use of cyclosporine in moderate-to-severe psoriasis

4.   Efficacy observed in erythrodermic psoriasis, generalized pustular psoriasis, and palmoplantar psoriasis

 

MONITORING GUIDELINES FOR CYCLOSPORINE

 

Drug                              Initial screening           Follow-up monitoring   Special considerations

 

Cyclosporine

1.   At least 2 baseline blood pressure readings 2.   At least 2 baseline BUN and serum creatinine levels 3.   CMP (must include BUN, magnesium, potassium and uric acid) 4.   CBC with PLT count 5.   UA with microscopic examination 6.   Fasting lipid profile (TG, cholesterol, HDL)

1.   CBC with PLT count at 1 month, then every 2–4 months 2.   CMP (must include BUN, creatinine, uric acid, potassium, magnesium) every 2 weeks for 1–2 months, then monthly or every 3 months if stable 3.   UA with microscopic examination every month if abnormal; otherwise yearly 4.   Fasting lipid panel every 2–4 weeks for 1–2 months, then every 3 months if stable

1.   Blood pressure must be monitored every 2 weeks for first 3 months and then monthly if stable 2.   Lower dose by 25–50% if serum creatinine remains elevated (over 2 weeks) by >25% of baseline 3.   Lower dose by 25–50%, or discontinue, if at any time serum creatinine is elevated by ≥50% of baseline 4.   Consider creatinine clearance if >6 months of therapy 5.   Skin examination at least yearly and age-appropriate cancer screening 6.   Consider trough whole drug cyclosporine level if non-compliance, poor absorption or drug interactions are suspected

  

Side effects

Cyclosporine can produce dramatic rapid improvement of psoriasis, but this must be balanced by the requirement for an appropriate replacement therapy, given the need to ultimately stop cyclosporine therapy.

The most serious side effects of cyclosporine use in psoriasis are nephrotoxicity and hypertension.

An important aspect is assessment of renal function, and creatinine clearance should be estimated using the Cockcroft–Gault formula:

  

In elderly patients and patients with a history of hypertension, the risks of renal impairment and hypertension are increased.

 

Cyclosporine treatment in psoriatic patients has been reported to increase the frequency of SCCs, especially in those previously treated with PUVA. The underlying mechanism is not mutagenesis but a decrease in immunosurveillance of the skin. In particular, psoriatic patients who have been exposed to high cumulative doses of UV radiation are at risk for development of cutaneous malignancies. Although cyclosporine is an immunosuppressive agent, no increase in serious infections has been reported in patients treated with cyclosporine alone. Other side effects include: gastrointestinal discomfort, hypertrichosis, paresthesias, gingival hyperplasia, headache, vertigo, muscle cramps, and tremor. Metabolic side effects include hyperkalemia, hypomagnesemia, hyperuricemia (due to decreased clearance of uric acid), and elevated cholesterol and triglycerides.

 

Contraindications

Absolute   ·       Impaired renal function   ·       Uncontrolled hypertension   ·       Past or present malignancy   ·       History of excessive photo (chemo) therapy (>200 PUVA treatments) or concurrent photo (chemo) therapy   ·       Radiotherapy   ·       Severe infections    ·       Hypersensitivity to cyclosporine   ·           Unreliable patient     Relative   ·       Active infections   ·       Concomitant drugs affecting cyclosporine pharmacokinetics†   ·       Primary or secondary immunodeficiency   ·       Concomitant immunosuppressive therapy   ·       History of arsenic exposure   ·       Pregnancy or lactation   ·       Concurrent methotrexate administration   ·       Significant hepatic disease   ·       Hyperuricemia, hyperkalemia   ·       Vaccination with live vaccines   ·       Seizure disorder   ·       Poorly controlled diabetes mellitus   ·       Severe chronic organ dysfunction   ·       Alcohol and drug abuse   ·       Malabsorption

† Requires dose adjustment and careful monitoring; cyclosporine is inactivated by the cytochrome P450 3A isoform.

 

Dosage

Treatment is started from 2.5 to 5.0 mg/kg/day in two divided doses as clinically indicated and then the dosage is adjusted by 0.5 to 1 mg/kg/day every 1 week.

The starting dose depends on the clinical state. There are two approaches to determine the starting dosage. The speed of improvement and the success rate are proportional to the dosage.

 

Low-dose approach

Start at 2.5 mg/kg/day, and wait at least 1 month before considering increasing the dosage. This approach with slow increments in dosage increase is for patients with stable, generalized psoriasis or for patients in whom the severity lies between moderate and severe. Increase the dosage by 0.5 to 1.0 mg/kg/day increments every week, up to a maximum of 5 mg/kg/day if needed.

 

High-dose approach

Start at a 5 mg/kg/day dose when rapid improvement is critical. Patients with severe inflammatory flares, patients with recalcitrant cases that have failed to respond to other modalities, or distressed patients in a crisis situation are candidates for the high-dose approach. High doses are usually well tolerated for short-term use. As soon as there is a response, the dosage is decreased by 0.5 to 1 mg/kg/day, but no more than one step in the decrement of dosage per week, until the minimum effective maintenance dosage is defined.

 

Intermittent short courses

Another therapeutic strategy to manage moderate-to-severe plaque psoriasis with cyclosporine is the use of intermittent short courses. It is effective and well tolerated and reduces the risk of side effects. Cyclosporine is initially given at a dose of 2.5 mg/kg/day in two divided doses. This dosage could be increased by increments of 0.5 to 1.0 mg/kg/day each week up to a maximum of 5 mg/kg/day. Treatment is continued until clearance of psoriasis, defined as 90% or more reduction in the area affected occurs or for a maximum of 12 weeks. Cyclosporine is stopped abruptly. On relapse, patients are given another course of cyclosporine, commencing at the optimum dose from the previous treatment period. Intermittent short courses for up to 2 years appear safe and well tolerated.

 

Weekend therapy

Initiate treatment with cyclosporin A (CsA) at 5 mg/kg/day for 12 weeks (induction treatment). Then treat with CsA 5 mg/kg/day for 2 consecutive days (on weekends) per week.

 

TARGETED IMMUNOMODULATORS (“BIOLOGIC” THERAPIES) FOR PSORIASIS

The immunological basis of psoriasis continues to be refined and the ability of technology to produce targeted therapies has revolutionized treatment of psoriasis. Psoriasis is an autoimmune disorder involving activation of dendritic cells that stimulate aberrant T- cell pathways. Biologic agents are proteins that can be synthesized using recombinant DNA techniques (genetic engineering). Biologic agents bind to specific cells and proteins and do not have multiorgan adverse effects as seen with acitretin, cyclosporine, and methotrexate. The potential for interaction with other drugs is very low.

Biologic therapies are indicated for patients with moderate to severe psoriasis and/or psoriatic arthritis. Several guidelines restrict their use to “high-need patients” in whom all other existing treatments are contraindicated or have led to insufficient improvement, whereas some investigators have voiced the opinion that biologic therapies should be an option for patients who have failed to respond adequately to one classic systemic treatment; the latter recommendation has to be balanced against the high cost of these medications.

Their two major targets are T cells and cytokines, including TNF-α, IL-12/23, and IL-17.

 

COMMERCIALLY AVAILABLE BIOLOGIC AGENTS FOR THE TREATMENT OF PSORIASIS
Biologic agent	Target	Molecule	Approved*
Etanercept	TNF-α†	Human fusion protein	FDA + EMA
Infliximab	TNF-α‡	Chimeric antibody	FDA + EMA
Adalimumab	TNF-α‡	Human antibody	FDA + EMA
Ustekinumab	p40 subunit of IL-12/23	Human antibody	FDA + EMA
Secukinumab	IL-17A	Human antibody	FDA + EMA
Ixekizumab	IL-17A	Humanized antibody	FDA + EMA
Brodalumab	IL-17 receptor	Human antibody	FDA + EMA
Guselkumab	IL-23	Human antibody	FDA

EMA, European Medicines Agency; FDA, Food and Drug Administration; IL, interleukin; TNF, tumor necrosis factor.

Several biologic therapies are currently available worldwide for the treatment of psoriasis and/or psoriatic arthritis: adalimumab, etanercept, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab and guselkumab. Despite the availability of effective topical and classic systemic medications as well as phototherapy, safety concerns, lack of efficacy, and inconveniences are important restrictions, in particular for long-term use. For such patients, biologic agents can improve their skin disease as well as psoriatic arthritis (especially TNF-α inhibitors), with prevention of permanent destructive changes. Some investigators have proposed that reduction of inflammation due to active psoriasis may impact the development of metabolic syndrome and cardiovascular diseases.

Administration of live vaccines is contraindicated in patients receiving biologic agents for psoriasis.

INDICATIONS AND CONTRAINDICATIONS FOR COMMERCIALLY AVAILABLE TARGETED IMMUNOMODULATORS (“BIOLOGIC” AGENTS)

Indications

General indications

Patients with moderate to severe psoriasis, eligible for a systemic treatment   Patients with psoriatic arthritis, particularly those who have failed other disease-modifying antirheumatic drugs (DMARDs)

Restricted indication

Patients with moderate to severe psoriasis who are not candidates for topical treatments, photo(chemo)therapy, or classic systemic treatments because of insufficient efficacy or contraindications†

Contraindications

Absolute   ·       Significant viral, bacterial or fungal infection, including active Salmonella or dimorphic fungal infection   ·       Increased risk for developing sepsis   ·       Active tuberculosis   ·       Allergic reaction to the biologic agent   ·       Selective for TNF-α inhibitors: ANA+ (especially if high titer) or autoimmune connective tissue disease, blood dyscrasias, congestive heart failure (NYHA grade III or IV), or demyelinization disorders (the latter also if in first-degree relative)   Relative   ·       Selective for ustekinumab: BCG vaccination within the past 12 months (mode of action expected to increase susceptibility to mycobacterial infections)   ·       Selective for secukinumab, ixekizumab, and brodalumab: active Crohn disease (may cause exacerbation of bowel disease)   ·       History of hepatitis B viral (HBV) infection**   ·       History of hepatitis C viral infection (risk of activation)***   ·       Immunosuppressed patient   ·       Pregnancy (TNF-α inhibitors, ustekinumab and secukinumab are category B; ixekizumab was released after 2015   ·       Breastfeeding   ·       Malignancy within the past 5 years (does not include adequately treated single cutaneous squamous or basal cell carcinoma)   ·       Excessive chronic sun exposure or photo(chemo)therapy

 

† Guttate, pustular, or erythrodermic psoriasis are not established indications, but there is anecdotal evidence for efficacy and safety.

 

** If HBsAg-positive, measure HBV DNA and treat with antiviral agent (e.g. tenofovir, entecavir, telbivudine) prior to immunosuppressive therapy. Monitor for reactivation in those with anti-HBs or -HBc antibodies who are HBsAg-negative 

 

*** Need to monitor liver function tests and viral load.

 

With regard to the percentage of patients achieving PASI 75 improvement, there is significant overlap between the efficacies of biologic agents (as assessed after 3 months of therapy) and those of photo(chemo)therapy and classic systemic medications such as MTX and cyclosporine. In general, TNF-α inhibitors and anti-IL-12/23 antibodies have substantial efficacy and enable long-term control of psoriasis, as do secukinumab and ixekizumab recently approved anti-IL-17A antibodies. The latter have demonstrated greater efficacy than etanercept or ustekinumab in clinical trials.

 

US Food and Drug Administration (FDA) warnings and precautions for targeted immune modulators with dermatologic indications.

Live vaccines should not be given to patients receiving these medications. BCG, bacillus Calmette–Guérin; IL, interleukin; LE, lupus erythematosus; TNF, tumor necrosis factor.

 

FDA WARNINGS AND PRECAUTIONS FOR TARGETED IMMUNE MODULATORS WITH DERMATOLOGIC INDICATIONS

TNF inhibitors: adalimumab, certolizumab, etanercept, golimumab, infliximab

Increased risk of serious infections, including tuberculosis, bacterial sepsis, systemic fungal infections (e.g. histoplasmosis), and infections due to opportunistic pathogens   Risk of hepatitis B virus reactivation   Malignancies (especially lymphomas) have been reported in patients receiving these agents, including children and adolescents   For infliximab, lymphomas are seen more often than in the general population and fatal hepatosplenic T-cell lymphomas have developed in patients with inflammatory bowel disease who were also receiving azathioprine or 6-mercaptopurine   An increased risk of non-melanoma skin cancer and melanoma has been observed in patients with rheumatoid arthritis treated with TNF inhibitors   Congestive heart failure (exacerbation or new onset) has been observed   Demyelinating disease (exacerbation or new onset) has been observed   Anaphylaxis or severe allergic reactions can occur, including serum sickness-like reactions to infliximab   Other potential adverse events include autoimmune hepatitis, cytopenias, and a lupus-like syndrome;

Ustekinumab

Serious infections have been observed; may increase the risk of infection and reactivation of latent infections   Patients genetically deficient in IL-12/IL-23 have an increased risk of severe infections with mycobacteria and Salmonella   BCG vaccination should not be given in the year prior to initiation or the year following completion of ustekinumab therapy   Could potentially increase the risk of malignancies   Hypersensitivity reactions (e.g. angioedema, anaphylaxis) can occur   Reversible posterior leukoencephalopathy syndrome has been reported

IL-17 inhibitors: ixekizumab, secukinumab, brodalumab

Serious infections have been observed; may increase the risk of infection and reactivation of latent infections   Patients genetically deficient in IL-17 are prone to chronic mucocutaneous candidiasis   New onset and exacerbation of inflammatory bowel disease have occurred   Hypersensitivity reactions (e.g. angioedema, anaphylaxis) can develop   For brodalumab: suicidal ideation and behavior, including complete suicides, have occurred

 

 

Recommended laboratory evaluation for patients receiving targeted immune modulators for dermatologic disorders

 

Laboratory testing
Prior to treatment	During treatment
PPD**/interferon-γ release assay† and/or (e.g. if immunosuppression or history of tuberculosis) chest X-ray   CBC and CMP   Hepatitis B and C virus serologic profiles   Consider HIV testing	Annual PPD**/interferon-γ release assay† and/or chest X-ray   CBC and CMP every 3–12 months, or as noted below or clinically indicated

 

** ≥5 mm of induration should be considered as positive.

† e.g. QuantiFERON^® TB Gold or T-SPOT^®.TB.

 

CUTANEOUS SIDE EFFECTS OF TUMOR NECROSIS FACTOR INHIBITORS

New-onset psoriasis, especially palmoplantar pustulosis   Interstitial granulomatous dermatitis and other granulomatous eruptions   Cutaneous small vessel vasculitis   Eczematous eruptions   Lichenoid dermatitis   Lupus-like syndrome-associated malar rash or discoid lesions   Other types of cutaneous lupus, e.g. SCLE, chilblain lupus

New-onset palmoplantar and inverse psoriasis has also been reported to be by the interleukin-17 inhibitor sekukinimab. Allergic reactions manifesting with urticaria and angioedema can also occur with most agents.

 

Vaccination

Live vaccines are contraindicated in patients receiving TNF inhibitors. It is recommended that patients (especially children) be brought up-to-date with all immunizations prior to initiating treatment with TNF inhibitors.

 

Consider giving pneumococcal, hepatitis A and hepatitis B, influenza, and tetanus-diphtheria vaccines before initiation of immunosuppressive therapy. Once immunosuppressive therapy has begun, patients must avoid vaccination with live vaccines (including varicella; mumps, measles, and rubella; oral typhoid; yellow fever) and live-attenuated vaccines (including intranasal influenza and the herpes-zoster vaccine). Studies show adequate but attenuated immune responses to killed virus vaccines such as influenza vaccination and pneumococcal vaccine.

 

 

VACCINES THAT CONTAIN LIVE ATTENUATED VIRUSES OR BACTERIA

1.   Adenovirus 2.   Bacillus Calmette–Guérin (BCG) 3.   Cholera, oral form in the US 4.   Herpes zoster (shingles) 5.   Influenza (including H1N1), intranasal form 6.   Measles, mumps, and rubella 7.   Rotavirus 8.   Polio, oral form 9.   Typhoid, oral form Vaccinia (smallpox vaccine) Varicella Yellow fever

 

TNF-α inhibitors for the treatment of psoriasis

The introduction of TNFi has revolutionized the management of severe psoriasis. They are effective and are the most commonly prescribed biologic agents for psoriasis. Currently, three TNFi are licensed for this indication; adalimumab, etanercept and infliximab. The indication of psoriasis is same for each agent being limited to moderate/severe disease when other treatments (methotrexate, ciclosporin and phototherapy) have been ineffective, or are contraindicated.

Patients with an inadequate response to one TNF inhibitor may derive benefit from switching to another. Sequential tumor necrosis factor-α antagonist treatment can be considered for patients with psoriasis who do not respond, or lose response, during anti–tumor necrosis factor treatment.

 

Screening for latent tuberculosis infection

Patients on anti–tumor necrosis factor-α therapy are at risk of developing active tuberculosis. Perform tuberculin skin testing before initiating therapy and at 6- to 12-month intervals during therapy. However, there have been cases reported in which psoriasis patients on long-term etanercept therapy have manifested negative tuberculosis results and positive interferon-gamma release assay results. This suggests that tuberculin skin testing might be unreliable during long-term anti–tumor necrosis factor-αtherapy. QuantiFERON-TB Gold testing (interferon-gamma release assay) may be a more appropriate primary test in patients with risk factors for false-negative tuberculin skin test results. Interferon-gamma release assays may be very expensive.

 

Mechanism of action

 

Infliximab, adalimumab, golimumab, and certolizumab pegol are monoclonal antibodies, while etanercept is a dimeric fusion protein composed of the extracellular portions of two p75 TNF receptors linked to the Fc portion of IgG1. Although all four monoclonal antibodies target human TNF, infliximab is chimeric (human–mouse) IgG1, adalimumab and golimumab are human recombinant IgG1 and certolizumab pegol is a humanized pegylated Fab fragment.

 

Clinical studies have found that Infliximab and adalimumab to be slightly more effective than etanercept in the treatment of psoriasis. The different effects of these agents are associated with selectivity in their ability to perturb these receptor ligand interactions. It is known that Infliximab, adalimumab and etanercept bind TNF differently; infliximab and adalimumab bind to both soluble and membrane bound TNF, whereas etanercept bind primarily to soluble TNF. Binding to membrane bound TNF can induce a dose dependent increase in apoptosis of T cells.

 

Mechanism of action of the tumor necrosis factor (TNF) inhibitors.

 

All of the TNF inhibitors can bind to soluble TNF and block its ability to activate TNF receptors. By interacting with membrane-bound TNF, the IgG1 monoclonal antibodies can also activate complement-dependent cytotoxicity and induce cellular apoptosis. This capacity to destroy TNF-producing cells may explain the greater efficacy of these monoclonal antibodies compared to etanercept in the treatment of granulomatous conditions as well as the potentially higher risk of infections associated with their use. In addition to the anti-inflammatory effects of TNF inhibitors, blocking TNF signaling may have an impact on the neuroendocrine system.

 

Contraindications

 

Each TNF inhibitor is contraindicated in patients with known hypersensitivity to that particular medication, and infliximab is contraindicated in those with an allergy to murine proteins. These agents should be avoided in patients with a significant active infection, malignancy, congestive heart failure (especially if unstable), or multiple sclerosis.

 

 

Recommended Laboratory evaluation for patients receiving targeted immune modulators for dermatologic disorders.

 

Laboratory testing
Prior to treatment	During treatment
PPD**/interferon-γ release assay† and/or (e.g. if immunosuppression or history of tuberculosis) chest X-ray   CBC and CMP   Hepatitis B and C virus serologic profiles   Consider HIV testing	Annual PPD**/interferon-γ release assay† and/or chest X-ray   CBC and CMP every 3–12 months, or as noted below or clinically indicated

 

** ≥5 mm of induration should be considered as positive.

† e.g. QuantiFERON^® TB Gold or T-SPOT^®.TB.

 

Adalimumab

Indications

Adalimumab (a fully human monoclonal antibody with affinity for TNF‐α) is approved for the treatment of moderate to severe plaque-type psoriasis in adults. Additional approved indications include psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, uveitis, and Crohn disease in adults as well as JIA and Crohn disease in children ≥2 years and ≥6 years of age, respectively.

 

Dosages

Adalimumab is supplied in 10–80 mg prefilled syringes and a 40 mg autoinjector; it is administered subcutaneously. For the treatment of psoriasis, an initial loading dose of 80 mg is typically given on day 0, followed by 40 mg on day 8 and then 40 mg every other week.  Loss of efficacy of adalimumab over time related to the production of anti-adalimumab antibodies can occur and may be prevented by the concurrent administration of low-dose weekly methotrexate; loss of efficacy has also been associated with the development of antinuclear antibodies. The concomitant use of adalimumab and methotrexate is approved for the treatment of psoriatic arthritis, rheumatoid arthritis, and JIA.

 

The onset of treatment response in psoriasis is rapid, being significant at 2 weeks and maximal between weeks 12 and 16. PASI‐75 and PASI‐90 at 16 weeks are seen in 80% and 50%, respectively, of patients receiving the licensed dose (adalimumab 80 mg at week 0 then 40 mg every other week beginning at week 1). Adalimumab has shown greater efficacy after 16 weeks of treatment than methotrexate (7.5 mg/week initial dose increasing to a maximum of 25 mg/week as tolerated). Adalimumab is effective for chronic plaque psoriasis of the hands and feet. Adalimumab efficacy was well maintained over more than 3 years of continuous therapy for patients with sustained initial PASI-75 responses (i.e., 75% improvement in the Psoriasis Area and Severity Index score). Many dermatologist prescribed adalimumab as first-line treatment for psoriasis.

 

Side effects

Side effects shared with other TNF inhibitors, including risk of infection with mycobacteria and fungi. Moderately painful injection site reactions are noted in up to 15% of patients. These reactions usually resolve spontaneously within the first 2 months of therapy.

 

Interactions

The concomitant administration of other targeted immune modulators with adalimumab may increase the risk of infection and should be avoided.

 

Use in pregnancy

Adalimumab is classified as pregnancy category B. Its safety during lactation is unknown.

 

 

Infliximab

It is a chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF alfa.

Indication

Infliximab is approved for the treatment of adults with chronic severe plaque-type psoriasis. Compared with the other TNF inhibitors, its onset of action tends to be faster and a higher proportion of patients (~75–85%) achieve a 75% reduction in the PASI score. Infliximab is also approved for the treatment of adults with psoriatic arthritis, Crohn disease (including associated fistulas), ulcerative colitis, rheumatoid arthritis and ankylosing spondylitis, as well as children ≥6 years of age with Crohn disease and ulcerative colitis. Infliximab also has efficacy in psoriatic nail disease.

Dosages

In patients with plaque psoriasis, the drug is given by slow intravenous infusion over 2 hours and dose is based on body weight (5-10 mg/kg at weeks 0, 2 and 6 and then every 8 weeks). A response is often seen after the first infusion, and after an induction phase of three infusions 80% of patients at 5mg/kg dose and 90% of patients at 10mg/kg dose achieves PASI‐75. This rapid and reliable response makes the drug particularly suitable in urgent circumstances such as erythrodermic psoriasis and generalized pustular psoriasis. In the maintenance phase, efficacy is maintained to 50 weeks. Neutralizing anti-chimeric antibodies have been reported in a high proportion of individuals treated with infliximab, and correlate with lower serum drug levels, loss of efficacy and the development of infusion reactions; the concurrent administration of low-dose weekly methotrexate may help to prevent the formation of ADA.

Specific side effects

Infusion-related reactions and serum sickness are the most commonly reported side effect of infliximab. Infusion-related reactions occur in 15% of patients treated. Most are mild, consisting of pruritus or urticaria. Some patients will have moderate reactions consisting of chest pain, hypertension, and shortness of breath and only rarely will severe reactions with hypotension and anaphylaxis occur. Infusion reaction risk has been linked to the presence of human anti-chimeric antibodies. Risk of reactions can usually be managed by slowing the rate of infusion or stopping treatment entirely or concomitant use of methotrexate

 

Interactions

Infliximab should not be administered together with other targeted immune modulators due to the potential for additive immunosuppression.

 

Use in pregnancy

Infliximab is rated pregnancy category B. However, because it crosses the placenta and can lead to an increased risk of infection in the infant, use in pregnancy should be avoided unless the benefits outweigh the risks. It is not known whether infliximab is secreted in breast milk, and its administration to nursing mothers is not recommended.

 

 

Etanercept

Etanercept, a fully human soluble TNF‐α receptor fusion protein that binds and neutralizes TNF‐α. Response is of slower onset than with infliximab, becoming evident after 4–8 weeks of treatment.

Indications

Etanercept has been approved for the treatment of moderate to severe plaque-type psoriasis in adults since 2004 and in children ages 4–17 years since 2016. Depending on the regimen (see below), ~30–60% of patients achieve a 75% improvement in their Psoriasis Area and Severity Index (PASI) score; significant decreases in fatigue and depression have also been described. Other approved indications for etanercept include rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis in adults as well as juvenile idiopathic arthritis (JIA) in children ≥2 years of age.

 

Dosages

 

The dosing of etanercept differs in psoriasis than for its other indications. In rheumatoid and psoriatic arthritis, etanercept are often used in combination with methotrexate. In psoriasis, all clinical studies have been performed with etanercept as monotherapy. Rebound does not typically occur when etanercept is discontinued. The approved dose for moderate to severe plaque psoriasis is 50 mg twice/week given subcutaneously for 3 months followed by 50 mg once/week. Some physicians choose to initiate therapy at a dose of 50 mg weekly and only escalate the dose if the patient fails to respond after 6 to 12 months. The recommended dose for pediatric psoriasis is 0.8 mg/kg (maximum 50 mg) weekly.

 

Specific side effects

Injection site reactions are the most common side effect of etanercept. Mean duration of reactions is 3 to 5 days; these reactions generally occur in the first month and subsequently decrease. Erythema, pruritus, pain, and swelling have been described, and “recall” reactions at sites of previous injections have been reported. These reactions do not progress to anaphylaxis. The needle cover of the prefilled etanercept syringe contains latex so this formulation should not be used in latex-sensitive patients. Loss of efficacy over time may occur. This is possibly related to the development of antibodies.  Pooled clinical trial data demonstrate that etanercept is a safe drug even when used at higher doses or extended periods of time.

 

Interactions

 

The concomitant use of etanercept and methotrexate is approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Due to the potential for increased immunosuppression, combination of etanercept with other targeted immune modulators should generally be avoided. Etanercept has been used together with narrowband UVB without an increase in adverse events and with added therapeutic benefit.

 

Use in pregnancy

 

Etanercept is pregnancy category B. Studies in pregnant women have not been conducted. It has been suggested that etanercept and other TNF inhibitors be avoided after the first trimester. It is not known whether etanercept is secreted in breast milk; however, in general, this drug is not absorbed via an oral route.

 

Golimumab

 

Golimumab is a human recombinant IgG1 monoclonal antibody with specificity for human TNF. It is approved for the treatment of psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis; it can be administered along with methotrexate. It is supplied in a 50 mg prefilled syringe or autoinjector that is administered subcutaneously monthly for psoriatic arthritis.

 

Certolizumab

 

Certolizumab pegol is a pegylated Fab fragment of a humanized monoclonal antibody with specificity for human TNF. It is approved for the treatment of psoriatic arthritis, rheumatoid arthritis, and Crohn disease. It is supplied in a 200 mg prefilled syringe and administered subcutaneously. For psoriatic arthritis, 400 mg is given at weeks 0, 2 and 4, followed by 200 mg every 2 weeks or 400 mg monthly for maintenance.

 

Biologics that target cytokines interleukin-12 and interleukin-23

Psoriasis results in part from the activation and migration of T cells into the epidermis and the release of inflammatory mediators, which leads to hyper proliferation of skin cells. The cytokines interleukin-12 (IL-12) and IL-23 are produced by activated antigen-presenting cells and have a role in the differentiation and proliferation of type 1 T-helper cells. There is evidence of high levels of IL-12 and IL-23 expression in psoriatic lesions.

Site of action of ustekinumab (anti-p40) and IL-23 inhibitors (anti- p19)

 

Ustekinumab and Guselkumab

 

Ustekinumab is a monoclonal antibody that targets IL-12 and IL-23, whereas guselkumab is a monoclonal antibody that target IL-23.

 

Mechanism of action

Ustekinumab is a human IgG1 monoclonal antibody that targets interleukin-12 (IL-12) and IL-23. It binds to the p40 subunit, common to both IL-12 and IL-23, which prevents these cytokines from binding to the cell surface of T cells, thereby disrupting the inflammatory cascade implicated in psoriasis.  

Guselkumab is also a human monoclonal antibody (IgG1lamda) that selectively targets the p19 subunit of IL-23. This is a highly effective biological agent for psoriaisis.

Indications

Ustekinumab and guselkumab are approved for the treatment of adults with moderate to severe plaque-type psoriasis, with ~65–80% and ~80–90% of patients achieving a 75% improvement in their PASI score. In addition to psoriasis, ustekinumab is also approved for the treatment of various aspects of psoriatic arthritis (peripheral and axial disease, dactylitis, enthesitis) and Crohn disease.

For the treatment of moderate-to-severe plaque psoriasis, ustekinumab may be more efficacious than adalimumab and etanercept, but not infliximab.  Ustekinumab produces a stable clinical response over time, with no rebound after withdrawal of the drug and a retreatment PASI-75 response of approximately 85%. Although approved for psoriatic arthritis (PsA), in some patients PsA may worsen on ustekinumab. A small percentage of patients develop anti-ustekinumab antibodies and it is not known if these antibodies affect clinical outcomes.

 

Dosages

For the treatment of psoriasis, ustekinumab is administered as a subcutaneous injection of 45 mg for patients who weigh 100 kg or less, and 90 mg for patients who weigh more than 100 kg. An initial dose is administered subcutaneously at week 0, followed by another dose at week 4, and then a further dose every 12 weeks. No dose adjustment is needed for patients older than age 65. It is not recommended for children younger than age 18 because of a lack of data. At week 12, a PASI-75 response was achieved by 67% of patients receiving 45 mg of ustekinumab and 75% of patients receiving 90 mg of ustekinumab.  Consider increasing dose to once every 8 weeks with ustekinumab 90 mg in patients who do not achieve PASI-75 at 28 weeks.

At week 16, 80% of patients on guselkumab achieve a PASI 75 and 73% a PASI 90.

Contraindications

Ustekinumab and IL-23 inhibitors are contraindicated in patients with known sensitivity to the agents, and they should be avoided in patients with serious active infections or malignancies.

 

Major side effects

 

Ustekinumab is associated with an increased incidence of mucocutaneous candidiasis (~5% of patients) and a potential risk of severe and disseminated infections with mycobacteria and Salmonella. These particular infections mirror those seen in patients with genetic deficiencies in the IL-12/IL-23 signaling pathway. Assessment for tuberculosis is required at baseline and typically repeated annually during therapy with all IL-12/23 or 23 inhibitors. Patients with untreated latent tuberculosis should receive antituberculous therapy prior to beginning treatment.

 

A possible excess of major adverse cardiovascular events (MACEs) such as myocardial infarction or stroke was noted in patients who received anti-IL-12/23 therapy in individual clinical trials, but meta-analyses and a 5-year follow-up study did not find a significant increase in the risk of MACEs associated with the use of these agents. Although the effects of IL-12/23 inhibitors on vascular inflammation and thrombosis, especially early in the course of therapy, remain to be determined, cardiovascular risk factors should be assessed prior to initiating treatment. Injection site reactions can occur but are less frequent than with the TNF inhibitors. Retiform purpura progressing to cutaneous necrosis on the leg was reported in a patient treated with ustekinumab.

Interactions

Live vaccines should be avoided. The response to vaccines may be muted. Other targeted immune modulators should not be administered together with ustekinumab or IL-23 inhibitors. The concomitant administration of other immunosuppressive agents might increase the risk of infection.

 

Use in pregnancy

Ustekinumab is pregnancy category B; guselkumab was approved after June of 2015 and therefore was not labeled with a pregnancy category. The safety of these drugs during lactation is unknown.

Recommendations for Ustekinumab

 

Indication: Moderate-to-severe plaque psoriasis in adults

 

Dosing:  45 mg for people who weigh 100 kg or less, and 90 mg for people who weigh more than 100 kg. An initial dose is administered subcutaneously at week 0, followed by another dose at week 4, and then a further dose every 12 weeks. No dose adjustment is needed for patients older than age 65. It is not recommended for children younger than age 18 because of a lack of data.

 

Short-term response: At week 12, a PASI-75 response was achieved by 67% of patients receiving 45 mg of ustekinumab, 66% of patients receiving 90 mg of ustekinumab. 

 

Long-term response: Maintenance of PASI-75 was significantly superior with continuous ustekinumab treatment compared with treatment withdrawal; at week 76, 84% of patients rerandomized to maintenance treatment achieved a PASI-75 response compared with 19% of patients rerandomized to placebo.

 

Increasing dose: Consider increasing dose to once every 8 weeks with ustekinumab 90 mg in patients who do not achieve PASI-75 at 28 weeks.

 

Toxicity

 

·       The most common adverse reactions (>10%) are nasopharyngitis and upper respiratory tract infection. Most were considered mild and did not necessitate drug discontinuation.

 

·       Contraindications include clinically important active infection.

 

·        Reports of serious adverse events, including serious infections, malignancies, and cardiovascular events, were low.

 

Baseline monitoring

1.    PPD and consider chest x-ray

2.    LFT, CBC, and hepatitis profile

 

Ongoing monitoring

3.    Consider yearly PPD and periodic CBC and LFT

4.    Periodic history and physical examination

  

Interleukin-17 Inhibitors

Plaque psoriasis arises in part because of activation of autoimmune CD4+ and CD8+ Th17 cells that proliferate and target the epidermis where they interact with keratinocyte (keratin 7 and LL-37) and melanocyte (ADAMTSL, a disintegrin and metalloproteinase with thrombospondin motifs like 5) auto antigens and produce IL-17 and IL-22. Currently, there are three biological agents targeting the IL-17 pathway: secukinumab and ixekizumab, which target IL-17A, and brodalumab, which blocks the IL-17 receptor A (IL-17R). These biological agents are among the most effective for the treatment of moderate to severe plaque psoriasis. These agents are relatively fast-acting with results as fast as 4 weeks. 

Site of action of IL-17 inhibitors

 

Contraindications

 

Each IL-17 inhibitor is contraindicated in patients with a known hypersensitivity to that particular agent or components of its formulation. These medications should be used with caution in patients with chronic/recurrent infections or inflammatory bowel disease, with Crohn disease representing a contraindication for brodalumab. Administration of an IL-17 inhibitor should be avoided or discontinued in patients with a serious active infection.

 

Major side effects

The most common adverse events in clinical trials of IL-17 inhibitors were nasopharyngitis, upper respiratory tract infections, and injection-site reactions. Hypersensitivity reactions have also been reported, including anaphylaxis, angioedema, and urticaria. Mucocutaneous candidiasis, most often oral or vulvovaginal, develops in ~5% of patients; this reflects the important role of IL-17 in defense against Candida. These infections are typically mild or moderate and resolve with standard treatment. Neutropenia (<1500 cells/mm³) occurs in ~1–2% of patients, which is similar to the frequency in patients receiving etanercept. Assessment for tuberculosis is required at baseline and typically repeated annually during therapy. Patients with untreated latent tuberculosis should receive antituberculous therapy prior to beginning treatment.

New onset and exacerbation of Crohn disease and ulcerative colitis have occurred in patients receiving IL-17 inhibitors. An increased risk of adverse cardiovascular events was not observed in clinical trials.

Interactions

Live vaccines should be avoided. To avert a potential increased risk of infection, other targeted immune modulators should not be coadministered with IL-17 inhibitors.

Use in pregnancy

Secukinumab is pregnancy category B; the other IL-17 inhibitors were approved after June of 2015 and therefore were not labeled with a pregnancy category. There are no available data on IL-17 inhibitor use in pregnant women, although human IgG is known to cross the placenta. Safety during lactation is unknown.

 

Secukinumab

Mechanism of action

Secukinumab is a recombinant human IgG1κ monoclonal antibody that binds to IL-17A and blocks its interaction with the IL-17A receptor. 

Indications

Secukinumab is approved for moderate to severe plaque psoriasis in adults. After 12 weeks of treatment, approximately 77% and 67% of patients treated with the 300 mg and 150 mg doses, respectively, achieve a 75% improvement in their PASI score. This response is durable with 76% of patients achieving a 90% reduction in PASI at 52 weeks. It is also approved for psoriatic arthritis and ankylosing spondylitis.

 

Dosages

Secukinumab is administered as a subcutaneous injection of 300 mg at weeks 0, 1, 2, 3, and 4; thereafter, it is given every 4 weeks. A dose of 150 mg may be considered for patients weighing <90 kg. It is available in 150 mg prefilled syringes and autoinjectors.

Ixekizumab

Mechanism of action

Ixekizumab is a humanized IgG4 monoclonal antibody that binds and inhibits IL-17A, resulting in neutralization of IL-17A homodimers and IL-17A/F heterodimers. In its hinge region, there is substitution of proline for serine which prevents the formation of half-antibodies (half-mers) that can undergo Fab-arm exchange with endogenous human IgG4.

 

Indications

Ixekizumab is approved for the treatment of moderate to severe plaque-type psoriasis and PsA. After 12 weeks, 90% of patients are capable of achieving a PASI 75, making Ixekizumab one of the most effective biological agents for psoriasis.

 

Dosages

Ixekizumab is administered as a subcutaneous injection, with a loading dose of 160 mg followed by 80 mg every 2 weeks for 12 weeks and then every 4 weeks. It is supplied in 80 mg prefilled syringes and autoinjectors.

 

 

Brodalumab

Mechanism of action

Brodalumab is a human IgG2κ monoclonal antibody that selectively binds the IL-17 receptor A, inhibiting its interactions with IL-17A/F and IL-17E (also known as IL-25).

Indications

Brodalumab is approved for the treatment of moderate to severe psoriasis in adults who have failed or become unresponsive to other systemic therapies. Approximately 80–85% and 60–70% of patients treated with the 210 mg and 140 mg doses, respectively, achieve a 75% reduction in their PASI score. This is a very effective biological agent for psoriasis, however, there is a concern about suicidal ideation and completed suicides in clinical trials.

Dosages

Brodalumab is available in prefilled syringes and administered as a 210 mg subcutaneous injection every 2 weeks.

 

 

PHOSPHODIESTERASE 4 INHIBITOR

 

A novel, small-molecule inhibitor of phosphodiesterase 4, apremilast works intracellularly to reduce the production of proinflammatory mediators and increase those that are anti-inflammatory. When administered orally, apremilast is 70–75% bioavailable, with peak plasma concentrations observed at ~2.5 hours. Nearly 70% of the drug is bound to plasma proteins, and it is metabolized by cytochrome P450 (CYP) enzymes, predominately CYP3A4; this is followed by glucuronidation and non-CYP-mediated hydrolysis. Apremilast has a terminal elimination half-life of 6–9 hours and is excreted in the urine and feces.

Mechanism of Action

Apremilast inhibits phosphodiesterase 4, which is an intracellular enzyme that degrades cAMP and represents the predominant phosphodiesterase in keratinocytes, dendritic cells, monocytes, and neutrophils. Increasing intracellular cAMP levels activates protein kinase A, leading to enhanced expression of several transcription factors including cAMP-response element binding protein (CREB), while inhibiting others such as nuclear factor kappa B (NF-κB). By inhibiting phosphodiesterase 4 and increasing intracellular cAMP levels, apremilast has multiple downstream effects: it decreases the production of inflammatory mediators such as TNF-α, IFN-γ, and interleukins (IL)-2, -12, and -23; it increases the production of anti-inflammatory mediators including IL-10; and it inhibits natural killer responses.

Dosages

The recommended dosage for psoriatic arthritis and psoriasis is 30 mg twice daily. In order to reduce gastrointestinal symptoms, an upward titration of the dose by 10 mg/day is recommended, starting with an initial dose of 10 mg/day. Apremilast is available in 10, 20 and 30 mg tablets. For individuals with severe renal impairment, the recommended maximum daily dose is 30 mg; there is no dosing adjustment for hepatic impairment.

Major Side Effects

The most common side effects are gastrointestinal, especially nausea, vomiting and diarrhea, and they are most evident during the first 15 days of administration and gradually resolve over several weeks. Headache and nasopharyngitis are additional potential side effects. Because depression, including suicidal ideation, can be observed in up to 1% of patients, patients with a history of depression should be monitored closely. Loss of ~5–10% of body weight occurs in ~10% of patients. No laboratory monitoring is recommended, but serial measurements of weight can be performed.

Indications

Apremilast is FDA-approved for the treatment of adult patients with active psoriatic arthritis and patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. At week 16, only 33.1% of patients receiving apremilast (30 mg BID) achieve a PASI 75. It is currently being investigated for other inflammatory skin diseases including discoid LE, lichen planus, granulomatous dermatoses, and atopic dermatitis.

Contraindications

Apremilast is contraindicated in patients with known hypersensitivity to the drug or its components. Dosing should be adjusted for renal failure. Relative contraindications include a history of depression or suicidal ideation.

Use in Pregnancy and Lactation

Apremilast was formerly pregnancy category C. However, it has not been evaluated in well-controlled studies involving pregnant women and should only be used during pregnancy if the potential benefit justifies the potential risk. It is not known whether apremilast or its metabolites are present in human milk.

Drug Interactions

Apremilast is a strong cytochrome p450 inducer and should not be used with drugs metabolized by this pathway such as rifampin, phenobarbital, carbamazepine, and phenytoin.

 

 

 

Management of psoriasis at specific sites

These sites do improve with systemic therapies, but involvement of these sites alone is usually not a sufficient indication for a systemic therapy.

MANAGEMENT OF PSORIASIS AT SPECIFIC SITES
Specific sites	Special considerations and practical treatments
Scalp	Remove scale with topical 10–15% salicylic acid   Apply potent or ultrapotent corticosteroids in a lotion, gel, foam or shampoo formulation, either alone or in combination with calcipotriene
Face; groin, axilla, and other body folds	First-line: mild topical corticosteroids   Second-line: topical calcineurin inhibitors or tacalcitol/calcitriol in combination with a mild topical corticosteroid
Nail	Differentiate proximal versus distal nail unit pathology due to nail matrix versus nail bed pathology, respectively; consider coexisting onychomycosis   For distal nail unit pathology: vitamin D3 analogues topically (limited evidence)   For proximal pathology: intralesional corticosteroids and/or systemic antipsoriatic therapies

 

How to combine treatments

Enhanced clinical response and a possible reduction in side effects are the goals of combination therapy. However, for safety reasons, some combinations are contraindicated.

 

Beneficial combinations

For topical treatments, the combination of calcipotriene with super potent topical corticosteroids has been shown to be more effective than either treatment as monotherapy, whereas the combination of calcipotriene plus medium-strength corticosteroids did not have a substantial additive effect compared with each as monotherapy. However, the irritation caused by calcipotriene can be reduced by the addition of medium-strength corticosteroids. Improved efficacy has also been observed with the combination of calcipotriene–cyclosporine and calcipotriene–acitretin, compared with each as monotherapy. For example, with low-dose cyclosporine (2 mg/kg/day) plus topical calcipotriene, marked improvement or clearing was seen in 90% of patients. In a dose-escalating study of acitretin, the combination of acitretin and calcipotriene was more effective and permitted a lower dose of both acitretin and calcipotriene as compared to each as monotherapy. The combination of calcipotriene and PUVA is characterized by a marked reduction in the cumulative dose of UVA required and enhanced efficacy, compared with the respective monotherapies. However, evidence for a beneficial effect of the combination of UVB and calcipotriene is less convincing. Combining etanercept (25 mg subcutaneously once weekly) and acitretin has been shown to be as effective as etanercept 25 mg subcutaneously twice weekly.

Topical corticosteroids are frequently combined with other antipsoriatic treatments. Although increases in the duration of subsequent remission periods have been noted, controlled studies are required to substantiate these claims. Depending upon the anatomic site, it is advisable to prescribe daily potent or medium-strength corticosteroids for a maximum of 4–8 weeks. Then intermittent schedules (e.g. 2–3 applications per week) can be considered.

 

Contraindicated combinations and combinations with restricted use

 

The combination of acitretin and cyclosporine carries the risk of accumulation of cyclosporine, because cyclosporine is inactivated by the cytochrome P450 system, which is inhibited by acitretin. An increased occurrence of SCCs has been observed in patients treated with the combination of cyclosporine and PUVA, either simultaneously or sequentially (PUVA followed by cyclosporine). As a result, the combination of cyclosporine and PUVA is contraindicated. Although a combination of methotrexate and PUVA has been reported to be safe, long-term data are not available.

 

The combination of coal tar with PUVA is contraindicated as it may induce significant phototoxic responses. The combination of cyclosporine and methotrexate has been viewed as high risk because both are immunosuppressants. However, this combination has been used with success by rheumatologists, and, in recalcitrant psoriasis, the combination has proved to be very effective without major side effects. The combination of methotrexate and acitretin has been used in those patients in whom all treatments have failed. Although this combination can be very effective, severe hepatotoxicity has been reported; therefore, careful monitoring is mandatory.

 

How to manage childhood psoriasis

Topical calcipotriene is considered as first-line therapy for mild to moderate juvenile psoriasis, combined with mild- to moderate-strength topical corticosteroids (if necessary). For treatment-resistant flexural and/or facial psoriasis, tacrolimus 0.1% ointment can be added to the treatment regimen. The next step is to recommend treatment with narrowband UVB, especially in adolescents. Although controversial, the use of antibiotics can be considered in patients with guttate psoriasis where there is suspicion of a streptococcal infection. Of the systemic medications, methotrexate is regarded as the treatment of choice, with retinoids considered in pustular and erythrodermic psoriasis. Cyclosporine is occasionally utilized for exceptional cases, and etanercept should be considered as a third-line drug for therapy-resistant psoriasis.

 

TREATMENT LADDER

 

Mild plaque psoriasis without psoriatic arthritis

 

First line

·        Coal tar

·        Potent topical corticosteroid

·        Vitamin D analogue

Second line

·        Local NB‐UVB or PUVA

·        Excimer laser

 

Moderate to severe plaque psoriasis without psoriatic arthritis

First line

·        NB‐UVB or PUVA

Second line

·        Acitretin

·        Ciclosporin

·        Methotrexate

Third line

·        Adalimumab

·        Etanercept

·        Infliximab

·        Secukinumab

·        Ustekinumab

 

Moderate to severe plaque psoriasis with psoriatic arthritis

 

First line

·        Apremilast

·        Methotrexate

Second line

·        Adalimumab

·        Etanercept

·        Infliximab

·        Ustekinumab

Third line

·        Combination therapy

Future Developments and Treatments

To date, a stepwise approach is the treatment paradigm for psoriasis, starting with a topical agent, then phototherapy or a classic systemic medication, and ultimately a “biologic” therapy. It remains to be determined whether the introduction of even more targeted biologic therapies (e.g. inhibitors of IL-17A, IL-23, and the IL-17 receptor) will influence this paradigm. In the future, there will be additional targeted biologic therapies (e.g. inhibitors of IL-20, IL-22, GM-CSF), topical or oral small molecules (e.g. JAK1/2 inhibitors, protein kinase C inhibitors, p38 kinase inhibitors), and oligonucleotides that target Toll-like receptors 7, 8 and 9 or function as a STAT3 decoy. Hopefully, the future development of biomarkers that predict individual responses to different therapies will provide a more cost-effective approach to therapy.

 

 

Conclusion

Psoriasis is a complex disease. Three way interactions between adaptive immunity, innate immunity and skin barrier defect may best explain the pathophysiology of psoriasis. That the role of adaptive immunity is crucial to the development of psoriasis is beyond doubt, as validated by the successful use of biologic response modifiers. However, there is increasing evidence on the role played by innate immunity and the skin barrier function in initiating and perpetuating inflammation in psoriasis. This is likely to open up newer targets for therapeutic interventions.

 

 

 

French guidelines on the use of systemic treatments for moderate-to-severe psoriasis in adults, 2019

Treatment algorithm for patients suffering from plaque psoriasis without comorbidities. CSA, cyclosporin; MTX, methotrexate; NBUVB, Narrowband UVB; PUVA, psoralen UVA; re-PUVA, retinoid psoralen UVA