Systemic lupus erythematosus 

 

Introduction

 

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with multi systemic involvement. The disease has several phenotypes, with varying clinical presentations in patients ranging from mild mucocutaneous manifestations to multi organ and severe central nervous system involvement. Several immunopathogenic pathways play a role in the development of SLE. The lupus erythematosus (LE cell) was described by Hargraves in 1948. Several pathogenic auto antibodies have since been identified. Despite recent advances in technology and understanding of the pathological basis and risk factors for SLE, the exact pathogenesis of SLE is still not well known. Diagnosis of SLE can be challenging and while several classification criteria have been posed, their utility in the clinical setting is still a matter of debate.

The improvement in patient survival – 50% four year survival in 1950; 85% 15 year survival in 2019 – is probably due to multiple factors, including earlier disease recognition with more sensitive diagnostic tests and improved treatment.

Management of SLE should be individualized according to predominant symptoms, organ involvement, response to previous therapy and disease activity and severity.

Despite the improvement in outcome, patients with SLE still have mortality rates two to five times higher than the general population.

 

Clinical and Immunologic Criteria Used in the Systemic Lupus International Collaborating Clinics (SLICC) Classification System^*2012

Classify a patient as having SLE if he or she satisfies four of the clinical and immunologic criteria, including at least one clinical criterion and one immunologic criterion, or if he or she has biopsy-proven nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies.  The criteria are cumulative and do not need to be present concurrently.

Clinical criteria

1.   Acute cutaneous lupus, including:

1.   Lupus malar rash (do not count if malar discoid)

2.   Bullous lupus

3.   Toxic epidermal necrolysis variant of SLE

4.   Maculopapular lupus rash

5.   Photosensitive lupus rash in the absence of dermatomyositis

OR

Subacute cutaneous lupus (non-indurated psoriasiform and/or annular polycyclic lesions that resolve without scarring, although occasionally with post inflammatory dyspigmentation or telangiectasias)

2.   Chronic cutaneous lupus, including:

1.   Classic discoid rash

·       Localized (above the neck)

·       Generalized (above and below the neck)

2.   Hypertrophic (verrucous) lupus

3.   Lupus panniculitis (profundus)

4.   Mucosal lupus

5.   Lupus erythematosus tumidus

6.   Chilblain lupus

7.   Discoid lupus/lichen planus overlap

 

3.   Oral ulcers:

Palate, buccal, tongue OR nasal ulcers in the absence of other causes, such as vasculitis, Behçet’s disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic foods

4.   Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia

 

5.   Synovitis involving 2 or more joints, characterized by swelling or effusion

OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness

6.   Serositis:

·       Typical pleurisy for more than 1 day duration OR pleural effusions OR pleural rub

·       Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day duration OR pericardial effusions OR pericardial rub OR pericarditis by electrocardiography in the absence of other causes, such as infection, uremia and Dressler pericarditis

 

7.   Renal:

1.   Persistent proteinuria >500 mg of protein/24 hours

2.   or red blood cell casts

 

8.   Neurologic:

Seizures; psychosis; mononeuritis multiplex in the absence of other known causes such as primary vasculitis; myelitis; peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection and diabetes mellitus; or acute confusional state in the absence of other causes, including toxic/metabolic, uremia, drugs.

9.   Hemolytic anemia

 

10.                   Leukopenia (<4000/mm³ at least once) in the absence of other known causes such as Felty syndrome, drugs and portal hypertension OR

Lymphopenia (<1000/mm³ at least once) in the absence of other known causes such as corticosteroids, drugs, and infection

11.                   Thrombocytopenia (<100,000/mm³) at least once in the absence of other known causes such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura

 

Immunologic criteria

1.   ANA level above laboratory reference range

2.   Anti-dsDNA antibody level above laboratory reference range (or >2-fold the reference range if tested by ELISA)

3.   Anti-Sm: presence of antibody to Sm nuclear antigen

4.   Antiphospholipid antibody positivity as determined by any of the following:

·       Positive test result for lupus anticoagulant

·       False-positive test result for rapid plasma reagin

·       Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)

·       Positive test result for anti–β₂-glycoprotein I (IgA, IgG, or IgM)

5.   Low complement:

·       Low C3

·       Low C4

·       Low CH50

6.   Direct Coombs’ test in the absence of hemolytic anemia

 

 

Epidemiology

 

Varying prevalence and incidence rates of SLE have been reported, with differences mostly attributes to the population differences.

The strongest factor affecting risk for lupus is gender. SLE predominantly affects women of childbearing age, with female to male ratio of 9 to 1; it is likely that hormonal factors influence susceptibility. The risk, however, decreases after menopause in women although still is twice as compared to men. Studies have indicated that although rare, lupus in men tends to be more severe. Although SLE is much more common in female patients, its diagnosis, treatment and management remains the same for male patients.

 

Age plays an important role in SLE, and although the disease is more common in childbearing age in women, it has been well reported in the pediatric and elderly population. The condition tends to occur in early adult life, and the peak age of onset of the first symptom or sign in females is approximately 38 years. SLE is more severe in children while in the elderly, it tends to be more insidious onset and has more pulmonary involvement and serositis and less Raynaud's, malar rash, nephritis, and neuropsychiatric complications.

 

Etiology

 

SLE is a multi factorial disease with unknown exact etiology; however, several genetic, immunological, endocrine, and environmental factors play a role in the etiopathogenesis of SLE.

 

Genetic factors

 

Familial segregation and high concordance rates in identical twins suggest a strong genetic contribution in SLE, although there is no obvious pattern of inheritance. Concordant rates for identical twins have been reported to be as high as 50%. More than 50 genes or genomic loci have been identified to be associated with SLE, most encoding proteins implicated in the function of the immune system. These genes are associated with activation of the immune system in response to foreign antigens, self-antigen generation, and activation of innate and adaptive immune systems. Some gene mutations that are rare, but are considered very high risk for the development of SLE include deficiencies of early complement components C1q, C1r, C1s (>90% risk), C4 (50%), C2 (20%) and TREX1. One of the chromosome regions having the strongest association with SLE is the human leucocyte antigen (HLA) locus, especially the class region containing HLA‐DRB1, ‐DQA1 and ‐DQB1.  Women are at 10 times more risk of developing SLE than men, and the risk of SLE is 14 times more in Klinefelter syndrome (47, XXY). This suggests an association with genes on the X-chromosome, however, despite several studies, the exact genes have not been identified. 

 

Immunological factors

 

Interactions between susceptibility genes, hormonal influences (90% of SLE patients are female) and environmental factors result in abnormal immune responses, resulting in autoantibody production and consequent dysregulation of the inflammatory response, leading to induction and maintenance of the disease. Autoantibodies may be present for a several years before the first clinical symptom appears.

 

Endocrine factors

 

Female sex and hormonal influence is a significant risk factor for SLE. Estrogens and prolactin promote autoimmunity and increase the B-cell activation factor production and modulate lymphocyte and pDC activation. The use of estrogen-containing contraceptives and postmenopausal hormone replacement therapy can cause flares in patients with SLE and have been associated with a higher incidence of SLE. Elevated levels of prolactin are seen in patients with SLE. Androgens, on the other hand, are considered protective. 

 

Environmental Factors

Genetic predisposition for a lupus diathesis does not, in itself, produce disease. Rather, it appears that induction of autoimmunity in such patients is triggered by some inciting event, likely an environmental exposure. Drugs, viruses, UV light, and, possibly, tobacco, have been shown to induce development of SLE.

 

Ultraviolet radiation

 

Ultraviolet radiation (UVR) is probably the most important environmental factor in the induction phase of SLE and especially of LE-specific skin disease. UV radiation may precipitate the onset or exacerbate the course of SLE in up to 60% of patients. UV light likely leads to self-immunity and loss of tolerance because it causes apoptosis of keratinocytes, which in turn, makes previously cryptic peptides available for immunosurveillance. UVB radiation has been shown to displace autoantigens such as Ro/SS-A and related autoantigens, La/SS-B, and calreticulin, from their normal locations inside epidermal keratinocytes to the cell surface. UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine), which upregulates the expression of chemokines that activate autoreactive T cells and interferon-α (IFN-α), producing dendritic cells (DCs), which likely play a central role in lupus pathogenesis.

 

 

Tobacco smoking

 

Smoking is also thought to be a risk, with a dose-response. Smokers are at a greater risk of developing SLE than are nonsmokers and former smokers (lipogenic aromatic amines). Patients with treatment resistant CLE are much more likely to smoke. Several authors have shown that patients with LE-specific skin disease who smoke are less responsive to antimalarial treatment.

 

Drugs 

Several drugs have been implicated in causing a lupus-like phenomenon by causing demethylation of DNA and alteration of self-antigens. While procainamide and hydralazine have the highest incidence of causing drug-induced lupus, more than 100 drugs have been associated with drug-induced lupus. Further, several drugs such as the sulfa-drugs are well known to cause flares in patients with SLE.A range of medications can induce systemic LE (SLE) and cutaneous LE, most commonly subacute cutaneous LE (SCLE).  In the former, patients may develop fever, malaise, polyarthritis, and serositis from drugs such as hydralazine and procainamide, but associated acute cutaneous LE is rare. Although symptoms typically appear at least one month after drug initiation and resolve days to weeks after discontinuation of the responsible medication, the skin lesions of SCLE are sometimes more persistent.

 

The pathogenesis of drug-induced SLE is not well understood, but one possibility is that reactive drug metabolites, interacting with nuclear histones, could act as haptens and activate the complement cascade. For example, procainamide-induced SLE occurs more frequently in patients who are slow acetylators as compared to rapid acetylators.

 

The precipitation of SLE by drugs, especially hydralazine and procainamide is well known. However, there are features to suggest that drug‐induced SLE differs from spontaneous disease: it occurs in an older age group, renal and central nervous system involvement are infrequent, antihistone antibodies are frequent, antibodies against double-stranded DNA are typically absent and serum complement is normal.

While drug-induced SLE is characterized by the presence of antihistone antibodies in up to 95% of cases, these antibodies are not specific and may be seen in patients with idiopathic SLE. The seroconversion from negativity to positivity for antinuclear antibodies alone is not sufficient to discontinue a particular medication, but if symptoms develop, the offending drug should be withdrawn. However, the antinuclear antibodies may persist for 6 to 12 months. 

Cutaneous involvement in drug‐induced SLE may be vasculitic, bullous or erythema multiforme‐like or resemble pyoderma gangrenosum. Minocycline‐induced SLE is uncommon, it usually occurs after 2 years of therapy. Patients who require more than 1 year's therapy should have ANA and liver function tests monitored. Other drugs, particularly certain anticonvulsants, are known to precipitate SLE‐like syndromes.

In drug-induced SCLE, anti-SSA/Ro and anti-SSB/La antibodies are often present and the cutaneous and histologic findings are indistinguishable from those seen in the idiopathic form of the disease. It therefore behooves the clinician to carefully review all medications in patients with the diagnosis of SCLE, in particular terbinafine, thiazide diuretics, proton pump inhibitors, calcium channel blockers, and taxanes. Of note, patients receiving TNF-α inhibitors may develop cutaneous lesions of chronic (discoid), subacute, or acute cutaneous LE as well as antinuclear and anti-DNA antibodies. In these patients, arthritis often predominates over cutaneous manifestations and some patients tolerate a switch to a different TNF inhibitor.

There is an increased incidence of HLA-DR4 in drug-induced SLE and the ratio of females to males is 4: 1, indicating a possible genetic predisposition. It appears that individuals who are slow acetylators are more likely to develop drug- induced LE or LE-like syndromes. The determination of acetylator type and DR typing may enable susceptible patients to be identified.

 

Viruses

 

There has been much speculation about the role of infectious agents, particularly viruses, in the induction of SLE and CLE. Seroconversion to Epstein-Barr virus (EBV) among patients with SLE is nearly universal, and recent data have demonstrated that patients with SLE have defective control of latent EBV infection that probably stems from altered T-cell responses against EBV. Antibodies against Epstein-Barr virus (EBV) are more prevalent in children and adults with SLE compared to the general population.

 

Other potential risk factors include silica exposure, other viral infections, vitamin D deficiency, alfalfa sprouts and foods containing canavanine.

 

Pathogenesis

SLE is a disorder in which the interplay between host factors (susceptibility genes, hormonal milieu, etc.) and environmental factors [ultraviolet (UV) radiation, viruses, and drugs] leads to loss of self-tolerance, and induction of autoimmunity. This is followed by activation and expansion of the immune system, and eventuates in immunologic injury to end organs and clinical expression of disease.

 

 

 

 

The pathogenesis of SLE is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals, on exposure to environmental factors, leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens leading to activation of T and B cells which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production then lead to organ damage.

Both innate and adaptive immune systems play a role in the pathogenesis of SLE. The innate immune system activation is either Toll-like receptor (TLR) dependent, or independent. The cell membrane-bound TLRs (TLR 2, 4, 6) are activated on exposure to the extracellular DNA and RNA from dying cells, which leads to downstream activation of the Interferon regulatory family (IRF-3), NF-κB and MAP-kinases, which serve as transcription factors for the production of pro inflammatory mediators such as IFN-b. The endosomal TLRs (TLR 7, 9) are activated by single-stranded RNA and demethylated DNA and lead to the production of Interferon-alpha, and RNA binding autoantibodies such as antibodies against Ro, La, Sm, and RNP. The TLR-independent pathway is activated by intracytoplasmic RNA sensors (RIG-1, MDA-5) and DNA sensors (IFI16, DAI) and leads to activation of IRF3 and NF-κB. Both self DNA/RNA and foreign DNA/RNA such as from viruses can lead to this activation. NETosis has recently gained attention in the pathogenesis of SLE. Neutrophils, on activation by various factors such as cytokines, activated platelets and vascular endothelial cells systematically release their nuclear aggregates in the extracellular environment. These nuclear aggregates can then promote Interferon-alpha production by the dendritic cells, mediate thrombosis and vascular damage and serve as self-antigens for T-lymphocytes. 

T-lymphocytes and B-lymphocytes play a significant role in the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen-presenting cells. T-cells in SLE display a distorted gene expression leading to the production of several cytokines. These T-cells produce less IL-2, which leads to altered regulatory T-cell production. Increased IL-6, IL-10, IL-12 and IL-23 increases mononuclear cell production while increased IL-17 and IL-21 leads to increased T-cell production. Increased Interferon-γ leads to defective T-cell production. T-cells lead to the activation of auto reactive B-cells by CD40L and cytokine production, which leads to autoantibody production, which is a hallmark of SLE. Toll-like receptors on interaction with DNA and RNA lead to activation of these B-cells, and the nucleic acid and protein-containing intranuclear complexes are the most prominent antigens leading to B-cell activation. These auto antibodies are pathogenic and cause organ damage by immune complex deposition, complement, and neutrophil activation, and altering cell function leading to apoptosis and cytokine production. Further, the auto reactive B-cells in SLE which are stimulated by self-antigens, are not readily eliminated due to a deficiency of the process involved in the functional neutralization of auto reactive B cells. The B-cells can also serve as antigen-presenting cells and can activate T-cells by presenting internalized soluble antigens to T-cells. This creates a loop where both B and T cells activate each other, both leading to more autoimmunity.

 

IMMUNOLOGY OF SLE

 

 

The production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) is a common mechanism of pathogenesis in SLE. Dying tissue cells release nucleic acids; these form large complexes with antimicrobial peptides, such as LL37 and with endogenous DNA-binding proteins, such as high mobility group protein B1 (HMGB1). These DNA and RNA complexes activate pDCs via Toll-like receptor 9 (TLR9) and TLR7, respectively, and they induce the production of type I IFN. In turn, type I IFN promotes T cell activation, autoantibody production by B cells and the release of neutrophil extracellular traps (NETs) that consist of DNA–antimicrobial peptide complexes. Autoreactive antibodies activate neutrophils and form DNA-containing immune complexes that are preferentially endocytosed by pDCs via Fc receptors. Self-nucleic acids also activate classical DCs (cDCs) and they promote the release of inflammatory cytokines and the priming of T cells that are specific for self-antigens in a process that is also facilitated by type I IFN.

 

Histopathology

 

Tissue pathology is SLE can demonstrate a variety of aberrant immunologic mechanisms including immune complex formation, autoantibody formation, and immunologically mediated tissue injury.

LE body or hematoxylin body is a hallmark of SLE pathology. It is a homogeneous globular mass of nuclear material that stains bluish-purple with hematoxylin. It can be observed in the lungs, kidneys, spleen, heart, lymph nodes, and serous and synovial membranes. They contain immunoglobulins as well as DNA, and engulfment of LE body by phagocytes leads to the formation of the classic LE-cell.

Pathology from skin lesions in SLE demonstrates immune complex formation leading to tissue damage, vascular and perivascular inflammation and chronic mononuclear cell infiltration. Acute lesions demonstrate fibrinoid necrosis at the dermo-epidermal junction and the dermis along with liquefactive degeneration of the epidermis and perivascular inflammatory cell infiltration with T-cell predominance. Chronic lesions can also demonstrate hyperkeratosis and follicular plugging. Edema and RBC extravasation can be seen in all SLE lesions. Immunofluorescence demonstrates deposition of IgG, IgA, and IgM immunoglobulins and complement components along the dermal-epidermal junction. 

Vasculitis is common in SLE and vascular lesions in SLE may demonstrate various different pathologies. Immune complex deposition with an inflammatory response is the most common lesion, although it may be seen without significant inflammatory response as well. Small and large vessel necrotizing vasculitis with fibrinoid necrosis is less common but can be seen and can be differentiated from other vasculitides by immune complex deposition in the vessel wall. Thrombotic microangiopathy can be seen in patients with SLE and antiphospholipid antibody syndrome.

Central nervous system pathology in SLE reveals small intracranial vessel involvement with thrombotic lesions with or without perivascular inflammation and endothelial proliferation. Necrotizing vasculitis can be seen rarely. Thromboembolism from Libman-Sacks endocarditis has been seen as well. 

Cardiac pathology may include valvular involvement leading to Libman-Sacks endocarditis which is sterile verrucous endocarditis. It tends to involve the mitral valve most commonly with vegetations seen on the forward flow side of the valve. Pathology reveals platelet thrombi, necrotic cell debris, proteinaceous deposits, and mononuclear cells. Pericarditis with fibrinous exudate is common and pathology reveals fibrinoid necrosis and perivascular infiltration with mononuclear cells. Myocarditis can be seen as well. SLE poses a very high risk for atherosclerotic coronary artery disease, and vasculitis, immune complex deposition in addition to corticosteroid use and hypertension are thought to be contributory.

Lymphadenopathy is common in SLE, and pathology may reveal follicular hyperplasia with giant cells, plasma cells infiltration of the interfollicular zones, and necrosis of the paracortical T-cell zones. LE bodies may be rarely seen. The necrotic vessel wall shows immunoglobulin and Complement C3 deposition. Splenomegaly is also common in SLE, with pathology showing the classic onionskin lesion with has multiple concentric rings of perivascular collagen. Follicular hyperplasia and periarterial fibrosis are common. 

Lupus pneumonitis can be seen in up to 10% of lupus patients. Interstitial pneumonitis, alveolitis, alveolar wall injury, and edema and hemorrhage are commonly seen in these patients. Immunoglobulin and complement deposition is seen in the vessel wall. Chronic interstitial lung disease can occur in up to 50% of these patients and is characterized by interstitial lymphoid aggregates and fibrosis, septal thickening and type-2 pneumocyte hyperplasia. Medial hypertrophy and intimal fibrosis involving the branches of the pulmonary artery lead to pulmonary hypertension in SLE. Again, immunoglobulin and complement deposition can be seen in the vessel wall.

Lupus nephritis can involve the glomeruli, interstitium, tubules and the vessels with immune complex deposition in all four compartments. The World Health Organization classification criteria for lupus nephritis describe 6 classes of lupus nephritis all with distinct pathological features and significant differences in clinical outcomes. This has led to a different treatment approach for each class and knowing the class of lupus nephritis before initiating treatment is vital. 

·        Class I: Minimal mesangial lupus nephritis

·        Class II: Mesangial proliferative lupus nephritis

·        Class III: Focal lupus nephritis

·        Class IV: Diffuse segmental or Diffuse global lupus nephritis

·        Class V: Membranous lupus nephritis

·        Class VI: Advanced sclerosing lupus nephritis

 

Immunohistology

The lupus band test (LBT) Immunoglobulins, predominantly IgG, but less frequently IgM and IgA, together with complement (C1q, C3) can be demonstrated at the dermal–epidermal junction by immunofluorescence techniques. Such deposits are present in lesional skin but are also present in clinically normal skin of SLE. They occur in more than 80% of skin lesions of DLE and SLE. If IgG, IgM and IgA are all present, the diagnosis of SLE is likely, and the more common combination of IgG and IgM is also suggestive. The basement‐membrane phenomenon can be demonstrated in uninvolved skin in three‐quarters of active cases of SLE if the biopsy specimens are taken from the exposed skin, preferably from the dorsum of the wrist or forearm. Biopsy specimens from the unexposed skin are positive in only approximately 50% of patients. However, a positive LBT on uninvolved sun‐protected skin is a specific criterion for identifying patients with LE. In addition to dermal–epidermal immunoreactant deposition, epidermal nuclear deposits, usually giving a speckled IgG pattern, occur in the basal epidermal nuclei and cells of the lower epidermis in nearly one‐third of patients.

Autoantibodies

Non‐organ‐specific humoral auto antibodies are the hallmark of SLE. A range of auto antibodies may be present in the disease, although some are more disease‐specific (anti‐dsDNA and anti‐Sm antibodies) and some are much more common (antinuclear and anti‐Ro antibodies). The B cells that make auto antibodies are activated by elevated levels of B‐lymphocyte stimulator (BLys; also known as B‐cell‐activating factor (BAFF)), a growth factor that is particularly important for the survival of T‐cell‐dependent B cells that promote autoantibody formation. Clinical trials have demonstrated that belimumab, a monoclonal antibody to BAFF, improves mucocutaneous and arthritis symptoms in patients with SLE. This drug has become the first US Food and Drug Administration (FDA) approved therapy for SLE.

In SLE, antigen–antibody complexes containing DNA and RNA products activate the innate immune system through the stimulation of Toll‐like receptors (TLRs) 9 and 7, respectively. Innate immune activation culminates in INF‐α and TNF‐α release by dendritic cells and this release promotes T cells to release IFN‐γ, interleukin 6 (IL‐6) and IL‐10; all cytokines that promote continued antibody formation. The autoantibody‐producing cells are subsequently inadequately down‐regulated by anti‐idiotypic antibodies and regulatory T cells.

 

Clinical features

Due to the clinical and serological diversity, the disease may affect almost any organ of the body, and can manifest in a broad variety of ways. Despite the female sex predominance, clinical gender differences are found in organ involvement and prognosis. Men with lupus tend to have higher frequencies of renal disease, skin manifestations, cytopenias, serositis, neurological involvement, thrombosis and vasculitis, with an increased risk of myocardial infarction, possibly due to an increased frequency of hypertension and positive lupus anticoagulant.

An autoantibody profile can sometimes be helpful in predicting the disease course and clinical features. Several studies have indicated the development of serological abnormalities several years before the onset of clinical lupus. This is termed as pre-clinical lupus, where a patient may have serological abnormalities consistent with SLE and may have some clinical features, but still does not meet the criteria for SLE. There is evidence that a significant percentage of these patients with pre-clinical lupus that include those with incomplete lupus, or undifferentiated connective tissue disease may transition to clinical lupus and fulfill the SLE criteria later in life.

The main clinical features include fever, rashes and arthritis, but renal, pulmonary, cardiac and neurological involvement may occur, with increased mortality.

 

1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus.

Criterion	Definition
1. Malar rash	Fixed erythema, flat or raised, over the malar eminences, tending the spare the nasolabial folds
2. Discoid rash	Erythematous raised plaques with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3.Photosensitivity	Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers	Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis	Non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
6. Serositis	a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion
	Or
	b. Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion
7. Renal disorder	a. Persistent proteinuria— >0.5 g/day or greater than 3+ if quantitation not performed
	Or
	b. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder	a. Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
	Or
	b. Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
9. Hematologic disorder	a. Hemolytic anemia—with reticulocytosis
	Or
	b. Leukopenia— <4,000 μL total on two or more occasions
	Or
	c. Lymphopenia— <1,500/μL on two or more occasions
	Or
	d. Thrombocytopenia— <100,000 μL in the absence of offending drugs
10. Immunologic disorder	a. Anti-DNA—antibody to native DNA in abnormal titer
	Or
	b. Anti-Sm—presence of antibody to Sm nuclear antigen
	Or
	c. Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G or immunoglobulin M anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear antibody	An abnormal titer of antinuclear antibody by immunofluorescence of an equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome

* The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.

 

 

 

Presentation

The initial manifestations vary. The most commonly observed presenting symptoms are arthralgia followed by cutaneous involvement. Presentation with serositis and renal abnormalities are less common.

In fulminating cases there is usually marked constitutional disturbance, with fever, weight loss, anorexia, malaise and joint pains; the skin may be involved later, if at all. On the other hand, the evolution can be gradual, starting with localized skin lesions and systemic involvement developing later. Fatigue is a prominent symptom, both at presentation and subsequently. The diagnosis in many cases is made only by considering the condition in a patient with an obscure illness. As most patients are female, sex is an important diagnostic point. Although weight loss is a feature in nearly 50% of cases, some patients may gain weight. Menstruation is irregular in 18% and absent in 75%.

 

Clinical manifestations of cumulative systemic lupus erythematosus and prevalence over the entire course of disease. Adapted from ‘Systemic Lupus Erythematosus’ Harrison's Principles of Internal Medicine, 20th edition

Manifestation	Prevalence
1. Systemic: ·       Fatigue, malaise, fever, anorexia	95%
2. Musculoskeletal:	95%
·       Arthralgias/myalgias	95%
·       Non‐erosive polyarthritis	60%
·       Hand deformities ·       Myopathy/myositis	10% 25/5%
·       Ischaemic necrosis of bone	15%
3. Cutaneous:	80%
·       Photosensitivity	70%
·       Malar rash	50%
·       Oral ulcers	40%
·       Alopecia	40%
·       Discoid/vasculitis rash	20%
·       Other	15%
4. Haematological:	85%
·       Anaemia (chronic disease)	70%
·       Leukopenia	65%
·       Lymphopenia	50%
·       Thrombocytopenia	15%
·       Lymphadenopathy	15%
·       Splenomegaly	15%
·       Haemolyticanaemia	10%
5. Neurological:	60%
·       Cognitive disorder	50%
·       Mood disorder	40%
·       Headache	25%
·       Seizures	20%
·       Mono‐, polyneuropathy	15%
·       Stroke, transient ischemic attack	10%
·       Acute confused state or movement disorder	2–5%
·       Aseptic meningitis, myelopathy	<1%
Manifestation	Prevalence
6. Cardiopulmonary:	60%
·       Pleurisy, pericarditis, effusions	30–50%
·       Myocarditis, endocarditis	10%
·       Lupus pneumonitis	10%
·       Coronary artery disease	10%
·       Interstitial fibrosis	5%
·       Pulmonary hypertension, acute respiratory distress syndrome, haemorrhage	<5%
·       Shrinking lung syndrome	<5%
7. Renal:	30–50%
·       Proteinuria ≥500mg/24h,	30–50%
·       cellular casts
·       Nephrotic syndrome	25%
·       Endstage renal disease	5–10%
8. Gastrointestinal:	40%
·       Nonspecific (nausea, mild pain, diarrhoea) ·       Abnormal liver enzymes                                                      40% ·       Vasculitis 5% 9. Thrombosis: 15% ·       Venous 10% ·       Arterial 5% 10. Ocular 15%% ·       Sicca syndrome 15%    ·       Conjunctivitis, episcleritis 10% ·       Vasculitis 5%	30%

 

Constitutional symptoms

 

Constitutional symptoms are seen in more than 90% of patients with SLE and are often the initial presenting feature. Fatigue, malaise, fever, anorexia and weight loss are common. While more than 40% of patients with SLE may have lupus flare as a cause of fever, infections must always be ruled out first given the immunocompromised state of these patients. Further, SLE is a very rare cause of fever of unknown origin.

 

 

Mucocutaneous manifestations

 

Most of the patients with SLE suffer from mucocutaneous involvement, which is one of the most well-known and identified clinical features.

Approximately 80% of cases have a rash at some stage, and in up to 25% it is the presenting sign.

The cutaneous changes described by Gilliam is divided between: (i) those specific for LE and showing the characteristic histopathological appearances of interface dermatitis of LE; and (ii) those that are less specific in their origin and not showing histological changes of LE and many of these are also seen in the other connective tissue diseases. Non‐specific LE skin diseases are more frequently associated with SLE than LE‐specific lesions.

 

The Gilliam Classification of Skin Lesions Associated with Lupus Erythematosus

LE-Specific Skin Disease [Cutaneous LE (CLE)]

LE-Nonspecific Skin Disease

(A) Acute cutaneous LE (ACLE) 1.   Localized ACLE (malar rash; butterfly rash) 2.   Generalized ACLE (lupus maculopapular lupus rash, SLE rash, rash, photosensitive lupus dermatitis) (B) Subacute cutaneous LE (SCLE) 1.   Annular SCLE (syn. lupus marginatus, symmetric erythema centrifugum, autoimmune annular erythema, lupus erythematosus gyrates repens) 2.   Papulosquamous SCLE (syn. disseminated DLE, subacute disseminated LE, superficial disseminated LE, psoriasiform LE, pityriasiform LE, and maculopapular photosensitive LE) (C) Chronic cutaneous LE (CCLE) 1.   Classic discoid LE (DLE) ·       Localized DLE ·       Generalized DLE 2.   Hypertrophic/verrucous DLE 3.   Lupus profundus/lupus panniculitis 4.   Mucosal DLE ·       Oral DLE ·       Conjunctival DLE 5.   Lupus tumidus (urticarial plaque of LE) 6.   Chilblain LE (chilblain lupus) 7.   Lichenoid DLE (LE/lichen planus overlap, lupus planus)

(A) Cutaneous vascular disease 1.   Vasculitis (a)Leukocytoclastic ·       Palpable purpura ·       Urticarial vasculitis (b) Periarteritis nodosa-like cutaneous lesions 2.   Vasculopathy (a)Degos disease-like lesions (b)Secondary atrophie blanche (syn. Livedoid vasculitis, livedo vasculitis) 3.   Periungual telangiectasia 4.   Livedo reticularis 5.   Thrombophlebitis 6.   Raynaud phenomenon 7.   Erythromelalgia (erythermalgia) (B) Nonscarring alopecia ·       “Lupus hair” ·       Telogen effluvium ·       Alopecia areata (C) Sclerodactyly (D) Rheumatoid nodules (E) Calcinosis cutis (F) LE-nonspecific bullous lesions (G) Urticaria (H) Papulonodular mucinosis (I) Cutis laxa/anetoderma (J) Acanthosis nigricans (type B insulin resistance) (K) Erythema multiforme (L) Leg ulcers (M) Lichen planus

 

 

 

Cutaneous features of SLE in 73 patients

Cutaneous feature	Occurrence in SLE (%)
BUTTERFLY RASH AS PART OF ACLE	51
Facial edema	4
SUBACUTE CUTANEOUS LE	7
CHRONIC DLE	25
SCARRING DLE ALOPECIA	14
Non‐scarring alopecia	40
Chilblain lupus	20
Mouth ulceration	31
Bullous eruptions	8
Photosensitivity	63
Raynaud's phenomenon	60
Chronic urticaria (>36 h)	44
Cutaneous vasculitis	11
Livedo reticularis	4
Episcleritis	4
Cheilitis	4

 

The cutaneous features in bold are considered LE‐specific skin changes, with the characteristic histology of cutaneous lupus. The other cutaneous features are considered lupus non‐specific cutaneous features.

Lupus‐specific changes

The LE‐specific changes can be divided into three groups based on the amount of time that the skin symptoms typically take to present. These include chronic cutaneous LE (CCLE), SCLE and acute cutaneous LE (ACLE). CCLE includes localized and generalized DLE, hypertrophic LE, lupus profundus and lupus tumidus. SCLE includes annular and psoriasiform variants and ACLE includes acute localized and generalized LE, and toxic epidermal necrolysis (TEN) like variants. Patients with any of these LE‐specific features may have skin disease alone or SLE if they fulfill the new SLICC criteria. The risk of SLE with localized versus generalized DLE is 5% versus 20% over time, whereas it is rarely seen with LE tumidus. Lupus panniculitis is reported to occur in approximately 2–3% of patients with SLE. Similarly, although the incidence of SLE in patients with SCLE is approximately 50%, only 10–15% has serious organ involvement.

The three major types of cutaneous LE are not mutually exclusive. In a given patient, more than one type of cutaneous lesion may occur.

ACLE is often associated with active SLE. Cutaneous erythema is the most common feature, particularly on light‐exposed areas. Localized ACLE has commonly been referred to as the classic butterfly rash or malar rash of SLE (wolf-like erythema is coined). In localized ACLE, confluent symmetric erythema and edema with mildly scaling are centered over the malar eminences and bridges over the nose. The nasolabial folds are characteristically spared (photoprotected). In particular, the malar rash is seen in approximately 60% of patients with SLE, and often a sign of underlying systemic disease and may fluctuate with lupus disease activity. It usually has an acute onset and these lesions tend to be transient, follow sun exposure and lasting only hours, days, or weeks, and resolve without scarring (but sometimes with dyspigmentation). An association with anti-dsDNA antibodies and lupus nephritis has been proposed. The presence of telangiectasias, erosions, dyspigmentation and epidermal atrophy (i.e. poikiloderma) may help to distinguish the malar erythema of ACLE from that of common facial eruptions such as seborrheic dermatitis and the vascular type of rosacea.

 

 

 

In systemic lupus erythematosus (SLE) (left) the eruption is often just an erythema, sometimes transient, but occupying most of the ‘butterfly’ area. In discoid LE (right) the fixed scaling and scarring plaques may occur in the butterfly area (dotted line), but can occur outside it too.

 

In generalized ACLE, a widespread brightly erythematous macules and papules are seen on the photo-exposed areas on the face, upper trunk, and extensor aspects of the arms and hands and V-shaped region of the neck that can resemble a viral exanthem or a drug eruption.

Photosensitivity is present in SLE in more than 90% cases and is characterized by abnormal skin reaction on exposure to Ultraviolet A/B and visible light, a reaction that may last weeks to months. These patients also experience worsening of their systemic symptoms on sun exposure. ACLE is typically precipitated or exacerbated by exposure to sunlight. UV radiation such as that found in discos, fluorescent lighting and UVA from photocopiers may also cause exacerbations. Because UV‐induced lesions of cutaneous LE are characterized by a latency period of up to several weeks, a negative history of photosensitivity does not exclude sensitivity to light as the patient may be unaware of the relationship. Occasionally, more acute lesions with bullae may follow exposure to the sun, and bullae may be hemorrhagic. Importantly, the rash in generalized ACLE usually spares the distal interphalangeal, proximal interphalangeal and metacarpophalangeal joints – an important distinguishing feature from dermatomyositis.

An extremely acute form of ACLE is rarely seen that can simulate toxic epidermal necrolysis (TEN). This form of LE-specific vesiculobullous disease results from widespread apoptosis of epidermal keratinocytes, and eventuates in areas of full-thickness epidermal skin necrosis, which is subsequently denuded. This must be differentiated from drug‐induced TEN in a patient with SLE. Patients with this form of cutaneous LE often occurs on predominantly sun-exposed skin and has a more insidious onset and have significant systemic disease activity such as cerebritis or nephritis. In other cases, lesions are like those of erythema multiforme. The presence of erythema multiforme-like lesions in lupus patients has been termed Rowell’s syndrome.

 

Subacute cutaneous lupus erythematosus (SCLE) rash is photosensitive, widespread, nonscarring, and nonindurated. SCLE may be either papulosquamous resembling psoriasis or an annular/polycystic lesion with central clearing and peripheral scaling. SCLE lesions may last several months but usually, heal without scarring. SCLE rash is seen in patients with a positive Anti-Ro (SSA) antibody in up to 90% of the cases. SCLE can also be caused by some drugs such as hydrochlorothiazide. It has also been reported in patients with Sjogren syndrome and rheumatoid arthritis. 

 

Discoid lupus erythematosus (DLE) is the most common form of chronic cutaneous lupus erythematosus (CCLE). DLE may occur with or without SLE, and can be either localized (only head and neck) or generalized (above and below the neck). The lesions are disk-shaped erythematous papules or plaques with adherent scaling and central clearing. DLE heals with scarring, and when present on the scalp, can be associated with permanent alopecia. Mucosal DLE lesions can be seen in the oral cavity, and these tend to be painful erythematous round lesions with white radiating hyperkeratotic striae. Hypertrophic DLE may mimic squamous cell carcinoma histologically. Lupus panniculitis can occur above the waist and is less likely to be associated with SLE. The lesions result in depressed areas, and when associated with DLE lesions overlying them, are known as lupus profundus. Lupus tumidus lesions are erythematous edematous smooth plaques without epidermal involvement. 

Chilblain LE is a rare form of CCLE and presents with erythematous tender plaques on fingers and toes. Persistence of lesions beyond the cold months, a positive ANA, or presence of one of the other criteria for SLE at the time of diagnosis of chilblain lesions helps to distinguish chilblain LE from idiopathic chilblains. Approximately 20% of patients presenting with chilblain LE later develop SLE. These lesions may ulcerate.

Lesions resembling chronic discoid lesions are initial manifestations in approximately 10% of patients and about 20% of patients with SLE develop DLE lesions at some point in the course of their disease, and such patients tend to have less severe forms of SLE.

Lupus non‐specific changes

The presence of nonspecific LE skin lesions raises the possibility of SLE and may signify more significant internal disease.

 

Nonspecific manifestations of SLE are distinguished by the absence of lupus-specific changes on histopathology. These include a variety of reactive and inflammatory eruptions and are typically observed in active SLE.

 

Reticulate telangiectatic erythema seen on the thenar and hypothenar eminences of the palms, on the pulps and dorsum of the fingers and, to a lesser extent, on the toes and over the lateral borders of the feet and heels and sometimes there may be small vascular necroses on the tips of the fingers and alongside the nails. Erythromelalgia (erythermalgia) is characterized by intense burning pain in the feet and hands aggravated by heat and dependence and relieved by cooling and elevation accompanied by local macular erythema and warmth may be a presenting feature.

Non‐specific changes in the skin associated with SLE include nail changes, hair changes, vasculitis, urticarial lesions, mucinoses, bullous lesions, mucosal lesions and others. These are detailed below.

Nail changes

Nail changes occur in approximately 25% of patients. Nail changes in SLE includes nail fold erythema, red lunulae, nail fold hyperkeratosis and ragged cuticles. Other nail findings include nail ridging, onycholysis, onychomadesis and punctate or striate leukonychia caused by altered keratinization of the nail matrix. Blue‐black nail pigmentation may also be observed, and is thought to occur from increased melanin deposition. This dyschromia may be diffuse or longitudinal and may be caused by medications, most frequently antimalarials, but occasionally associated with methotrexate, cyclophosphamide and gold. Capillaroscopy may reveal glomerulization of the capillaries. Telangiectasia and erythema of the proximal nail fold are found in 76% of patients who had both DLE and SLE, but none in patients with DLE in the absence of SLE, suggesting that it, too, is a rather sensitive indicator for systemic disease activity.

Hair changes

These changes can be scarring or non‐scarring. The most common non‐specific skin manifestation of SLE is the diffuse, non‐scarring loss of hair with a reddish scalp known as telogen effluvium which occurs in more than 60% of patients, especially in the active phase of the disease or, less frequently, permanent scarring alopecia is found in DLE lesions on the scalp. Alternatively, the alopecia can be chronic leading to coarse, dry and fragile hair, especially on the frontal margin. This leads to an unruly appearance with short, broken-off hair, the so-called ‘lupus hair’. This occurs in 30% of patients, predominantly females. The hair loss recovers as the disease becomes inactive, but ‘lupus hair’ usually persists longer than alopecia. Alopecia areata is also found in approximately 10% of patients with SLE.

Cutaneous vascular reactions

They can be divided into vasculitis or vasculopathy and the distinction between the two conditions is important as their management is distinctly different. Vasculitis is caused by primary inflammation of the vessel walls with secondary occlusion by fibrin, whereas vasculopathy can be defined as narrowing of the vessel walls (i.e. ischaemic) or non‐inflammatory vessel lumen occlusion from thromboembolic disease.

 

Vasculitis

Arterioles and venules of the skin are frequently affected in SLE; all sizes of blood vessels may be affected. Vasculitis in SLE usually presents as a small‐vessel leukocytoclastic vasculitis with palpable purpura in dependent areas which is seen in 8–11% of patients with SLE. Cutaneous vasculitis in a patient with SLE may predict the development of lupus nephritis. Chronic urticaria occurs in 44% of SLE patients and is considered to be brought about by immune-complex deposition. Clinically, lesions may be indistinguishable from typical hives; but unlike hives, they are usually nonpruritic, painful and tender urticarial lesions, often over bony prominences, which last longer than 24 hours. It often involves nondependent areas of skin that characteristically leaves post‐inflammatory hyper pigmentation or purpura. This clinical presentation is typical of urticarial vasculitis. In most cases a biopsy reveals necrotizing vasculitis, and the lupus band test is generally positive. Involvement of medium and/or large vessels in the skin, may present as purpuric plaques with stellate or retiform borders with or without necrosis and ulceration, or as subcutaneous nodules.

 

Vasculopathy

Raynaud phenomenon can be seen in 25–60% of patients with SLE and is the most common nonspecific findings in such patients. It is characterized by reversible vasospasm of the fingers and toes, often caused by cold exposure, with triphasic color change; there is cold‐induced pallor, followed by cyanosis pain and numbness, then erythematous discoloration on rewarming. Predictors associated with SLE and Raynaud phenomenon on include persistent periungual telangiectasia, involvement of the thumbs, ears, nose and toes, ice‐pick or pitted scarring of the pulps and high ANAs, anti‐RNP and nucleolar antibodies. Raynaud's phenomenon seems to herald a worse prognosis and is associated with higher disease activity scores. Raynaud phenomenon on in SLE is also associated with migraine and pulmonary artery hypertension.

Livedo reticularis is seen in up to 35% of SLE patients. It may be seen in patients with SLE both with and without the antiphospholipid syndrome. It presents as a fishnet‐like, complete or incomplete, red-purple rings, which blanches on pressure, and is not affected by temperature changes, may develop, most commonly on the buttocks and legs, followed by the outer aspects of the arms and less commonly on the trunk. Superficial ulceration can occur in areas of livedo. The net‐like discoloration results from hypo‐oxygenation due to slow arterial blood flow in the dermal arterioles and the increased collection of the hypo‐oxygenated blood in the dermal venules. Livedo racemosa is distinguished from livedo reticularis based on a ‘broken net’ type of pattern and is thought to be a sign of more severe disease due to the presence of cholesterol and fibrin thrombi and calcification in the vessels. The appearance of livedo reticularis in patients with SLE and antiphospholipid syndrome may herald central nervous system involvement. Catastrophic antiphospholipid syndrome (CAPS) is rare (<1%), but has a high mortality of approximately 50%. CAPS presents in patients with APAb syndrome with a disseminated, intravascular, coagulation‐type picture with purpura fulminans. The diagnosis is made based on evidence of thrombosis in at least three organs, a histological finding of small‐vessel occlusion in at least one organ, a laboratory confirmation of APAbs and the rapid development of clinical manifestations

Atrophie blanche‐type lesions (painful, ivory, stellate scars on the lower extremities) may occur. Lesions similar to those in Degos disease (malignant atrophic papulosis;) – small, porcelain‐white, atrophic macules with peripheral erythema and telangiectasia – may also occur in patients with APAbs. In SLE patients with Degos‐like lesions, a more benign course is usual without the characteristic visceral involvement (digestive tract or central nervous system) that is commonly described in Degos syndrome. Lesions of primary anetoderma may also be seen and consist of localized areas of herniated sac‐like or flaccid skin as a result of localized elastic loss.

 

Large vessel disease

Gangrene of the tips of the fingers and toes may develop insidiously. At first the digits become blue and cold and may be painful. Radiography of the fingers in cases with peripheral ischemia shows absorption of the distal part of the terminal phalanges, as in systemic sclerosis. Later, the phalanges may become exposed, and spontaneous separation of the tips of the fingers may occur. Amputation of digits may be required. Occlusion of large- and medium-sized arteries can occur suddenly and result in gangrene requiring amputation of a limb. This may be the result of vasculitis or thrombosis. Patients with thrombosis frequently have antiphospholipid antibodies. Leg ulcers occur in approximately 10% of patients, usually near the malleoli but sometimes on the feet and elsewhere, from breakdown in reticular livedo and in areas of cutaneous vasculitis.

Mucinosis

Although mucin deposits are a common and often prominent histological feature of cutaneous lupus, specific clinical patterns of mucinosis also occur. Papular or nodular lesions resulting from mucinous deposits in the dermis (papulonodular mucinosis) without microscopic features of LE have been reported and form a distinct entity, which may be the presenting feature of LE. It presents as multiple, asymptomatic, firm flesh‐colored dermal papules and nodules, usually on the trunk, arms or head and neck, and can be associated with SLE, SCLE or DLE or can occur alone. The overlying epidermis appeared normal.

 

Other connective tissue changes

Dystrophic calcinosis is rare, and is most often seen in association with lupus panniculitis but can also occur in association with SLE. It occurs most often on the extremities and buttocks as asymptomatic nodules discovered by radiology. Occasionally, the skin overlying the calcinosis can ulcerate, leading to the extrusion of chalk‐like material. The mechanism underlying calcinosis cutis in SLE is unknown, but may be due to increased calcium concentration in the presence of necrotic and apoptotic cells, secondary to trauma or tissue damage. Subcutaneous nodules occur in approximately 5% of patients. They occur mainly over the backs of the proximal phalangeal joints and wrists, but are also found on the elbows, knees, occiput and flexor aspects of the fingers. They may resemble rheumatoid nodules and can respond to hydroxychloroquine. Some are identical histologically with classic rheumatoid nodules, while others are probably caused by vasculitis and thrombosis.

Bullous lesions

Blistering is uncommon in SLE and can be divided into three categories:

1.   Subepidermal bullae in ACLE and SCLE lesions due to separation of the epidermis and dermis as a result of severe liquefaction degeneration of the basal layer and dermal edema (TEN‐like ACLE and Rowell syndrome).

2.   SLE‐associated autoimmune bullous disease including dermatitis herpetiformis, pemphigus vulgaris (so‐called pemphigus erythematosus), pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, pseudoporphria, epidermolysis bullosa acquisita and IgA disease.

3.   A separate subset, bullous SLE (BSLE), is a distinct type of non‐specific, autoantibody‐mediated, cutaneous SLE that results in a subepidermal blister.

 

The diagnosis of BSLE requires the presence of: (i) SLE; (ii) a vesiculobullous eruption arising but not limited to sun‐exposed skin; (iii) histopathological subepidermal bulla containing neutrophils. Neutrophils accumulate within dermal papillae forming neutrophilic microabscesses, often resembles dermatitis herpetiformis; and (iv) DIF demonstrates linear IgG (± IgA and IgM or C3) deposits at the basement‐membrane zone, contrasting with the granular immunostaining seen in LE interface dermatitis. Electron microscopy shows the immunoreactants to be in the sublamina densa. The disease is mediated by circulating antibodies against type VII collagen as demonstrated by indirect immunofluorescence (IDIF).

 

Clinically, the bullous lesions arise predominantly on normal or erythematous sun‐exposed skin on the face, neck and upper trunk or flexural skin, but they may be more widespread, and can heal with milia formation. Glomerulonephritis is common. Given that BSLE occurs in the setting of SLE, the ANA test is generally positive, and anti‐dsDNA, anti‐Sm, anti‐Ro, anti‐La and anticardiolipin antibodies may also be detected. Low complement, proteinuria or cellular casts on urinalysis as well as hematological abnormalities may also reflect disease activity.

Dapsone either alone or in combination with prednisolone is the treatment of choice. The response may be dramatic, with cessation of new bullae within 1–2 days. However rapid recurrence may occur upon withdrawal of dapsone, with remission after re‐initiation of therapy.

Pemphigus erythematosus combines the immunological features of pemphigus and LE and presents with erythematous, scaly, hyperkeratotic or crusted lesions, sometimes adversely affected by the sun, occur in a butterfly distribution on the cheeks and in a seborrhoeic distribution on the trunk of patients with Senear–Usher syndrome. DIF demonstrates immunoglobulin and complement in the intercellular substance and at the dermal–epidermal junction of perilesional and, to a lesser extent, of light‐exposed and non‐exposed skin. Circulating pemphigus‐like antibodies and antinuclear factor occur in 80–100% of patients, but anti‐DNA and ENA antibodies are not found. Antidesmoglein antibodies 1 and 3 have also been demonstrated. The condition occurs spontaneously, but has been induced by penicillamine, propranolol, captopril, pyritinolol and thiopronine. Topical steroids alone may control the condition, but systemic steroids, immunosuppressives or dapsone may be required.

 

Oral and naso‐pharyngeal ulcers are one of the SLICC criteria for identifying patients with SLE and are found in active phase of the disease. Lesions start as small erythematous or purpuric areas, which break down to form shallow ulcers, with a dirty yellow base and surrounding reddish halo. LE ulcers are usually painless and can affect any part of the oral cavity with most common locations being the hard palate, the buccal mucosa, and the vermilion border. Histology and immunohistology show changes similar to those in the skin. DIF is usually positive. Repeated sore throats and oral ulceration may be presenting features. Chelitis occurs in approximately 4%, the lips having a silvery appearance, with erythema, scaling and blurring of the vermilion border. The larynx is occasionally involved. Ulceration of the mucosa of the nasal septum occurs in approximately 5%. Perforation of the nasal septum is a complication of exacerbations and presents with epistaxis. Erythema of the vulva and perianal area occurs and vulval ulceration may develop, but is less common than oral ulcers.

Given the potential risk of transformation to squamous cell carcinoma in these patients (increased age >60 years), mucosal biopsy should be considered in any non‐healing ulcerated lesion.

 

Musculoskeletal manifestations

Approximately 80% to 90% of patients with SLE suffer from musculoskeletal involvement at some point during their disease course and may range from mild arthralgias to deforming arthritis. Lupus arthritis is typically a non-erosive, symmetrical inflammatory polyarthritis affecting predominantly the small joints of the hands, knees, and wrists, although any joint can be involved. Jaccoud arthropathy is the result of the joint capsule and ligament laxity leading to non-erosive deformities of the hands including ulnar deviation and subluxation of the metacarpophalangeal joints that may mimic rheumatoid arthritis. Usually, these deformities are reducible, although rarely, they may become fixed. Avascular necrosis (with or without steroid use) can occur in up to 10% of patients with SLE and is usually bilateral and involves the hip joints. Inflammatory myopathy with histopathological features similar to but less striking than polymyositis has been seen in less than 10% of SLE cases. Patients with SLE are at high risk for the development of fibromyalgia with incidences as high as 20% reported. Rheumatoid nodules have been reported in patients with SLE.  

 

 

Hematologic manifestations

Anemia is present in more than 50 % of patients with SLE and most commonly is anemia of chronic disease. Other causes of anemia in SLE may include iron deficiency anemia, coomb's positive autoimmune hemolytic anemia, red blood cell aplasia and microangiopathic hemolytic anemia which may be associated with antiphospholipid antibody syndrome. Leukopenia secondary to neutropenia or lymphopenia is also very frequent and can be severe. Thrombocytopenia can be mild or severe and may be associated with antiphospholipid antibody syndrome and autoantibodies against platelets, glycoprotein IIb/IIIa or thrombopoietin receptor. Pancytopenia is not infrequent and may occasionally be associated with myelofibrosis. Soft non-tender lymphadenopathy is common in SLE, although rare cases of histiocytic necrotizing lymphadenitis have been reported (Kikuchi-Fujimoto disease). Splenomegaly is common in SLE, while splenic atrophy and asplenism have been reported.

 

 

Neuropsychiatric manifestations

Both central (CNS) and peripheral (PNS) nervous systems may be involved in SLE in addition to several psychiatric manifestations, although the diagnosis can be difficult. The most common CNS manifestation is intractable headaches, reported in more than 50% cases. Focal or generalized seizures may be seen, and are associated with disease activity, although they carry a favorable prognosis. Other CNS manifestations include aseptic meningitis, demyelinating syndrome including optic neuritis and myelitis, movement disorders such as chorea and cognitive dysfunction. Patients with SLE are also at high risk for ischemic strokes. Cranial and peripheral (sensorimotor, axonal) neuropathies, mononeuritis multiplex, autonomic neuropathies, and syndromes mimicking Guillain-Barré syndrome and Myasthenia gravis are the peripheral nervous system manifestations. Psychiatric manifestations are especially difficult to diagnose and manage and may range from depression and anxiety to frank psychosis. 

 

Renal manifestations

Lupus nephritis is a well-known and common complication of SLE. The involvement may range from mild subnephrotic proteinuria to diffuse progressive glomerulonephritis leading to chronic kidney damage. Lupus nephritis usually occurs early in the course of SLE. New-onset hypertension, hematuria, proteinuria, lower extremity edema, and elevation in creatinine shall raise suspicion for lupus nephritis. A biopsy is crucial in staging the lupus nephritis and ruling out other causes. The six classes of lupus nephritis are mentioned in the histopathology section of this article. The treatment of lupus nephritis is dictated by the biopsy findings and prognosis varies for each class with an excellent prognosis for classes I and II, and poor outcomes with classes III and IV. Class V usually carries a favorable prognosis except for complications of nephritis syndrome such as thromboembolism which are common in this class. Other renal manifestations may include thrombotic microangiopathy, interstitial nephritis, lupus vasculopathy, vasculitis, and arteriolosclerosis.

 

 

Pulmonary manifestations

Pleuritis is the most common pulmonary manifestation, and may not always be associated with pleural effusion. Other pulmonary manifestations include exudative pleural effusions, acute lupus pneumonitis with bilateral pulmonary infiltrates, interstitial lung disease which may be nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP), diffuse alveolar hemorrhage associated with capillaritis, pulmonary arterial hypertension, pulmonary embolism (with or without antiphospholipid antibody syndrome) and shrinking lung syndrome.

 

 

Cardiovascular manifestations

SLE may involve any layer of the heart including the pericardium, myocardium, endocardium and even the coronary arteries. Pericarditis associated with exudative pericardial effusions is the most common cardiac manifestation. Cardiac tamponade is rare. Myocarditis is rare and is associated with anti-Ro (SSA) antibodies. Hydroxychloroquine associated cardiomyopathy shall be ruled out and this may occasionally require an endomyocardial biopsy. Valvular abnormalities including Libman-Sacks endocarditis involving the mitral valve are common and may be associated with antiphospholipid antibody syndrome. Patients with SLE are especially at high risk for coronary artery disease, either due to coronary vasculitis or more frequently due to generalized atherosclerosis.

 

 

Gastrointestinal manifestations

Any part of the gastrointestinal tract may be involved in SLE and these manifestations include esophageal dysmotility (especially the upper one-third part of the esophagus), mesenteric vasculitis, lupus enteritis, peritonitis and ascites, protein-losing enteropathy, pancreatitis, and lupoid hepatitis. Further, patients with SLE and antiphospholipid antibody syndrome can develop Budd-Chiari syndrome, mesenteric vessel thrombosis, and hepatic veno-occlusive disease.

 

 

Other manifestations

Eye involvement is common and keratoconjunctivitis sicca is frequently seen in SLE, in presence or absence of secondary Sjogren syndrome. Retinal vasculitis, optic neuritis, uveitis, scleritis, peripheral ulcerative keratitis, and episcleritis are other ocular manifestations. Patients with SLE are also more susceptible to drug-induced ocular damage including steroid-induced glaucoma or cataract and hydroxychloroquine induced maculopathy. Ear involvement may lead to sudden sensorineural hearing loss. Adrenal infarction secondary to adrenal vessel thrombosis may be seen in patients with SLE and antiphospholipid antibody syndrome.

 

Differential Diagnosis

 

SLE is a systemic disease with multi organ involvement, and several other diseases can mimic SLE. The manifestations of SLE are so varied and protean that the disease is often referred to as ‘the great mimicker’.

·        Other autoimmune diseases

o   Rheumatoid arthritis (RA) can present with several extra-articular manifestations in addition to the classic polyarticular inflammatory arthritis and may be difficult to differentiate from SLE. Positive ANA, Anti-Ro, and Anti-La can also be seen in RA although other SLE specific auto antibodies and hypocomplementemia are rare. SLE can be associated with a positive rheumatoid factor, but the Anti-CCP is negative in SLE

o   Drug-induced lupus may be difficult to differentiate from SLE especially due to a significant overlap in the clinical and serological features. Drug-induced lupus is characterized by the resolution of symptoms after drug withdrawal and lack of more severe manifestations although the auto antibodies may remain positive for several years.

o   Adult-onset Still disease characterized by arthralgia, fever, lymphadenopathy, and splenomegaly but no malar rash or other organ manifestations and lacks the SLE specific auto antibodies.

o   Behcet disease presents with aphthous ulcers, uveitis, and arthralgia, but lacks the other systemic and serological features of SLE.

o   Sarcoidosis presents with fever, cough, dyspnea, fatigue, night sweats, rash, and uveitis. It shows non-caseating granuloma on chest radiography and bilateral adenopathy, which is rarely present in SLE.

·        Infections

o   Several viral infections can mimic SLE. Parvovirus B19 infection can cause fever, rash, inflammatory arthritis and cytopenias. ANA and rheumatoid factor have been reported. Hepatitis B and C can be associated with arthralgia/inflammatory arthritis and positive ANA and rheumatoid factor. CMV and EBV viral infections can cause fever, fatigue, cytopenias, and transaminitis. HIV can cause fever, fatigue, oral ulcers, and cytopenias. More specific autoantibodies and systemic manifestations of SLE are absent in these viral infections. Further, positive viral serologies may help make the right diagnosis.

o   Infectious endocarditis characterized by fever, arterial emboli, arthralgia, myalgia, and a heart murmur; may be confused with cardiac manifestations of SLE, but can be differentiated by the absence of specific SLE associated auto antibodies and positive blood cultures.

·        Malignancies

o   Lymphomas especially Non-Hodgkins lymphoma can present with fatigue, weight loss, fever, arthralgia, cytopenia, lymphadenopathy, and a positive ANA. The more specific SLE associated auto antibodies are absent. In elderly patients presenting with lupus-like symptoms, malignancy shall be rule out by cancer screening.

 

 

 

 

 

 

CLASSIC DISTINCTIONS BETWEEN DRUG-INDUCED SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS (DI-SCLE) AND DRUG-INDUCED SYSTEMIC LUPUS ERYTHEMATOSUS (DI-SLE)
Disease	Most commonly associated medications	Cutaneous findings	Systemic findings	Associated autoantibodies
DI-SCLE	Terbinafine Thiazide diuretics (e.g. hydrochlorothiazide) TNF-α inhibitors Proton pump inhibitors (e.g. lansoprazole, pantoprazole, omeprazole) Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil) Anti-epileptics (e.g. carbamazepine)	SCLE	Usually none Sometimes arthralgias	Anti-SSA/Ro
DI-SLE	Hydralazine, procainamide, isoniazid, quinidine, methyldopa, chlorpromazine, minocycline, TNF-α inhibitors*	Usually absent May have malar or photodistributed erythema	Serositis (arthralgia, pleuritis, pericarditis) Fever, weight loss, myalgia Nephritis and CNS disease are not expected	Anti-histone** Anti-dsDNA (reported with TNF-α inhibitors)

* TNF-α inhibitors have been associated with DI-SCLE and DI-SLE (as well as drug-induced discoid lupus erythematosus).

** Anti-histone antibodies are not specific for DI-SLE as they are commonly found in patients with classic SLE, as well as in other autoimmune connective tissue diseases.

 

Complications and co‐morbidities

 

Complications in patients with SLE may occur either from a result of organ damage by the disease or due to the adverse effects of the medications.

Disease process-related complications include but are not limited to accelerated atherosclerosis with a several-fold higher risk of coronary artery disease even in the younger population, end-stage renal disease, and neurological deficits including blindness secondary to neuropsychiatric manifestations. Patients with severe cutaneous lupus especially discoid lupus can suffer from permanent skin damage and alopecia. Anxiety and depression are more common in patients with SLE. Several pregnancy-related complications are well known including fetal loss, pre-eclampsia and eclampsia, congenital heart block and neonatal lupus. 

Medication-induced complications are common and require close monitoring. Long-term corticosteroid use in SLE patients frequently leads to osteoporosis which is under-diagnosed and under-treated leading to osteoporotic fractures. Other complications of long-term use corticosteroid therapy include avascular necrosis, glaucoma, cataract, weight gain and poor control of Diabetes mellitus. High dose corticosteroid use can also be associated with opportunistic infections and acute psychosis. Long term use of hydroxychloroquine may rarely result in maculopathy and retinopathy that is irreversible, and close ophthalmology examinations are recommended. Cyclophosphamide use is associated with a significantly high risk of interstitial cystitis and bladder cancer even after drug discontinuation. SLE patients are immunocompromised and at a significantly high risk of infections which is one of the major causes of morbidity and mortality in SLE.

SLE in childhood

Approximately 15–20% of SLE has its onset in childhood. The clinical picture, course and treatment are similar to the disorder in adults, but on the whole children have more severe disease. Malar rash, mucocutaneous involvement, hematological abnormalities, seizures, renal involvement and fever are more common in children. Enlargement of the liver, spleen and lymph nodes are also more common in childhood cases. The prognosis of patients with renal disease is now better than earlier reports suggested.  Prolonged therapy with high‐dose steroids may increase disease‐related damage; this may be avoided by judicious use of immunosuppressives.

SLE in the elderly

Women of child-bearing age are most often affected; however, approximately 10-20% of cases occur in older patients. Elderly-onset lupus has been defined in various studies as onset of lupus after age 50-65 years. Menopause and changes in cellular immunity with aging may contribute to development of lupus in older adults. Many studies suggest that the clinical and serological features of elderly-onset lupus differ from those of lupus in younger patients. Arthritis, fever, serositis, sicca symptoms, Raynaud's syndrome, lung disease and neuropsychiatric symptoms are more common in patients with elderly-onset lupus, while malar rash, discoid lupus and glomerulonephritis are less common in elderly-onset patients compared with younger lupus patients. Most elderly-onset lupus patients have a positive anti-nuclear antibody test, but the prevalence of anti-double-stranded DNA and hypocomplementaemia is lower in elderly-onset patients than in younger patients. Rheumatoid factor, anti-Ro/Sjögren's syndrome (SS) A and anti-La/SSB are more often positive in elderly-onset patients. The diagnosis of elderly-onset lupus may be delayed for many months: insidious onset, low prevalence and similarity to other more common disorders make the diagnosis of lupus challenging in this population. Treatment of lupus in the elderly may be complicated by co-morbidities and increased risk of toxicities from usual treatments. Optimal management of elderly-onset lupus is empiric because of a lack of randomized controlled studies. However, the approach to treatment is similar regardless of the age of the patient.

SLE in pregnancy

Fertility is normal if renal function is good. Worsening of SLE is uncommon in pregnancy, especially in those on immunosuppressive therapy. Clinical remission for 6 months before conception should indicate an uncomplicated pregnancy and a live birth. Anti-Ro (SSA) and Anti-La (SSB) antibodies can cross the placenta leading to fetal heart block and neonatal lupus presenting with a photosensitive rash, cytopenias, and transaminitis. The risk is 2% with the first pregnancy but increases to 20% if a history of neonatal lupus in past pregnancy. There is a higher risk of complicated pregnancies in SLE in all patients, regardless of whether or not SLE is active. Active lupus nephritis poses the greatest risk to pregnancy outcomes in lupus. Lupus nephritis can be difficult to differentiate from pre-eclampsia although several clinical and laboratory features (low complements, positive Anti-Ds-DNA antibody, normal serum uric acid level, and active urinary sediment) may help. There is a higher risk of premature delivery, fetal loss and perinatal mortality in all patients. The increased risk of fetal death may be because of immune complex deposition on the trophoblast basement membrane, or the transplacental passage of antiphospholipid antibodies. SLE patients with positive antiphospholipid antibodies are at a high risk of spontaneous abortions and fetal loss, pre-eclampsia and maternal thrombosis, but the presence of these antibodies without a previous history of fetal loss or vascular thrombosis is not an indication for treatment. With a history of recurrent fetal loss or vascular thrombosis, treatment with low‐molecular‐weight heparin (LMWH) and low‐dose aspirin may be effective. Patients with more severe SLE manifestations such as pulmonary hypertension, severe cardiovascular disease or cerebrovascular accident are especially at a very high risk of mortality during pregnancy.

 

 

Disease course and prognosis

Despite the advancements in therapeutic options of SLE and a better understanding of the disease process, SLE patients suffer from significant morbidity and carry a high mortality.  Early diagnosis with therapy aimed at preventing organ damage, monitoring and screening patients for cardiovascular disease and infections with early intervention may improve these outcomes.

The course of SLE is very variable. Acute fulminating cases are much less common than subacute cases, which smoulder on for many years. Approximately three-quarters will now survive 15 years. Survival is related to organ involvement and to the frequency of exacerbations. Of those without renal involvement, 84% survive 15 years, compared with 57% whose kidneys are affected. The highest standard mortality rates (SMRs) are seen in female patients, those of younger age, those with SLE duration <1 year. Serological as well as clinical remission is uncommon. Exacerbations are more frequent in the first 5 years of the disease. Pregnancy does not affect long‐term survival. Prolonged survival is associated with an increased risk of atherosclerosis, avascular necrosis and neuropsychiatric dysfunction. In elderly people the presentation is insidious and the clinical course is relatively benign. Renal disease and serological abnormalities are less frequent, and arthritis, with subcutaneous nodules, and pleuropericarditis are more prominent in elderly people.

The better prognosis of the more recent series is a result not only of the administration of corticosteroids, but also of earlier diagnosis, the avoidance of stress and drugs such as sulphonamides, and the control of infections by antibiotics. Persistent causes of death include renal disease, severe lupus disease activity, infection and cardiovascular disease. In an international study, a lower total cancer mortality risk in SLE was observed with an increased mortality from hematological cancers such as non‐Hodgkin lymphoma and lung cancer but a decreased mortality from breast cancer.

 

The spectrum of lupus erythematosus, as envisaged by the late Dr. James N. Gilliam

The left comprises conditions that define cutaneous disease only and it can be seen that chronic cutaneous lupus extends into the systemic disease section. This is also true for Iupus profundus (lupus panniculitis) and subacute cutaneous lupus, whereas acute cutaneous lupus is characteristic for systemic disease only. The bottom shows that immune complex disease dominates systemic disease and cell-mediated immunity (CMI) is predominant in the cutaneous disease manifestations.

 

Evaluation

The diagnosis of SLE can be challenging, and no single clinical feature or lab abnormality can confirm a diagnosis of SLE. SLE is diagnosed based on the constellation of signs, symptoms and appropriate laboratory workup. Imaging and histopathology may play a crucial role as well.

 

Connective tissue laboratory screening tests

The signs and symptoms often associated with connective tissue disease (fatigue, arthralgias, fever, and weight loss) are not specific for autoimmune disease and occur in many other diseases. This makes early and accurate diagnosis difficult. The Mayo Medical Laboratories developed a Connective Tissue Diseases Cascade of tests for the primary care physician to evaluate patients with signs and symptoms compatible with a connective tissue disease in a setting of low disease prevalence. It provides immediate disease-specific, follow-up tests in those patients with presumptive serologic evidence of disease.

 

 

Antinuclear antibody screening

Several auto antibodies have been described in SLE, with varying degrees of sensitivity and specificity. While some auto antibodies may be associated with a certain clinical subset of SLE, others may serve as a marker of disease activity.

Following clinical assessment, if the pretest probability of SLE is high, ANA testing is ordered to support the diagnosis.

ANA is the first test to order when autoimmune connective tissue disease is suspected. ANA tests identify antibodies present in serum that bind to auto antigens present in the nuclei of mammalian cells.

Immunofluorescence assay is considered the gold standard test for ANA, and although other methods of detection such as ELISAs and multiplex assays are widely available, they lack sensitivity. A positive ANA is seen in more than 97% of cases of SLE, although it can also be seen in several other disorders, as well as a significant proportion of the healthy population and have a specificity of only 20%. Hence, a positive ANA does not confirm the diagnosis of SLE, but a negative ANA makes it very less likely. ANA negative SLE has been rarely described, although it is considered to be mostly due to methodical error and those cases have either a positive ANA on immunofluorescence, or have a positive Anti-Ro (SSA) antibody.

A negative result suggests that an autoimmune connective tissue disease is unlikely; a positive result, especially a high titer in a patient with appropriate clinical findings, supports a diagnosis of an autoimmune connective tissue disease.

False-positive test results

Positive results occur in normal blood donors and in patients with chronic liver disease, neoplasms, or active chronic infections. These patients usually have lower titers than those in patients with autoimmune diseases. Any autoantibody test must be interpreted in the context of available clinical information.

 

Specific diagnostic antibody tests

Specific antibody tests should be ordered. The clinical presentation and ANA pattern help to determine the tests that should be ordered.

 

Titers

Specimens are screened by diluting them 1:40 with saline. If there is no nuclear fluorescence at this dilution, the result is reported as “negative.” If there is green fluorescence, the level of ANA present is determined by repeating the test after serially diluting the specimen. ANA results are now reported by many laboratories using the international unit system (e.g., 1 international unit rather than a titer of 160).

 

Patterns

Antibodies to nuclear antigens attach to the various components of the nucleus. The fluorescein-labeled antihuman immunoglobulins are applied to the preparation and react with ANAs that have attached to the nucleus. The preparation is visualized with a fluorescent microscope. Diverse patterns of nuclear fluorescence (homogeneous, peripheral, speckled, or nucleolar) reflect the binding of antibodies to different nuclear components. Nuclear staining patterns were once used as criteria for sub setting, but, with the availability of direct measurements for specific auto antibodies, pattern identification has become less important. The test requires interpretation by visual inspection and consequently lacks a high degree of specificity.

 

One or more ANAs can be detected by fluorescent antibody techniques in over 80% of cases. The incidence depends on the substrate used. Most laboratories now use human cell lines for antibody testing, particularly Hep‐2 cells derived from a human laryngeal cell line. This produces a reduction in the proportion of patients said to be antinuclear factor negative. Five staining patterns of ANAs are demonstrated:

 

Immunofluorescence Patterns of ANA in SLE and Other Connective Tissue Diseases

 

Several patterns of ANAs have been reported including speckled, homogenous, centromere, nucleolar, and peripheral patterns. These staining patterns are produced by separate antibodies, but more than one antibody may be present in a single serum, usually in different titers. No particular antibody is specific for any disease.

With the availability of more specific ANAs targeting specific antigens, the staining patterns of ANAs are not considered significant enough by themselves. The speckled pattern is seen when ANAs are directed against the antigens such as SSA, SSB, Smith, Ribonucleoprotein. The homogenous pattern is associated with ANAs targeted at Histones, Chromatin, and Ds-DNA, while centromere pattern is associated with Anti-centromere antibodies seen in limited systemic sclerosis. 

Homogeneous antinuclear factor (which is the same factor as the LE cell factor) is more than twice as common as the speckled factor, but antinucleolar antibody is only occasionally found. The peripheral factor is present in high titer in more than 50% of cases in the active phase of the disease and is infrequent in other diseases. The so‐called shrunken peripheral pattern is thought to be associated with a poor prognosis and a high incidence of renal disease. It may appear 10–15 days before an exacerbation of the disease and be associated with a fall in serum complement. A high titer (over 1: 64) of antinuclear factor(s) in a patient with the symptoms and signs of a multiple system disorder suggests the possibility of SLE or systemic sclerosis, and almost certainly excludes polyarteritis nodosa or primary cutaneous vasculitis. Any person in apparently good health found to have a high titer of antinuclear factor should be followed up for years, as there is a considerable likelihood of developing LE or systemic sclerosis. On the other hand, a low titer (less than 1: 16), in the absence of clinical symptoms and signs, can be ignored.

A positive ANA shall be followed by testing for more specific auto antibodies to detect the antigen responsible for the positive ANA. It must be noted that frequently, a positive ANA will not be associated with any of the known more specific auto antibodies. There are several possible targets for ANAs, with any peptide synthesized inside the nucleus of the cell serving as a potential antigen, however, so far, only a few have been identified as having clinical relevance. A positive ANA with negative testing for more specific autoantibody testing is less likely to be associated with systemic autoimmune disease. 

 

Circulating Anti-Ds-DNA antibodies are almost always present in active disease and have more than 95% specificity for SLE but are seen in only about 60% to 70% of SLE patients. Anti-Ds-DNA antibodies may occur in the absence of antinuclear factors, although this is very uncommon using Hep‐2 cells. Thus a negative Anti-Ds-DNA does not rule out the diagnosis of SLE. Farr radioimmunoassay test is considered the gold standard test for the detection of Anti-Ds-DNA antibodies and the combination of an elevated titer of Anti-Ds-DNA antibodies and a low serum C3 had a high positive predictive value for the diagnosis of SLE. Of all the Anti-Ds-DNA antibodies detection methods, the Crithidia Luciliae immunofluorescence test (CLIFT) is thought to have the highest specificity for SLE and can be used to confirm the presence of Anti-Ds-DNA antibodies. Changes in Anti-Ds-DNA antibodies titers can correlate with disease activity and can correlate with the development of lupus nephritis and can be useful in monitoring disease activity. Indeed, high (>200 IU/mL) titers of Anti-Ds-DNA antibodies have been shown to be an independent predictor of moderate to severe SLE flares. Low C3 has been shown to be an independent predictor of severe lupus flare. Despite this, a subset of patients with elevated Anti-Ds-DNA antibodies titers and hypocomplementaemia do not demonstrate evidence of clinical disease activity when followed up. The peripheral staining pattern of antinuclear antibody does not correlate with anti-DNA antibodies or with disease activity. Anti-Ds-DNA antibodies can also be seen in drug-induced lupus especially secondary to anti-TNF agents and interferon-alpha. Rarely, low titers of Anti-Ds-DNA antibodies have been reported in rheumatoid arthritis and Sjogren syndrome.

Several other antibodies occur in patients with SLE. Antibodies to soluble cellular antigens include anti-Sm antibody are seen in less than 30% of SLE patients but have 99% specificity for SLE and are included in the ACR criteria and appears to be specific for the disease, occurring particularly in patients with nephritis, neuropsychiatric lupus, renal disease, pulmonary fibrosis, serositis and peripheral neuropathy, although they are not of use in monitoring overall lupus disease activity.  Anti-Smith antibodies in SLE are usually always associated with Anti-U1-RNP antibodies which are seen in up to 30% of SLE patients. Anti-U1-RNP antibodies can also be seen in mixed connective tissue disease (MCTD), although in MCTD, Anti-Smith antibodies are lacking.Anti‐RNP antibodies occur in 25% of patients with SLE. The presence of high titers of anti‐RNP antibodies is characteristic of mixed connective tissue disease. It has been reported that titers correlate with disease activity. Antihistone antibodies are associated with drug‐induced lupus but are of limited value in the diagnosis or clinical assessment of patients with SLE. Anti-Histone antibodies are not specific for drug-induced lupus and can be seen in 50% to 70% of cases of SLE. Anti-Ribosomal-P antibodies are very specific for SLE, although their prevalence in SLE is less than 5%, and they may correlate with neuropsychiatric manifestations of SLE. Anti-Ro (SSA) and Anti-La (SSB) antibodies target ribonucleoprotein particles. Anti-Ro and Anti-La antibodies are seen in up to 90% of cases of Sjogren syndrome but can be seen in SLE as well (Anti-Ro in up to 50% and Anti-La in up to 20%). In SLE, they may be associated with secondary Sjogren syndrome and keratoconjunctivitis sicca, photosensitivity, congenital heart block, and neonatal lupus. Anti‐Ro antibody is also found in SCLE as well as ANA‐negative SLE patients and lupus‐like syndromes with genetic deficiencies of C1q, C2 or C4. Anti‐Ro is an antibody to an RNP derived from RNA polymerase III‐transcribed hY RNAs with a protein component that appears to be the main target. Two different proteins, one of 60 kDa and another of 52 kDa, react with most positive sera. The 60 kDa protein predominates in SLE, the 52 kDa in Sjögren syndrome. Anti‐La, an antibody to another RNP product of RNA polymerase III, is present with anti‐Ro antibody. Anti‐Ro and anti‐La antibodies should be tested in any female patient with SLE, mixed connective tissue disease, Sjogren syndrome or other systemic rheumatology conditions who is planning a pregnancy because of the increased risk of neonatal lupus syndrome. Anti-Centromere and Anti-topoisomerase-I (SCL70) antibodies are seen in systemic sclerosis and rarely in SLE (less than 5%). Anti-Histidyl-tRNA-synthetase antibodies are seen in myositis. Patients with SLE may also have antiphospholipid antibodies (lupus anticoagulants, anti-cardiolipin, and anti-beta-2-glycoprotein I antibodies) and are associated with more thrombotic events and adverse pregnancy-related outcomes.

 

Although several different antibodies occur in the same patient, they fluctuate independently, and the antibody profile may alter over the years. The only characteristic pattern of antibody appears to occur in the LE–erythema multiforme syndrome, in which there is a speckled type of antinuclear factor, a specific precipitating antibody (originally designated SjT but now thought to be anti‐La) and rheumatoid factor. This syndrome is occasionally found in cases of SLE as well as DLE, in which it was originally described. In cases associated with SLE, homogeneous antinuclear factor is also usually present.

Cryoglobulins may be found in 11% of patients. Cryoglobulinaemia may precede the manifestations of SLE by many years. Cold agglutinins occur in 6%.

Inherited deficiencies of the major complement components may occur in SLE, usually as autosomal recessive traits. These include C1, C2 and C4, as well as C5–C9. The most common is homozygous C2 deficiency in which SLE occurs in approximately 30% of patients. Clinically, the lupus‐like syndrome in C2 deficiency shows a low incidence of renal disease, but more cutaneous involvement and arthralgia. Serum antinuclear antibodies and anti‐dsDNA antibodies are often lower in patients with complement deficiency‐associated SLE, compared with idiopathic SLE; however anti‐Ro antibodies appear more frequent. Isolated C1q deficiency has also been reported, and there is an association between C1 esterase inhibitor deficiency and SLE. These patients may be helped by danazol. In addition to a tendency to SLE, patients with homozygous deficiencies of C1, C2 or C4 often have a high risk of recurrent bacterial infections.

 

Major Autoantibodies Associated with SLE

 

Severity of disease

Disease activity is categorized into mild forms, moderate and severe. Mild disease forms are clinically stable with no life‐threatening organ involvement, mainly manifesting as arthritis or mucocutaneous lesions. Patients with moderate disease activity have more serious manifestations, such as cutaneous vasculitis or pericarditis, and severe disease activity is defined as organ‐ or life‐threatening.

 

Predictors

The most useful laboratory tests to predict a SLE flare (particularly lupus nephritis) are an increasing serum level of anti‐DNA antibodies and a fall in complement levels (especially C3). High levels of antibodies to complement C1q are also associated with activity of lupus nephritis.

However, not all patients with these serologic markers have active disease, and these markers do not necessarily predict disease exacerbation.

It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include urinalysis for hematuria and proteinuria, hemoglobin levels, platelet counts, and serum levels of creatinine or albumin.

In any year approximately 50–60% of patients will experience a flare, with 10% of this group experiencing a severe flare. The leading causes of death in the first decade of disease are systemic disease activity, renal failure, infections and thromboembolic events. Subsequently, atherosclerosis and cancer become more common causes of death.

 

Antinuclear antibody‐negative SLE

The concept of ANA‐negative lupus was introduced in 1976 with many patients presenting to dermatologists with cutaneous findings similar to SCLE, positive anti‐Ro antibodies and photosensitivity. Clinically, a non‐scarring malar flush, oral ulceration and photosensitivity, with papulosquamous or annular lesions on the face, trunk and arms, are prominent, but arthritis, serositis, renal disease and hematological involvement are less frequent than expected in SLE. In approximately 5–10% of patients with SLE, antinuclear factor cannot be demonstrated using standard substrates such as rat or mouse liver. This is a problem in less than 2% if Hep‐2 cells are used. These patients frequently have anticytoplasmic antibodies. Over 60% of patients have anti‐Ro antibodies and approximately one‐third have anti‐La antibody (anti‐La rarely occurs without anti‐Ro). Twenty‐five per cent have antibodies to single‐stranded DNA. There is no difference in the histology of the skin between antinuclear‐negative and ‐positive cases. Immunoglobulins and complement are found at the dermal–epidermal junction in 70% of patients, but are rare in the non-light-exposed uninvolved skin. Topical steroid therapy may be helpful, but oral antimalarials and steroids may be required. Approximately 10% of patients eventually become positive for antinuclear factor.

 

Evaluation for systemic lupus erythematosus
ANA, antinuclear antibodies; BUN, blood urea nitrogen; CBC, complete blood count; CRP, C-reactive protein; ds, double-stranded; ESR, erythrocyte sedimentation rate; Sm, Smith.

EVALUATION FOR SYSTEMIC LUPUS ERYTHEMATOSUS

History and review of systems

Physical examination

·       Specific cutaneous lesions    ·       Nonspecific cutaneous lesions    ·       Lymphadenopathy, arthritis

Laboratory tests

·       ANA with profile (anti-dsDNA, -Sm)   ·       Urinalysis   ·       CBC with differential, platelet count   ·       Chemistries (BUN, creatinine)   ·       ESR, CRP   ·       Complement levels (C3, C4)   ·       Anti-phospholipid antibodies

 

Laboratory investigations are frequently necessary to confirm the diagnosis. Complete blood counts, liver function tests and renal function tests including serum creatinine, urinalysis and urine protein quantification (24-hour urine protein, or spot urine protein/creatinine ratio) shall be checked to assess organ involvement. Anemia, of some degree, is found in approximately 75% of patients and is brought about by deficiency of iron, autoimmune hemolytic anemia (AIHA), drug‐induced myelotoxicity or renal failure. The serum iron is usually low and may rise after corticosteroid therapy. A positive Coombs’ test can occur in the absence of hemolytic anemia, and was present in 15% of cases. Although leukopenia occurs in roughly 50% of patients with SLE, more specifically, lymphopenia is a characteristic feature of the condition, leukocytosis may occasionally be found. The platelet count is reduced in approximately 20% of cases (<100 000/mm2) and is usually below 40 000/mm2  in patients presenting with thrombocytopenic purpura. The presence of thrombocytopenia correlates with increased morbidity and cumulative damage. Hyposplenism may occur. The ESR is raised at some time in nearly 90% of patients; C‐reactive protein is usually normal in the absence of infection, however an elevated level may also indicate disease activity so these values should be interpreted in context. Polyclonal gammopathy is commonly observed in patients with SLE and is an indication of an autoimmune reaction. Hypoalbuminaemia is also reported in 30–50% of patients and the measurement of baseline immunoglobulins may help diagnose primary or secondary immune deficiencies associated with SLE and treatment, respectively. IgE antibodies may be raised and may correlate with disease activity including nephritis in SLE. False positive serological tests for syphilis are found in approximately 25% of patients. Thrombosis occurs with the lupus anticoagulant, but occasionally hemorrhage results from other hematological abnormalities such as disseminated intravascular coagulopathy or thrombocytopenia, seen in up to 50% of patients with CAPS. The lupus anticoagulant is one of a number of APAbs that may be found in up to 50% of patients with SLE. As well as thrombosis, central nervous system disease is strongly related to the presence of these antibodies.

Complements C3 and C4 shall be checked in patients with SLE or suspicion of SLE and low complement levels indicate complement consumption and may correlate with disease activity. Joint radiographs may demonstrate peri-articular osteopenia, deformities or subluxation, but rarely show erosions. Chest imaging with CT-scan, cardiac workup including echocardiography (trans-esophageal when suspecting Libman-sacks endocarditis), CNS work up with MRI and/or lumbar puncture shall be pursued if specific organ involvement is suspected. Renal biopsy shall always be performed if suspicion of lupus nephritis. Skin biopsies can be considered especially if atypical presentation.

The LE cell phenomenon, first described by Hargraves et al., is the basis for the LE cell test, which is positive in over 80% of patients. LE cells are neutrophils that have engulfed the nuclear material from degenerative white cells in the presence of an antibody to deoxyribonucleoprotein (the LE cell factor). The phagocytosed nuclear material is homogenous and displaces the neutrophil nucleus to one side. Sometimes, large masses of nuclear material are found extracellularly and, with surrounding leukocytes, form rosettes. LE cells, if present in large numbers, are highly suggestive of SLE, but the occasional LE cell is sometimes demonstrated in other conditions, including chronic DLE.  A positive LE cell test is also a feature of drug‐induced LE; LE cells are demonstrated in most patients with procainamide‐induced lupus. The LE cell test has now been superseded by tests for antinuclear factors and anti‐DNA antibodies.

 

 

Treatment

The goal of treatment in SLE is to prevent organ damage and achieve remission. The choice of treatment is dictated by the organ system/systems involved and the severity of involvement and ranges from minimal treatment (NSAIDs, antimalarials) to intensive treatment (cytotoxic drugs, corticosteroids).Treatment is broadly divided into two: Non-pharmacological and preventive intervention and Pharmacological therapies.

 

 

Non-pharmacological and preventive intervention

Several non-pharmacological measures and other medical interventions are important in the comprehensive management of SLE, in addition to the specific medication regimens.

 

Education of the patient

Patient education, physical and lifestyle measures and emotional support play a central role in the management of SLE. Patients with SLE shall be well educated on the disease pathology and the potential signs and symptoms of organ involvement that may lead to early recognition and intervention which may prevent organ damage. Further, patients shall be educated about the importance of compliance with medications, clinical and laboratory evaluations. Patients with SLE suffer from significant stress related to the disease and complications and have higher rates of anxiety and depression. Stress reduction techniques, good sleep hygiene, exercises, and use of emotional support shall be encouraged and sometimes involvement of psychiatry may help. Dietary recommendations shall include avoiding alfalfa sprouts and echinacea and including a diet rich in vitamin-D.

 

Sun protection

 

Exposure to ultraviolet (UV) light may exacerbate or induce systemic manifestations of SLE. Therefore, all patients with SLE should avoid exposure to direct or reflected sunlight and other sources of UV light, by timing their activities appropriately. Patients should be advised to wear broad‐brimmed hats, light-weight loose-fitting dark clothing covering the maximum portion of the body and using broad-spectrum (UV-A and UV-B) sunscreens with sun protection factor (SPF) ≥55as patients with photosensitivity may develop fatigue and disease flares following UV light exposure. Sunscreen with avobenzone (blocks UVA‐1), titanium dioxide or zinc oxide (block UVB and UVA‐1) are also recommended to block longer UVA wavelengths.

 

 

Smoking cessation

Smoking has been associated with more active disease. Smoking increases the already higher risk of accelerated atherosclerosis in those with SLE. There is also evidence to suggest that smoking diminishes the efficacy of hydroxychloroquine.

 

Immunizations

Patients should receive appropriate immunisations prior to the institution of corticosteroids (>10mg/day) or immunosuppressive therapies.

 

Vitamin D

 

The majority of patients with SLE have low serum levels of 25‐hydroxyvitamin D (calcifediol), probably due to avoidance of sun exposure and/or use of sunscreen products. So it is important to monitor serum 25‐hydroxy vitamin D at baseline and to treat appropriately to ensure that recommended minimum serum levels of 30 ng/mL (75 mmol/L) are achieved. To correct vitamin D deficiency, 1000 IU per day of oral vitamin D3 (cholecalciferol) is recommended as this is more effective than vitamin D2. Patients with SLE are advised to take oral vitamin D3 (cholecalciferol) 1000 IU daily PO to supplement dietary vitamin D. This measure is important to help counter the increased risk of osteoporosis associated with corticosteroid use.

 

Treating comorbid conditions

Cardiovascular risk factors and cardiovascular disease, pulmonary hypertension and antiphospholipid syndrome, as well as osteopenia or osteoporosis, are among the comorbid conditions that can be treated and for which screening tests need to be performed. Modifiable risk factors, such as hypertension and hyperlipidaemia, should be identified and concurrently managed.

 

Pharmacological therapies

The choice of therapy for SLE is highly individualized and depends on the predominant symptoms, organ involvement, response to previous therapy, and disease activity and severity. It is important to assess the patient's progress by general well‐being and relief of symptoms rather than by strict attention to laboratory abnormalities. The ESR and DNA antibodies are variable and a poor guide to the adequacy of therapy; the titer of ANAs often persists unchanged despite clinical remission. As mentioned previously, anti‐dsDNA antibody and serum complement levels may be helpful in predicting exacerbations. Despite this, a subset of patients with elevated anti‐dsDNA titers and hypocomplementaemia do not demonstrate evidence of clinical disease activity when followed up. Furthermore, although there is some evidence that a return of serological abnormalities to normal is followed by a prolonged remission, exceptions indicate that serological data alone cannot be used as a basis of therapy.

The use of the antimalarials chloroquine or hydroxychloroquine should also be encouraged, not only in the management of mild disease but in all disease subtypes because they prevent lupus flares and increase the long‐term survival of patients. Antimalarials have also been found to work synergistically with mycophenolate mofetil for the treatment of membraneous nephritis and are recommended by both the ACR and the European League against Rheumatism (EULAR) guidelines for patients with lupus nephritis. Additionally, they have a modest effect on lipid profile, cardiovascular disease and thrombotic risk. Hydroxychloroquine in particular has been found to decrease lupus activity in pregnancy without harming the baby. Quinacrine is contraindicated in pregnancy as it crosses the placenta.

Corticosteroids are useful, but dosage depends on the degree of organ involvement and disease severity. Low‐dose oral prednisolone (0.1–0.2 mg/kg) may be useful in patients with mild SLE and musculoskeletal manifestations resistant to other therapies. High doses of oral prednisolone (1–1.5 mg/kg) or IV methylprednisolone 1 g daily for 3 days (pulse therapy) may be useful for severe disease with major organ involvement (e.g. renal, systemic vasculitis or neurological involvement). Once the condition appears to be under control, the dosage may be reduced until a maintenance dose is reached, ideally <6 mg, as the Hopkins lupus cohort have demonstrated that doses of greater than 6 mg increase the risk of organ damage by more than 50%. A single daily dose given in the morning produces fewer side effects and does not impair the therapeutic response. Some fulminating cases have been treated with massive doses of steroids but the advantages of such therapy rarely outweigh the risks, and complications such as steroid‐induced psychosis may occur, which may be difficult to distinguish from neuropsychiatric SLE. Steroid myopathy also can occur with high‐dose steroids, but usually improves with tapering of steroids and physical therapy.

For more severe disease, immunosuppressive drugs are used to minimize the risk of damage and to act as steroid‐sparing agents. When considering the choice of immunosuppressant, as well as disease severity, the long‐term risk of malignancy must be considered. Cyclophosphamide has been associated with bladder cancer, myelodsplastic syndromes, hematological malignancies, cervical atypia and skin cancers. Mesna may reduce urotoxic side effects, and monthly IV therapy is rarely complicated by bladder injury. Azathioprine is associated with the development of lymphomas and an increased risk of human papillomavirus‐related premalignant and malignant lesions. Methotrexate is teratogenic and contraindicated in women within 3 months of planned conception. Additionally, mycophenolate is contraindicated in pregnancy and in patients wishing to become pregnant; a transition from mycophenolate mofetil to azathioprine should be made in the preceding months because of the teratogenic risk.

For induction therapy in lupus nephritis, pulsed IV cyclophosphamide is preferred to oral cyclophosphamide due to reduced toxicity, particularly bladder injury, and may be followed by mycophenolate mofetil or azathioprine (the former may be more efficacious as maintenance therapy). However, mycophenolate mofetil may also be used as an alternative for induction treatment of mild to moderate lupus nephritis with similar efficacy to cyclophosphamide.

Because of its slower onset of action, azathioprine is often used as a steroid‐sparing agent and as a maintenance drug following the control of more acute SLE. It has also been reported to be effective in severe cutaneous disease and in the treatment of chronic active hepatitis complicating lupus. Azathioprine may be used in pregnancy as there have been no reports of teratogenicity.

Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid (MPA), which is a non‐competitive reversible inhibitor of inosine‐5'‐monophosphate dehydrogenase, a necessary enzyme in the de novo pathway of purine synthesis. This de novo synthesis pathway is uniquely essential to activated lymphocytes. Inhibition of both T‐ and B‐lymphocyte proliferation, inhibition of antibody formation and prevention of leukocyte migration by MPA activity is the result. For patients with significant gastrointestinal side effects, which can occur in up to one‐third of patients, titrating the dose from 500 mg twice daily to 1–1.5 g twice daily with weekly increases may be useful. In those who are still intolerant, switching to sustained‐release MPA may be better tolerated and can smooth out blood levels.

Methotrexate may be a useful adjunct in patients with mild to moderate SLE and recalcitrant mucocutaneous lesions and musculosketal symptoms.  Following the failure of antimalarials in patients with predominant skin disease, methotrexate at doses of 7.5–15 mg is an effective and quick acting therapy. Patients should be monitored regularly for a decline in renal function, and their full blood picture and liver function tests followed. In addition, meticulous contraception is mandatory when used in women at risk of pregnancy.

Intravenous immunoglobulin may also be a useful adjunct in resistant skin disease. A trial of 400 mg/kg/day over 5 days led to a partial or complete remission of skin disease in 63% (10/16) of patients in one center. Cyclosporine has been used in resistant cases and for non‐renal lupus at a dose of 3-5mg/kg. Plasmapheresis may be useful in managing life‐threatening complications such as fulminating vasculitis or central nervous system disease or for renal disease that is resistant to corticosteroid or cytotoxic therapy. Although UV light may exacerbate SLE, UVA‐1 (340–400 mm) has been shown to have modest effects on cutaneous lesions. A low‐fat, high‐marine‐oil diet (eicosapentaenoic acid: Maxepa 20 g/day) modified disease activity in 27 patients in a placebo‐controlled trial over 3 months.

For patients with lupus non‐specific skin eruptions dapsone may be useful for the treatment of urticarial lesions and bullous eruptions.

An increasing understanding of the pathophysiology of lupus and the recognition of the multifaceted role that B cells play in lupus, has led to the development of novel biological drugs to treat lupus, including rituximab (monoclonal antibody to CD20) and belimumab (a B‐lymphocyte stimulator inhibitor). Both the ACR and EULAR support the use of rituximab in the treatment of refractory nephritis. In a post hoc analysis of two phase III trials (BLISS‐52 and BLISS‐76), belimumab has also been shown to improve overall SLE activity, particularly mucocutaneous and musculoskeletal activity at weeks 52 and 76, respectively. Other biological therapies that may be useful in SLE include the monoclonal antibody tocilizumab, an IL‐6 receptor inhibitor, and the T‐cell inhibitor abatacept, a fusion protein of the T‐lymphocyte‐associated antigen 4 and modified Fc portion of human immunoglobulin. It is now known that an increased serum concentration of IFN‐α is associated with a distinct IFN signature in the peripheral blood and increased disease activity. In view of this, there are ongoing studies investigating inhibitors of this pathway including the monoclonal antibodies that target IFN‐α, sifalimumab and rontalizumab.

 

Cutaneous manifestations 

 

For skin disease alone, topical therapy is an appropriate first line treatment for individual lesions. Potency depends on the site, but generally potent fluorinated steroids should only be used for short periods on very inflammatory lesions on the face because of the risk of atrophy and telangiectasia. Alternatively, the calcineurin inhibitors tacrolimus and pimecrolimus may be equally efficacious. Intralesional triamcinolone acetonide (2.5–5 mg/mL) may also be useful for individual lesions, particularly on the scalp. For patients with extensive or resistant cutaneous disease, antimalarials are used. Hydroxychloroquine is the drug of choice for most cutaneous manifestations and very efficacious. Quinacrine can be used if intolerance or adverse effects of hydroxychloroquine. Methotrexate can be used if no response to hydroxychloroquine. For severe or resistant disease, systemic corticosteroids, mycophenolate mofetil, and belimumab can be considered. Other alternatives include thalidomide, cyclophosphamide, IVIG and rituximab.

For patients with lupus non‐specific skin eruptions dapsone may be useful for the treatment of urticarial lesions and bullous eruptions.

 

Musculoskeletal manifestations

Hydroxychloroquine is the initial drug of choice for lupus arthritis. If no response, methotrexate or leflunomide can be considered. Belimumab and rituximab can be considered in refractory cases. Symptomatic therapy for joint pain using non‐steroidal anti‐inflammatory drugs is valuable.

 

 

Hematological manifestations:

 

Drug-induced cytopenias shall be excluded. Mild cytopenias usually require no treatment. For moderate to severe cytopenias, corticosteroids are the mainstay of treatment, and azathioprine or cyclosporine-A can be used as a steroid-sparing agent. Severe refractory cytopenias may require intravenous pulse dose steroids, mycophenolate mofetil, rituximab, cyclophosphamide, plasmapheresis, Recombinant G-CSF or splenectomy.

 

 

Cardiopulmonary manifestations

Serositis usually responds to NSAIDs or moderate to high dose oral corticosteroids. Hydroxychloroquine and methotrexate can be considered as steroid-sparing agents. Acute lupus pneumonitis requires high dose IV pulse corticosteroids while plasmaphereses and/or cyclophosphamide may be needed if diffuse alveolar hemorrhage present. Interstitial lung disease can e managed by low to moderate dose corticosteroids with immunosuppressive agents such as azathioprine or mycophenolate mofetil. Pulmonary arterial hypertension requires vasodilator therapy, while thrombotic complications such as pulmonary embolism require anticoagulation. High-dose corticosteroids are required for the management of myocarditis and coronary arteritis.

 

 

CNS manifestations

Accurate diagnosis, and ruling out other potential causes is critical before initiating treatment for neuropsychiatric manifestations of SLE. High dose corticosteroids with immunosuppressive agents such as cyclophosphamide, azathioprine, or rituximab are used for inflammation-related neuropsychiatric manifestations such as optic neuritis, aseptic meningitis, demyelinating disease, etc. Lifelong warfarin is indicated in cases of thromboembolic CNS events associated with antiphospholipid antibody syndrome. High dose corticosteroids can be used in cognitive impairment, although there is no robust data on this.

 

Renal manifestations

Lupus nephritis (LN) shall be confirmed with a biopsy which serves not only to confirm the diagnosis, but also to rule out other causes, and helps to classify the disease. Class I and II LN shall be treated with the Renin-angiotensin-aldosterone system blockade. Immunosuppression with high dose corticosteroids followed by azathioprine is indicated only if proteinuria more than 1 gram/day. Membranous LN (Class V) shall also be treated with the Renin-angiotensin-aldosterone system blockade. If proteinuria of more than 1 gram/day is present (which is frequent in Class V LN), induction therapy with high dose corticosteroids and azathioprine (mild disease) or cyclosporine A/mycophenolate mofetil/IV cyclophosphamide (moderate to severe disease) followed by maintenance therapy with azathioprine, mycophenolate mofetil or cyclosporine-A shall be used. Corticosteroids shall be gradually tapered during maintenance therapy. Proliferative LN (Class III/IV) requires more aggressive therapy. Induction therapy is with IV pulse dose methylprednisolone followed by high dose oral steroids in combination with mycophenolate mofetil, IV cyclophosphamide or azathioprine (only in mild disease). Maintenance therapy with mycophenolate mofetil or azathioprine shall be continued for at least 3 years. IV pulse cyclophosphamide for 1 year can be considered as maintenance therapy for severe disease. Lupus nephritis patients need very close monitoring of their renal function and proteinuria in addition to other SLE disease activity markers. Flares and incomplete remission are common. Renal replacement therapy and transplant may be needed in some patients.

 

 

Pregnancy manifestations

Pregnancy shall be considered only if the disease was quiescent at the time of and 6 months prior due to an increased risk of flares otherwise. Contraception if needed shall be used until then and shall be progesterone-only contraception.

Hydroxychloroquine is considered safe in pregnancy, has been associated with a significant reduction in flares and disease activity, and may decrease the risk of recurrent cardiac neonatal lupus and heart block in mothers with anti‐Ro antibodies and shall be continued through pregnancy. Azathioprine and low dose corticosteroids can be used for mild manifestations. Oral corticosteroids are relatively safe in the treatment of lupus during pregnancy. The dosage of corticosteroids should be temporarily increased at the time of delivery and postpartum. Corticosteroids do not appear to cause impairment of growth or malformation in the fetus, and, as in women who are not pregnant, an increased risk of maternal hypertension and diabetes, but high-dose steroids during early pregnancy can cause cleft palate. Babies of mothers with untreated SLE are usually smaller than expected, and corticosteroids may assist growth of the fetus in utero. Prednisolone is recommended, as less than 10% of the dose will cross the maternal–fetal membranes. If the patient is on azathioprine, this should be continued as there is no evidence of an increase in the malformation rate. However, mycophenolate mofetil is contraindicated and it is recommended that women transfer to an alternate immunosuppression prior to conception, such as azathioprine.

Other immunosuppressive agents including methotrexate, leflunomide, and cyclophosphamide are teratogenic and contraindicated in pregnancy. Rituximab and belimumab shall also be avoided during pregnancy. Patients with antiphospholipid antibody syndrome shall be transitioned from warfarin to low-molecular-weight heparin and aspirin before pregnancy. For females with positive Anti-Ro or Anti-La antibodies with a history of neonatal lupus in previous pregnancy close fetal heart monitoring with weekly or alternate-weekly fetal echocardiography is recommended during the second trimester. First or second-degree heart block shall be promptly treated with dexamethasone, although prophylaxis with dexamethasone is not recommended. A complete heart block is irreversible and requires a permanent pacemaker in the infant.

 

Although traditionally it was recommended that estrogen‐containing contraceptives, even at low dosage, should be avoided in women with SLE, clinical trials have now shown that the use of oral contraceptives in women with stable disease does not increase the risk of flare. However, estrogen‐containing contraceptives should be avoided in lupus patients with positive anticardiolipin ± lupus anticoagulant. Conversely, it is recommended that patients with SLE wishing to commence this method of contraception should be screened for these antibodies. If mechanical methods of contraception or intrauterine devices are not possible, then progesterone‐only contraceptive Depo‐Provera is an alternative option, although its use for more than 2 years may increase the risk of osteoporosis.

In patients taking azathioprine no adverse events have been reported in breastfed infants exposed to the drug, but a small study showed that the majority of azathioprine is excreted within 4 h of ingestion, prompting the recommendation that feeds be given at least 4 h post maternal dose. Breastfeeding is probably safe if the patient is on aspirin, low‐dose steroids or hydroxychloroquine, but should probably be avoided if other immunosuppressives are used.

 

Other management considerations

Hydroxychloroquine shall be used in all patients with SLE given its benefits beyond just the management of active manifestations including anti-thrombotic properties, and preventing flares. Patients on hydroxychloroquine will require regular ophthalmology exams to monitor for the rare but irreversible maculopathy associated with this drug. Corticosteroids are very frequently used in SLE, with many patients unable to completely taper them. Long term adverse effects of corticosteroids shall be considered and monitored for including osteoporosis, glaucoma, cataract, and avascular necrosis. Patients on high dose corticosteroids will also need antibiotic prophylaxis to prevent infections. Most immunosuppressive agents used in SLE have several potential adverse effects ranging from cytopenias and hepatotoxicity with most to an increased risk of urinary bladder cancer with cyclophosphamide. These patients shall be appropriately and closely monitored for adverse effects of these agents.

 

Enhancing Healthcare Team Outcomes

 

Lupus is a chronic inflammatory disorder with no cure. It can affect many organs and leads to a very poor quality of life without appropriate management. Premature death is common from a variety of causes. To reduce morbidity and mortality, an inter professional team should educate and manage patients with SLE.

The primary care provider and nurse practitioner should educate the patient on avoiding triggers that cause flare-ups. In addition, the patient should be told to avoid UV light and minimize exposure to the sun. When going out, appropriate garments, sunglasses, and a wide brim hat are recommended. The dietitian should educate the patient on the importance of a low-fat diet to prevent hyperlipidemia. In addition, because patients with lupus are told to avoid the sun, vitamin D supplements are recommended. The physical therapist should educate the patient on the importance of exercise. The pharmacist should educate the patient on the importance of medication compliance and avoiding smoking. The nurse practitioner should counsel the patient on family planning and contraception. Many drugs used to treat are teratogenic, and thus, contraception is highly recommended. Multispecialty involvement is often needed in managing and monitoring SLE. While the involvement of a rheumatologist is crucial, other specialties including dermatology, cardiology, neurology, pulmonology, ophthalmology, nephrology, gastroenterology and gynecology may be needed. Close communication between the providers and the patient and family, and consideration of patient preferences while deciding therapy is strongly recommended.