Systemic sclerosis

 

OVERVIEW

Systemic sclerosis (SSc, scleroderma) is an uncommon autoimmune connective tissue disease of unknown etiology. The clinical hallmark of the disease is cutaneous sclerosis. Ninety-five percent of SSc patients present with cutaneous sclerosis early in their course and therefore it is important for dermatologists to be able to recognize these skin changes. The cutaneous sclerosis of SSc is unique in that it is symmetric, affects the hands at a minimum, and may generalize. It is also accompanied by Raynaud phenomenon. The pathogenesis is not well understood, but involves interactions with the vasculature, the immune system (with characteristic autoantibodies), and the extracellular matrix. Internal organ involvement is commonly observed. Pulmonary involvement is the most common cause of death, and screening for lung disease is important. Treatment is focused primarily on managing associated internal organ involvement. Therapeutic options for the cutaneous sclerosis remain limited.

 

Salient features

·        Scleroderma (systemic sclerosis [SSc]) is a multi systemic autoimmune disease characterized by vasculopathy, inflammation, and fibrosis of the skin and many other organs.

·        Differential diagnosis of SSc includes severe forms of localized scleroderma, as well as many other scleroderma-like conditions.

·        Raynaud phenomenon, circulating auto antibodies, and skin sclerosis are almost always present and are important for the early diagnosis.

·        Patients with SSc are classified into 2 major subtypes depending on the extent of skin sclerosis (diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis).

·        Patients with an overlap syndrome, including mixed connective tissue disease, are characterized by additional clinical features of other rheumatic diseases.

·        Involvement of internal organs (digestive tract, lung, kidney, and heart) can lead to severe dysfunction and determines the prognosis.

·        The heterogeneity and clinical course of SSc and SSc overlap syndromes require the urgent need of interdisciplinary collaborations and regular follow up visits.

·        Although the disease is still not curable, there have been substantial advances in developing new therapeutic approaches and treating organ-based complications based on a better understanding of the pathophysiology.

 

Introduction

Systemic sclerosisis a multisystem autoimmune connective tissue disease of unknown aetiology characterized by vascular abnormalities, connective tissue sclerosis and atrophy, and auto antibodies that affect the skin, blood vessels and internal organs. The name systemic sclerosis is meant to convey the systemic nature of the disease, which has two major clinical subtypes: cutaneous limited and cutaneous diffuse. Limited SSc is characterized by fibrotic skin changes that are limited to the fingers, hands and face. In diffuse SSc, generalized cutaneous sclerosis is seen that usually begins in the fingers and hands but eventually extends to the forearms, arms, face, trunk, and lower extremities.

 

Epidemiology

Systemic sclerosis has a reported incidence of 2 to 12 cases per million people per year.

 

Age

 

Although SSc can occur in children and the elderly, onset is typically between the ages of 30 and 50 years. 

Approximately 1.5% of SSc patients have one or more affected first-degree relatives, representing a 10- to 15-fold higher risk of SSc in family members than in the general population. SSc is associated with significant mortality, with an overall 10-year survival of ~70%. Clinical features that predict a worse prognosis include male sex, older age at diagnosis, internal organ involvement (especially pulmonary) at time of diagnosis, skin fibrosis affecting the trunk, and elevated ESR.

Sex

 

Overall, there is a 4: 1 female predominance of SSc. This predominance is most marked in premenopausal women, leading to the suggestion that it is hormone dependent. There is a less marked female predominance in diffuse SSc. Approximately half of cases of male SSc fall into the diffuse subset. Males are thus more likely to have diffuse disease and interstitial lung disease and have a higher mortality.

 

Diagnostic criteria and classification

In 1980 the American College of Rheumatology (ACR) published preliminary criteria for the classification of SSc, which were updated in 2013.

In 1980, the criteria for diagnosis have been established by the Subcommittee for Scleroderma Criteria of the ARA and are generally accepted. Patients should have either:

1 Symmetric cutaneous sclerosis i.e. scleroderma proximal to the digits (metacarpophalangeal (MCP) or metatarsophalangeal (MTP) joints) – affecting limbs, face, neck or trunk—this is the single major criterion; or

2 At least two minor criteria, consisting of:

(a) Sclerodactyly

(b) Digital pitted scarring of fingertips or loss of substance of the finger pad

(c) Bilateral basal pulmonary fibrosis.

 

In 2013, American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) updated the above criteria for the classification of systemic sclerosis (SSc).

The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of ≥9 are classified as having definite SSc.

ACR/EULAR CRITERIA FOR THE CLASSIFICATION OF SYSTEMIC SCLEROSIS
Item	Sub-item	Weight/score
Skin thickening of the fingers of both hands extending proximal to the MCP joints (sufficient criterion)	–	9
Skin thickening of the fingers	Puffy fingers - or - Sclerodactyly	2 4
Fingertip lesion	Digital tip ulcers - or - Pitting scars	2 3
Telangiectasias	–	2
Abnormal nail-fold capillaries	–	2
Pulmonary arterial hypertension - or - Interstitial lung disease		2 2
Raynaud phenomenon	–	3
SSc-related autoantibodies	Anti-centromere Anti-topoisomerase I Anti-RNA polymerase III	3

 

In the 2013 classification scheme for SSc, the sole major criterion – skin thickening of the fingers on both hands extending proximal to the metacarpophalangeal (MCP) joints – leads to a diagnosis of definite SSc (9 points). If the patient does not meet this criterion, seven other minor criteria may be used to reach a diagnosis of SSc. These 2013 criteria have greater sensitivity (91%) and specificity (92%) compared to older criteria.

 

Based on the extent of skin sclerosis, there are two major clinical subtypes: limited (ISSc) and diffuse (dSSc). ISSc patients comprise 60%; patients are usually female; older than those with dSSc. Limited SSc is characterized by sclerosis/induration of skin that is limited to the extremities distal to the knee and elbow joints, including face and neck (acrosclerosis) and have a long pre-existing history of RP. This variant of SSc-subset often (50%–70%) presents with anticentromere-antibodies (ACA) and is frequently associated with isolated PAH. Systemic involvement may not appear for years; patients usually die of other causes. The traditional acronym CREST syndrome describes the clinical features in a subset of patients with lcSSc: calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly and telangiectasia. However, because not every patient has all five features, the term lcSSc is favoured.

When the skin disease involves the both distal and proximal portions of the extremities plus the trunk, face and neck, it is considered diffuse cutaneous disease i.e. if there is proximal extension above the knees or elbows or involvement of the anterior chest or abdominal skin then cases are diffuse (dSSc). Sclerosis usually starts in the fingers, hands and face but spread rapidly to involve the forearms, arms, and trunk and lower extremities. Diffuse cutaneous SSc (dcSSc) is defined as a progressive form with an early onset of RP, usually within 1 year before onset of skin thickening, showing very frequently, anti-Scl 70 (antitopoisomerase-I) (33%) or anti-RNAPIII antibodies. Furthermore, there is a higher propensity to develop PF, cardiac involvement, and SRC, a greater overall mortality and a tendency to maximal activity of the disease within the first 3 years and then often greater stability and even improvement of the skin sclerosis.

While both subtypes represent systemic diseases, there are variable degrees of internal organ involvement. Typically, diffuse SSc is associated with early internal organ involvement (within 5 years of disease onset) and a worse prognosis, whereas patients with limited SSc tend to develop internal involvement later in the disease course, occasionally after decades and have a better prognosis.

Patients with features of scleroderma together with those of another autoimmune connective tissue disease are combined such as dermatomyositis, Sjögren's syndrome, systemic lupus erythematosus, vasculitis, or polyarthritis; are designated overlap syndromes. These cases represent up to one‐fifth of many SScpatients. These patients present mostly high titters of anti-U1-RNP-, anti-nRNP-, antifibrillarin-, or anti-PmScl-antibodies.

A very small proportion of cases (1.5%) develop vascular (RP and/or PAH), immunologic (most commonly anti-centromere antibodies), characteristic internal organ involvement and abnormal nail-fold capillaries but no cutaneous sclerosis. This clinical presentation is referred to as systemic sclerosis sine scleroderma (ssSSc) and it behaves similarly to lcSSc.

 

 

 

Typical features of limited and diffuse forms of systemic sclerosis

Limited SSc	Diffuse SSc
RP for many years (even decades) before the onset of skin fibrosis   Most are ACA+ associated with the development of PAH	Short interval (<1–2 years) of RP before onset of skin fibrosis   Many are ATA+ associated with lung fibrosis RNAP+ in 25% associated with SRC
Skin sclerosis: distal to the elbow and knee, can involve face and neck	Skin sclerosis: both proximal and distal to the elbow and knee, trunk, face and neck
Late onset of PAH	Early onset of major internal organ involvement
Slower onset and progression	Rapid onset and progression
Capillary ectasias in nail fold (mega-capillaries) Peak skin sclerosis score (MRSS) <14	Capillary “drop-out” in the nail fold   Peak skin sclerosis score (MRSS) >14
Gastrointestinal disease (especially GORD) is universal	Skin disease may plateau and improve in years 2 and 3
Telangiectasia   Low‐risk scleroderma renal crisis and cardiac disease	Tendon friction rubs associated with SRC High‐risk scleroderma renal crisis (SRC) and cardiac disease
Digital ulcers, calcinosis	Digital ulcers

 

ACA, anticentromere antibody; ATA, antitopoisomerase; dSSc, diffuse systemic sclerosis; GORD, gastro‐oesophageal reflux disease; MRSS, modified Rodnan skin score; PAH, pulmonary arterial hypertension; RNAP, anti‐RNA polymerase.

 

Pathogenesis

The pathogenesis of SSc is unknown. Key pathogenic abnormalities in the skin and internal organs are vascular dysfunction, immune activation with autoantibody production, and tissue sclerosis characterized by deposition of collagen and other extracellular matrix proteins.

Overall scheme illustrating a current understanding of SSc pathogenesis

Hypothetical sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in tissue fibrosis.

 

 

 

 

The fibroblast activation and fibrosis underlying systemic sclerosis are induced by vascular injury and endothelial activation, leading to an uncontrolled inflammatory reaction.

Step 1: the vascular response to injury consists of endothelial activation; production of endothelin 1 and chemokines; increased expression of adhesion molecules; and platelet activation.

Step 2: in response to chemokines and adhesion receptors, several types of inflammatory cells are recruited. Activated type 2 T helper (T_H2) cells secrete TGFβ and IL-13; B cells produce auto antibodies and IL-6; macrophages release transforming growth factor-β (TGF); and dendritic cells secrete interferon-α (IFN) and platelet factor 4 (PF4).

Step 3: resident fibroblasts, activated by this cytokine ‘cocktail’, generate reactive oxygen species (ROS) and undergo differentiation into myofibroblasts, which are responsible for the excessive extracellular matrix (ECM) production. Activation of Toll-like receptor 4 (TLR4) on immune cells and myofibroblasts by the ECM further exacerbates this reaction.

CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor.

 

Vascular dysregulation

Vascular dysfunction in the form of impaired angiogenesis is an early event in the pathogenesis of SSc. The blood vessels affected range from the smallest capillaries within the proximal nail fold to the large pulmonary arteries. Endothelial cell injury occurs early (before fibrosis is evident), based on changes seen by electron microscopy, such as perivascular leak and oedema. Endothelial cell activation leads to increased expression of adhesion molecules and binding of circulating inflammatory cells. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are elevated in the dermis in SSc.

Surrounding smooth muscle cells are also affected and have altered production of and responsiveness to vasoconstrictive (e.g. cold, endothelin) and vasodilatory (e.g. nitric oxide) factors. Structural abnormalities such as intimal proliferation leading to luminal occlusion develop and lead to hypoxia which induces synthesis of profibrotic cytokines, fibroblast activation and collagen production. Raynaud’s phenomenon and digital ulcers are caused by reversible vasospasm as well as irreversible arterial damage with intimal proliferation and luminal obstruction. Scleroderma renal crisis and pulmonary artery hypertension are manifestations of large vessel dysregulation.

 

Immune dysregulation

Patients with SSc produce specific auto antibodies in particular anti-centromere, anti-topoisomerase I [Scl-70] and anti-RNA polymerase III and are useful for diagnostic and prognostic purposes. These three auto antibodies bind tissues of interest in SSc, as do anti-U3RNP (antifibrillarin), anti-Th/To, anti-U1RNP, anti-PM-Scl, and anti-Ku auto antibodies. The latter are rather rare and play a role in overlap syndromes.

Evidence of a direct pathogenic role for these auto antibodies includes complexes containing topoisomerase I autoantibody which, when bound to the surface of fibroblasts, have been found to stimulate monocyte adhesion and activation. In addition, anti-endothelial cell antibodies from SSc patient sera can trigger endothelial cell apoptosis. One group described stimulatory auto antibodies against the platelet-derived growth factor (PDGF) receptor in SSc sera, which induced reactive oxygen species and expression of type I collagen by normal human fibroblasts. However, two subsequent studies were unable to confirm these findings.

Lymphocytic infiltrates, composed of both T and B cells, have been observed in the skin and lungs of SSc patients before the development of fibrosis. Oligoclonal T-cell expansion has been identified in lesional skin, indicating an antigen-driven response, and T cells demonstrate a Th2-predominant profile with increased production of profibrotic cytokines such as interleukin (IL)-4 and IL-13. SSc patients also have expansion of naive B cells and chronic activation, but a decreased number, of memory B cells.

 

More recently, Th17 cells and IL-17 have been implicated in SSc, as have the innate immune system and types I (α,β) and II (γ) interferons. For example, elevated numbers of plasmacytoid dendritic cells have been observed in the blood and skin of SSc patients. In SSc, circulating levels of the chemokine CXCL4 are found to be significantly elevated, and the CXCL4 levels correlates with the presence and progression of pulmonary disease. So, it is proposed that CXCL4 is a biomarker to monitor for the development of lung disease in SSc patients.

 

Extracellular matrix dysregulation

 

Sclerosis represents the final common pathway for tissue damage in SSc. There is excessive deposition of collagens, proteoglycans, fibronectin, fibrillins and adhesion molecules (e.g. β₁-integrins), which sequester cytokines and growth factors. Attention has focused on transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). The latter is induced by TGF-β and may be responsible for maintenance of collagen synthesis.

 

Given the complex extracellular matrix changes seen in SSc, both the fibroblast and the myofibroblast have been a focus of investigation. There is evidence suggesting an inherent defect, an autocrine loop, or a hypersensitivity to growth factors in SSc fibroblasts. Alternatively, SSc fibroblasts may have a normal phenotype, but instead find themselves in an abnormal microenvironment with enhanced growth factors or ischemic mediators. The accumulation of collagen in SSc seems to be primarily the result of increased synthesis, rather than decreased degradation.

 

Genetic susceptibility loci that may increase the risk of developing systemic sclerosis include a region on chromosome 15q (which contains the fibrillin-1 gene) as well as polymorphisms in STAT4 and the promotor for CTGF. CTGF, connective tissue growth factor; EC, endothelial cell; ECM, extracellular matrix; IFN, interferon; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

 

 

Clinical features

 

The uncontrolled fibrosis and scaring of the skin and internal organs in systemic sclerosis leads to severe and sometimes life-threatening complications. The average frequency of the specific complications is indicated in parentheses. PAH, pulmonary arterial hypertension.

 

 

History

 

The majority of cases have onset in the adult years and many patients describe Raynaud phenomenon as the first symptom. Raynaud’s phenomenon is characterized by episodic vasospasm of the digital arteries and arterioles resulting in white, blue and red discoloration of one or more fingers or toes, the thumb is spared, triggered by exposure to cold or emotional stress both in winter and summer. Occasionally the ears and nose can be affected. In classic triphasic raynaud phenomenon there are three stages during a single episode: the digits become white, then blue and then arterial hyperaemic (red) and painful on rewarming, although in some cases only biphasic colour changes occur. Any case of new‐onset Raynaud phenomenon occurring over the age of 40 years is more likely to be associated with an underlying CTD.

Approximately 50% of patients with SSc are affected by digital ulceration associated with vasculopathy at some point in their disease. This is the major external feature of structural vessel disease, probably due to thickened intima and lumen-occluded vessels. Tender and painful pitting scars are very frequent and, on occasion, progress to ulcers. These occur on the finger- or toe-tips, over the extensor surfaces of the joints due to micro-trauma or in association with calcinosis cutis. Digital ulcers are associated with strong, local pain and a major impact on quality of life regarding all-day functions, i.e., dressing, eating, etc. Whereas ulcers on the tips of the digits are probably due to ischemia, those on the interphalangeal joints are more likely to persist because of continued trauma. They may also overlie sites of calcinosis cutis. Ulcers can lead to osteomyelitis. At its most severe, critical digital ischemia can lead to gangrene and auto‐amputation.

Another key early symptom is gastro‐oesophageal reflux or dysphagia and is often treated symptomatically with a proton pump inhibitor. Swelling and stiffness of the digits is often reported in the early stages of SSc and may lead to simple practical problems with jewellery (e.g. rings needing removal or enlargement). In cases of dSSc there is often a short pre‐existing history of Raynaud phenomenon and in some cases the vascular features may occur simultaneously or even after the onset of other features. Itch is a hallmark of diffuse skin involvement and can be confined to the skin of the forearms or be more generalized. It may be one of the most disabling symptoms although it generally improves over time. Constitutional symptoms of fatigue and weight loss are common in SSc, especially in early diffuse disease. The most common cause for weight loss is malnutrition due to reduced appetite, the physical difficulty with eating due to sicca symptoms, and dysphagia.

 

Presentation

 

Typically, a patient will present with Raynaud phenomenon and symptoms of gastro‐oesophageal reflux. This is followed by a phase of non‐pitting digital oedema, after which the skin thickens, and sclerodactyly develops. Inflammatory musculoskeletal symptoms may also be present at this stage. Telangiectasia and calcinosis tend to occur later in the disease, as do features of internal organ manifestations including cardio respiratory and more severe gastrointestinal tract involvement.

 

 

Raynaud phenomenon

 

Some cases of SSc present as isolated Raynaud phenomenon. Tests such as autoantibody profile and nail fold capillaroscopic examination are very helpful in making an early diagnosis and in identifying cases of isolated Raynaud phenomenon that are at risk of progression to CTD. Only a proportion of these cases will differentiate into SSc. The presence of a positive ANA, previous or current ‘puffy fingers’ and Raynaud phenomenon should raise the suspicion of very early SSc,  also known as undifferentiated SSc. Such patients are more likely to have an SSc pattern on nail fold capillaroscopy‐, sclerodactyly‐ and scleroderma‐specific antibodies (ACA, ATA, and ARA).

 

A drop of mineral oil is placed on each nail fold. Generally the capillaries are best seen in the nail fold of the fourth finger. A distinct pattern of capillary loss (“drop out”) alternating with tortuous and dilated loops is characteristic of SSc) and can be assessed more easily and with greater accuracy with a dermoscope.

 

Clinical and laboratory features of primary and secondary raynaud’s phenomenon
Feature	Primary Raynaud’s	Secondary Raynaud’s
Sex	F : M 20 : 1	F : M 4 : 1
Age at onset	Puberty	>25 years
Frequency of attacks	Usually <5 per day	5–10+ per day
Precipitants	Cold, emotional stress	Cold
Ischemic injury	Absent	Present
Abnormal capillaroscopy	Absent	>95%
Antinuclear antibodies	Absent/low titer	90–95%
Anticentromere antibody	Absent	50–60%
Anti-topoisomerase I (Scl-70) antibody	Absent	20–30%

Trophic changes                             Absent                      Present

Digital ulceration                           Absent                       Present

 

 

Cutaneous manifestations

 

In both diffuse and CREST syndrome there are three stages of skin disease: (1) edematous, (2) sclerotic, and (3) atrophic.

 

In the edematous phase, the earliest cutaneous manifestations are non‐pitting doughy edema and puffiness, which tend to be seen first in the fingers, hands and face producing the classic early signs of “sausaging” of the fingers and periorbital edema.  Hand motion is restricted. This swelling is usually painless and may be associated with intense pruritus. The disease progresses to the sclerotic phase, and the skin becomes taught, indurated, thickened, and wax-like and then fixed to deeper structures on the fingers and can no longer be lifted into wrinkles resulting in sclerodactyly. The extension of these changes proximally to the metacarpophalangeal joints is critical to the diagnosis of SSc.  Hand motion is further restricted. Eventually, there may be gradual thinning of the skin (late atrophic phase). Atrophy occurs first in the pulps of the fingers, and small painful ulcers are formed (rat bite necrosis). The fingers narrow or taper distally, and the terminal phalanges become shortened as a result of distal bone resorption with the nails curving over the atrophic phalanges (Madonna fingers). Later, the atrophy and sclerosis extends to involve the whole hand, which is held in semi-flexion, full extension of the fingers and metacarpal joints being impossible. There is leathery crepitation over joints and periungual telangiectasia. Bony resorption and ulceration can result in loss of distal phalanges. Skin sclerosis leads to progressive loss of skin appendages, reduced sweating which makes the skin dry and to joint contractures. Sclerotic skin may show diminished hair growth, but this is variable; hypertrichosis can also occur, particularly during the recovery phase.

 

Edema and fibrosis result in loss of normal facial lines producing mask like facies with stretched, waxy and shiny skin giving a younger appearance than the actual age. The facial appearance in a well-developed case is characteristic. In addition to mask like facies, the nose becomes small and pinched giving a beaklike sharp nose. The mouth opening is constricted, tightly pursed lips that lose their fullness (thinning of the lips) and perioral subcutaneous sclerosis result in small mouth (microstomia) and radial furrows around the mouth and sclerosis of the frenulum. The lower eyelids cannot be depressed by the fingers to show the conjunctivae, because of atrophy of the tissues. Small mat-like telangiectases are frequently found on the face.

 

Atrophy and softening of the dermis eventually make the skin more pliable.

 

In diffuse systemic sclerosis, sclerotic hardening of the skin can increasingly spread to the neck, the chest, abdomen and proximal upper and lower extremities. Tense, stiff and waxy appearing skin cannot be folded. Mobility is increasingly restricted, even respiratory movement of chest wall and of joint mobility is impaired. The abdominal wall appears stretched, drum-like. Dermatogenic stretch contractures develop on the legs. Finally, the patient is confined in the sclerotic skin as if in a suit of armor.

Distribution of lesions

Early: In lSSc, early involvement is seen on the fingers, hands, and face, and in many patients scleroderma remains confined to these regions. Late: The distal upper and lower extremities may be involved and occasionally the trunk. In dSSc, sclerosis of the extremities and the trunk may start soon after or concomitant with acral involvement.

 

The extent of skin sclerosis can be measured, most commonly employing a modified Rodnan skin score (MRSS). The scoring of each skin region is determined by skin thickness and tethering: 0 = normal 1 = possible thickening 2 = unable to pinch the skin 3 = unable to move the skin (which is fixed to deeper tissues)

There are a number of cutaneous changes other than sclerosis in patients with SSc. Dyspigmentation in areas of sclerosis is commonly observed. Some patients develop diffuse hyper pigmentation, with accentuation in sun-exposed areas and sites of pressure. The “leukoderma of scleroderma” is characterized by localized areas of depigmentation with sparing of the perifollicular skin; this helpful diagnostic finding is sometimes referred to as the “salt and pepper” sign. Pigment may also be retained in the skin overlying superficial veins. This leukoderma favours the upper trunk and central face and may overlie both sclerotic and non-sclerotic skin.

Pruritus is described in 40% of patients and may be intense during the early or active stages of disease. It correlates with the extent of skin sclerosis, MRSS and gastrointestinal symptoms.

 

Telangiectasias

Telangiectasias are common both in patients with limited SSc and diffuse disease and have a unique morphology. They occur as flat (macular), 0.5-cm, non pulsatile, rectangular collections of uniform, tiny vessels; these are the so-called telangiectatic mats or squared-off. These mats are most commonly found on the face, lips, upper trunk, palms, and backs of the hands.

 

Calcinosis cutis

Subcutaneous calcinosis in systemic sclerosis occurs most commonly (25%) in the fingers, especially on the palmar aspects of the terminal phalanges. Digital calcification is approximately 10 times as common in females as in males. Calcinosis also occurs over the bony prominences of the fingers joints, knees, elbows, spine, and iliac crests. The deposits appear as firm, subcutaneous nodules that may eventually rupture at the surface, discharging fragments of calcium. In response to this foreign material, the skin surrounding the calcium becomes painful, red, and sometimes chronically infected, requiring courses of oral antibiotics. Dystrophic calcinosis cutis develops in the later stages, particularly in lSSc.

 

Cutaneous signs of systemic sclerosis

 

Extracutaneous features

The majority of patients with SSc have internal organ involvement, which is the cause of significant morbidity and mortality in this disease. Occasionally, a patient with SSc will present with internal organ involvement before skin involvement is evident. The most commonly affected organs are the gastrointestinal tract, lungs, heart and kidneys.

 

Gastrointestinal tract

GI involvement is the most common internal organ involvement in patients suffering from both, limited and diffuse SSc. Fibrosis and atrophy of smooth muscle can occur in any part of the gastrointestinal (GI) tract resulting in aperistalsis and dilation.

At the level of the oesophagus >90% of SSc patients develops dysphagia and symptoms of gastro‐oesophageal reflux disease. A weakened lower oesophageal sphincter and impaired peristalsis increase the risk for esophagitis. If untreated, this could lead to peptic esophagitis, gastric/oesophageal ulcerations, peptic stricture formations, and fistulae. Chronic gastroesophageal reflux can be complicated after a time by a higher risk of Barrett's oesophagus, which may progress into an adenocarcinoma.

In the stomach, atrophy of the mucous membrane associated with anacidity, ulcerations and delayed gastric emptying.

Lower gastrointestinal manifestations tend to occur more commonly and more severely in patients with limited SSc. Atonic dilatation of the small bowel leads to a “stagnant loop” syndrome with bacterial overgrowth, malabsorption, and steatorrhea and episodes of pseudo‐obstruction. Involvement of the sigmoid colon and rectum cause constipation and overflow faecal incontinence.

The presence of esophagitis can be determined by upper GI endoscopy with histological evaluations. Impaired motility of the oesophagus can usually be diagnosed by scintigraphic evaluation following a radiolabeled meal or 24 hours ph-manometry.

 

Renal manifestations

 

Scleroderma renal crisis is still an important complication of SSc occurring in 5‐10% of patients, and may cause an abrupt onset of significant systemic hypertension (>150/85 mm Hg), proteinuria (>200 mg/g urine-creatinine), followed by an acute renal failure (≥30% reduction in estimated glomerular filtration rate). Studies suggest that a chronic vasculopathy with reduced glomerular filtration rate is frequent. In addition, there is evidence of an increase in fibrillar collagen deposition within the renal interstitium in SSc. Many cases occur within the first 12 months of disease. End-organ damage can result in encephalopathy with generalized seizures or flash pulmonary oedema. Microangiopathic anaemia is common, and sometimes disseminated, intravascular coagulation develops. RNA polymerase III antibodies are present in 59% of patients and confer increased susceptibility. SRC is rare in patients with anti-centromere antibodies. Most patients have diffuse disease. Nephrotoxic drugs and high-dose prednisolone (>7.5 mg/day) should be avoided in patients suffering from SSc. Early, aggressive treatment with angiotensin‐converting enzyme (ACE) inhibitors in patients with accelerated hypertension in the early stages of SRC has improved the prognosis, such that SRC is no longer the leading cause of death in scleroderma. Early diagnosis is the key role in improving the outcome of SRC using regular blood pressure monitoring, urine-analyses (protein-, albuminuria, micro electrophoresis) and serum levels of creatinine.

 

Cardiopulmonary manifestations

 

There are two major forms of pulmonary involvement in SSc. The first is interstitial lung disease (alveolitis) that eventuates into pulmonary fibrosis and the second form is pulmonary arterial hypertension. PAH occurs in both limited and diffuse cutaneous subsets, although the most typical cases are those of limited SSc (lSSc) associated with isolated PAH. Interstitial lung disease and PAH are currently the most common causes of disease‐related death in SSc. The differentiation between these manifestations is often clinically difficult because of similar, overlapping clinical features, such as dyspnea, nonproductive cough, palpitation, cyanosis, syncope and peripheral oedema. Besides the right-heart worsening due to PAH, the heart could also be involved because of diffuse interstitial myocardio-fibrosis. This could lead to a diastolic dysfunction as well as a restricted contractibility of the myocardium. These patients clinically present cardiac arrhythmia, paroxysmal tachycardia, incomplete or complete right-heart blocks, and heart insufficiency.

Individuals with SSc should be followed up at least annually using pulmonary function tests, echocardiography, a 6-minutes’ walk test, and high-resolution computer tomography (HRCT). Pulmonary function tests are the most important techniques to determine possible cardiopulmonary involvement, because of impaired diffusion capacity (DLCO ≤75%) being an early marker of both lung fibrosis and PAH.

The gold standard for the diagnosis of PAH is right heart catheterization. Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary pressure (mPAP) of >25 mm Hg at rest together with a pulmonary capillary wedge pressure of <15 mm Hg as determined by right-heart catheterization.

Cardiac magnetic resonance imaging is also a further potential strategy for assessing myocardiac involvement in SSc.

 

Musculoskeletal manifestations

 

Tendon friction rubs – a feeling of ‘coarse cracking and crepitus’ over the finger flexors and extensors, wrists, elbows, knees and ankle joints – occur in approximately 10% of patients at presentation. They are due to thickening of the tendon retinacula and to deep connective tissue infiltrate surrounding the tendons. Their presence in early SSc has been associated with diffuse disease.

Muscle weakness is a common symptom occurring in some 90% of cases. Two patterns of muscle involvement are recognized, a low‐grade myopathy with mild weakness, minimal creatine kinase elevation, minimal electromyographic findings and mild fibrotic changes on histology, and a less common inflammatory myositis, usually in the context of an overlap syndrome. Muscle involvement is associated with male sex, early diffuses disease, ATA or RNAP positivity, interstitial lung disease and reduced survival.

 

Signs of Visceral Involvement in Systemic Sclerosis

 

	Mild	Severe
Raynaud’s phenomenon	Less than 5 times/day	More than 15 times/day, or digital ulcerations, or both
Esophagus	Dysphagia to solid foods; normal barium swallow	Dysphagia to solid and soft foods and weight loss (>10%); abnormal barium swallow with dilation of lower two thirds of esophagus
Lung	No symptoms: vital capacity >70% predicted and CO2-diffusing capacity between 50% and 75% of predicted, Po2 >69 mm Hg	Dyspnea + vital capacity <50% of predicted or CO2-diffusing capacity <33% of predicted, Po2 <69 mm Hg
Heart	Nonspecific ST	T changes; angina; definite ischemic changes by ECG; hypokinesis by MUGA scan or an ejection fraction <30%
Muscle	Mild EMG or CK abnormalities	Definite myositis clinically, biochemically, by EMG, or by muscle biopsy
Kidney	Mild hypertension or serum creatine level 1.5 times normal, or creatine clearance <80%, or 24-hour protein <500 mg	Refractory hypertension, or serum creatine level 4 times normal, or creatine clearance <20%, or 24-hour protein <3 gm
CK, Creatinekinase; ECG, electrocardiogram;  EMG, electromyogram; MUGA, multiunit gated acquisition.

 

Auto antibodies

Autoantibody testing is useful in confirming the diagnosis of SSc.  Over 80% patients have elevated titres of antinuclear antibodies (ANA), with the nucleolar or discrete speckled patterns being relatively specific for SSc. Patients with antibodies to topoisomerase I (Scl-70) are more likely to have diffuse disease with an increased risk of interstitial lung disease (ILD) leading to pulmonary fibrosis. In contrast, patients with anti-centromere antibodies are more likely to have limited disease (lcSSc), digital gangrene, and PAH. Lastly, the subset of patients with anti-RNA polymerase III antibodies is more likely to have rapidly progressive, diffuse skin disease and renal involvement.

 

Office nail fold capillary microscopy

A technique has been described for characterizing the telangiectasias seen in the proximal nail fold of the various connective tissue diseases. The scleroderma pattern is distinctive and is also seen in dermatomyositis. Familiarity with this technique may help to differentiate patients with lupus and dermatomyositis from patients who have cutaneous eruptions that appear to be similar. The technique used by Minkin and Rabhan is as follows:

A drop of mineral oil is placed on each nail fold. The ophthalmoscope is set at ×40, resulting in a ×10 magnifications. The instrument is placed close to, but not in touch with, the oil. Generally the capillaries are best seen in the nail fold of the fourth finger. Because the field of observation is smaller than in wide-field microscopy, the ophthalmoscope must be moved over the entire nail fold. A technique for using a television camera to record nail fold capillary characteristics has been described.

Normal

In normal people the capillaries are seen as fine, regular loops with a small, even space between the afferent and efferent limbs, in a row perpendicular to the nail.

 

Overlap syndromes (scleroderma, dermatomyositis)

The scleroderma pattern (megacapillaries and/or avascularity) seen in 74% of patients with scleroderma consists of enlarged and deformed capillaries with dilation of both limbs of the loop, which is often engorged with blood (“sausage loop”). There is marked disorganization of the loop arrangement. Loss of capillaries produces many avascular areas and disruption of the orderly appearance of the capillary bed. Patients with Raynaud’s phenomenon who present with avascularity and/or a mean of more than two megacapillaries per digit are likely to progress to a scleroderma spectrum disorder. The same pattern is seen in 82% of patients with dermatomyositis.

 

Mixed connective tissue disease

The scleroderma pattern is present in 63%, the lupus pattern in 22%; 73% have bushy capillary formation. The presence of bushy capillaries suggests mixed connective tissue disease.

 

 

Lupus

In lupus there are tortuous, “meandering” capillary loops, but there is relatively little dilation of the capillary limbs. At times the loop length is increased and may resemble a renal glomerulus. There is usually some disorganization of the capillary pattern, but only rarely are avascular areas seen.

The changes are distinctive enough that a relatively inexperienced observer can accurately distinguish between patients with scleroderma and those with systemic LE or rheumatoid arthritis. There is a close association between the degree of visible capillary abnormalities and organ involvement.

 

Histopathology

The histopathology of SSc shows dense sclerosis of the lower two-thirds of the dermis and the subcutaneous fibrous trabeculae, because of excessive deposition of ECM proteins, most notably collagen type I and III and subcutaneous fat is replaced by a fibrous connective tissue.

Histologically, areas of cutaneous induration are characterized by compact or hyalinized collagen, excessive deposition of collagen, atrophic eccrine and pilosebaceous glands, loss of subcutaneous fat, and a sparse lymphocytic infiltrate in the dermis and subcutis. Adnexal structures, especially eccrine glands, appear “trapped” by the excessive deposition of collagen.

 

Direct immunofluorescence studies are usually negative in patients with SSc. While endothelial damage can occur in cutaneous blood vessels, this finding is only seen at the ultrastructural level; reduplication of the basement membrane is also observed. It should be noted that, in its end stage, areas of sclerosis may be indistinguishable histologically from other diseases characterized by collagen deposition, such as morphea (which tends to have a more robust inflammatory infiltrate than SSc in its earlier stages).

 

 

Course and prognosis

Course of dSSc is characterized by slow, relentless progression of skin and/or visceral sclerosis; the 10-year survival rate is >5O%. Renal disease is the leading cause of death followed by cardiac and pulmonary involvement. Spontaneous remissions do occur. lSSc, including the CREST syndrome, progresses more slowly and has a more favourable prognosis; some cases do not develop visceral involvement

 

 

Management

 

Algorithm summarizing current approach to management of systemic sclerosis (SSc)

 

The principles of therapy for SSc include accurate diagnosis and treatment according to the disease subset, the presence of overlap features, and the likely predominant pathologic process according to the stage of disease. In all cases, screening for and treatment of organ-based complications has a major role in successful management. Education of patients and a multidisciplinary team, including specialist nurses, physiotherapists, occupational therapists and many subspecialty physicians, and surgeons, are central to providing appropriate care for severe cases of SSc.

 

 

 

 

Internal organ involvement in systemic sclerosis – screening and treatment options
Initial screening tests are in bold. ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; Cr, creatinine; CT, computed tomography scan; DLCO, diffusing capacity of the lung for carbon monoxide; N-Tpro-BNP, N-terminal pro b-type natriuretic peptide; PFTs, pulmonary function tests.

INTERNAL ORGAN INVOLVEMENT IN SYSTEMIC SCLEROSIS – SCREENING AND TREATMENT OPTIONS
Internal organ	Screening tools*	Treatment options
Lung*
Interstitial lung disease (ILD)	PFTs (DLCO, spirometry, and lung volumes)   High-resolution CT   Bronchoalveolar lavage and lung biopsy	Immunosuppression (e.g. cyclophosphamide vsmycophenolatemofetil)   Lung transplantation
Pulmonary arterial hypertension (PAH)	Transthoracic echocardiography   Serum N-Tpro-BNP level   Right heart catheterization	Oxygen   Anticoagulation   Endothelin receptor antagonists (e.g. bosentan)   Phosphodiesterase inhibitors (e.g. sildenafil)   Prostacyclin analogues (e.g. epoprostenol)   Prostacyclin receptor agonists (e.g. selexipag)   Lung transplantation
Kidney
Renal crisis   Hypertension	Close monitoring of blood pressure   BUN/Cr   Urinalysis	ACE inhibitors instituted early for treatment but not helpful for prevention
Heart
Fibrosis/restrictive cardiomyopathy   Heart failure secondary to PAH	Echocardiography	ACE inhibitors
Gastrointestinal tract
Esophageal dysmotility   Small bowel involvement	Barium swallow with small bowel follow through   Manometry   Endoscopy	Proton pump inhibitors   Promotility agents (e.g. ondansetron)

* Patients are typically asymptomatic in the early stages of ILD and PAH, which is when the diagnosis should be made and treatment instituted; cough, dyspnoea on exertion, and shortness of breath are typical later-onset symptoms.

 

Cutaneous features of systemic sclerosis – possible treatments.
BID, twice a day; ILD, interstitial lung disease; IV, intravenous; SR, slow release; UV, ultraviolet.

CUTANEOUS FEATURES OF SYSTEMIC SCLEROSIS – POSSIBLE TREATMENTS
Cutaneous feature	Possible treatment options
Cutaneous sclerosis	·       Manual lymphatic drainage (Vodder technique) ·       Physiotherapy ·       Topical therapies with steroids or calcineurin inhibitors   ·       Phototherapy (PUVA, UVA1)   ·       D-penicillamine*   ·       Minocycline**   ·       Methotrexate (if no ILD)†,++ 15–25 mg/week ·       Mycophenolate mofetil (when ILD) 2–3 g/day
Raynaud phenomenon	First-line ·       Cold avoidance   ·       Hand and feet warming packets   ·       Discontinue all tobacco products   Second-line ·       Calcium channel blockers (e.g. nifedipine SR 30 mg daily–BID, amlodipine 2.5–10 mg daily) Third-line (especially when accompanied by ulceration) ·       Phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil)   ·       α-Adrenergic blockers (e.g. prazosin)   ·       Angiotensin II receptor blockers (e.g. losartan)   ·       Endothelin receptor antagonists (e.g. bosentan) Fourth-line • Serotonin reuptake inhibitors (e.g. fluoxetine)
Cutaneous ulcers	·       Avoid excessive debridement   ·       Moist, non-adherent dressings   ·       Therapies listed above for Raynaud phenomenon   ·       Low-dose aspirin or clopidogrel   ·       IV prostanoid (e.g. epoprostenol)
Calcinosis cutis	·       Low-dose warfarin   ·       Calcium channel blockers   ·       Sodium thiosulfate
Mat telangiectasias	·       Lasers appropriate for vascular lesions ·       Camouflage

* Nowadays used infrequently.

** Minimal effect.

† Methotrexate-induced pneumonitis may complicate SSc-ILD picture.

++ Concern that concomitant administration of systemic corticosteroids may increase risk of developing renal crisis; low dose of corticosteroid (e.g. Prednisolone < 10 mg daily) may be safe.

 

SSc is a challenging disease to treat. Therapeutic interventions focus primarily on internal organ involvement, but unfortunately most of these treatments have minimal effect on cutaneous sclerosis and the other cutaneous manifestations.

 

Raynaud phenomenon

 

First-line therapy for Raynaud phenomenon is behavioural and involves educating patients to keep warm and avoid smoking to minimize the frequency and severity of attacks.

 

Second-line therapy is pharmacologic, starting with vasodilators. Calcium channel blockers (e.g. nifedipine, amlodipine) are the most widely used medications. Angiotensin II receptor blockers (e.g. losartan) may also be effective and combination therapy can be tried. More recently, phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil) that target the nitric oxide-mediated vasodilation pathway have been employed. Care must be taken so that the vasodilators do not excessively lower systemic blood pressure. In addition, calcium channel blockers may exacerbate gastroesophageal reflux disease and lead to peripheral oedema. In patients who cannot tolerate these medications because of hypotension, a selective serotonin reuptake inhibitor (e.g. fluoxetine) may be an option.

Oral antiplatelet agents (e.g. low-dose aspirin, clopidogrel) and/or pentoxifylline may provide additional blood flow to compromised distal sites. Biofeedback can also be helpful. Use of HMG-CoA reductase inhibitors (“statins”) as a vasoprotective treatment appears to be safe and well tolerated.

 

Cutaneous ulcers

 

Digital ulcers on the fingers are difficult to treat and a source of great morbidity. Management includes the treatments for Raynaud phenomenon outlined above. Detailed occupational and recreational histories are important to identify risk factors and sources of injury and cold exposure. Bosentan, an oral endothelin receptor antagonist, has been used for the prevention of new digital ulcers in SSc patients.  Prostacyclin analogue administered intravenously, results in a reduction in digital ulcers and improves healing.  Subcutaneous prostacyclin analogue treprostinil may also be effective. In refractory cases, nerve blocks and sympathectomies may be considered.

 

In patients with SSc, autolytic debridement of ulcers via occlusive dressings is thought to be safer than mechanical debridement. In general, moist hydrocolloid dressings provide a better wound healing environment than dry or wet-to-dry dressings. Enzymatic debriding agents (e.g. collagenase) and topically applied growth factors (e.g. PDGF gel) have been utilized in a few SSc patients. Skin equivalents or grafts can also be used to stimulate the wound bed and decrease wound pain. Topical vasodilators such as nitroglycerin are attractive because of ease of application and minimal systemic side effects.

 

Cutaneous sclerosis

 

In the early stage of SSc, cutaneous and subcutaneous oedema develops rapidly, but during the indurated and atrophic stages, the cutaneous involvement progresses more slowly and tends to gradually improve, independent of treatment. Unfortunately, objective, quantitative measurements of cutaneous sclerosis that are sensitive to change over short periods of time are currently lacking for SSc. The traditional instrument for measuring skin involvement in SSc is the modified Rodnan skin score. Although this is a validated outcome measure, it is not ideal and is relatively insensitive to small changes over short periods of time. An adapted engineering tool, the durometer, may be more suitable for assessing cutaneous induration and hardness in patients with SSc. Ultrasound and lasers have also been used to measure skin sclerosis.

 

In general, topical therapies with steroids and/or TCI and phototherapeutic regimens may help some SSc patients. With regard to systemic medications such as D-penicillamine for dcSSc, there is no difference between the low-dose and the high-dose treatment groups and this drug is now rarely used. Although minocycline looked promising in a pilot study, a larger follow-up study failed to show a benefit. Methotrexate (MTX) can be helpful in SSc patients with overlapping myositis and inflammatory arthritis and a 3- to 6-month trial of MTX is reasonable in patients without ILD.

 

Mycophenolate mofetil (MMF) is routinely used for SSc-ILD and in some patients it may be of benefit for early cutaneous sclerosis. However, there is no consensus regarding a 6- to 12-month empiric trial of MMF (2–3 g daily) for early dcSSc. As expected, the dosage may need to be adjusted based upon side effects, in particular cytopenias and gastrointestinal symptoms. MMF may be used in junction with MTX for severe, rapidly progressive cutaneous sclerosis, but close monitoring is required. Sirolimus is an mTOR inhibitor that has been used for renal transplant rejection and may also be a candidate drug for SSc. It has gained interest because sirolimus can improve certain vascular malformations and has an anti-fibrotic effect.

 

Imatinib, a tyrosine kinase inhibitor, has found to decrease skin thickness in dcSSc following 12 months of therapy.

 

Other cutaneous complications

 

Calcinosis cutis represents a serious problem for which no effective medical therapy exists. Low-dose warfarin can decrease the inflammatory reaction associated with calcium deposits. Sodium thiosulfate has been used intravenously and intralesionally to treat ulcers due to calciphylaxis, suggesting that topically it may improve ulcers of calcinosis cutis. In certain situations, surgical removal of the calcium deposits may be necessary. Treatment with extracorporeal shock wave lithotripsy has also been reported. Telangiectasias can be treated cosmetically with lasers appropriate for vascular lesions (e.g. pulsed dye).

 

Internal organ involvement

 

The use of ACE inhibitors to treat scleroderma renal crisis represents a major therapeutic advance.

 

Treatment with either cyclophosphamide or MMF has been shown to benefit SSc-ILD.  Oral cyclophosphamide is used at a dose of 1 to 2 mg/kg/day for 1 year. However, there are significant potential side effects associated with cyclophosphamide, such as cytopenias, hemorrhagic cystitis, and an increased risk of bladder carcinoma. Whereas MMF has a superior safety profile compared to cyclophosphamide, trials showed that both drugs are equally effective in SSc-ILD, but MMF had a superior tolerability and safety profile.

 

Advances in the treatment of PAH have also occurred, in particular the use of oral vasoactive compounds, some of which are also used for Raynaud phenomenon and digital ulcers. These include endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). Prostacyclin analogues (iloprost [inhaled], epoprostenol [intravenous], treprostinil [subcutaneous]) and the prostacyclin receptor agonist selexipag are approved for PAH in SSc patients, but are no longer sole or first-line therapy. Lung transplantation is an option, with survival rates as well as risks for developing acute rejection and bronchiolitis obliterans syndrome similar in SSc patients when compared to those without AI-CTDs.