Systemic Sclerosis (Scleroderma) and Related Disorders

Vascular dysregulation

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 edema . 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 lead to luminal occlusion hypoxia which induces synthesis of profibrotic cytokines, fibroblast activation, and collagen production . Raynaud 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

Autoantibodies unique to SSc, in particular anti-centromere, anti-topoisomerase I, and anti-RNA polymerase III, are useful for diagnostic and prognostic purposes (see Ch. 40 ) . These three autoantibodies bind tissues of interest in SSc, as do anti-U3RNP (antifibrillarin), anti-Th/To, anti-U1RNP, anti-PM-Scl, and anti-Ku autoantibodies . The latter are rather rare and play a role in overlap syndromes.

Evidence of a direct pathogenic role for these autoantibodies 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 autoantibodies 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 a proteome-wide analysis of five large cohorts, circulating levels of the chemokine CXCL4 were found to be significantly elevated (compared to controls), and the CXCL4 levels correlated with the presence and progression of pulmonary disease . The authors proposed CXCL4 as a biomarker to monitor for the development of lung disease in SSc patients. This recommendation awaits validation in prospective studies.

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. β ₁ -integrins), which sequester cytokines and growth factors (see Fig. 43.1 ). 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.

Classification and diagnostic criteria

In 1980 the American College of Rheumatology (ACR) published preliminary criteria for the classification of SSc, which were updated in 2013 ( Table 43.2 ) . These classification criteria ensure the patient population being studied is well-defined and homogeneous, which is particularly important in rheumatic diseases where nonspecific and overlapping symptoms may lead to misclassification. As a result, classification criteria are stricter than the diagnostic criteria used for an individual patient. Nonetheless, for our purposes, they will be used interchangeably.

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 (see Table 43.2 ). These 2013 criteria have greater sensitivity (91%) and specificity (92%) compared to older criteria .

Based upon the degree of skin involvement, there are two major clinical subtypes ( Fig. 43.2 ): limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) . When the skin disease involves the distal and proximal portions of the extremities, the trunk and the face, it is considered diffuse cutaneous disease, but when the induration is limited to the distal extremities and face, it is considered limited cutaneous disease . Although both subtypes can have systemic manifestations, there are variable patterns and severity of internal organ involvement ( Table 43.3 ). 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 and have a better prognosis.

The acronym CREST syndrome describes the clinical features in a subset of patients with lcSSc: c alcinosis, R aynaud phenomenon, e sophageal involvement, s clerodactyly and t elangiectasia. However, because not every patient has all five features, the term lcSSc is favored. Rarely, patients present with characteristic internal organ involvement, Raynaud phenomenon, abnormal nail-fold capillaries and positive serologies, but no cutaneous sclerosis. This clinical presentation is referred to as systemic sclerosis sine scleroderma (ssSSc) and it behaves similarly to lcSSc.

Cutaneous features

Many patients with SSc experience an early edematous phase, which often features pitting edema of the digits ( Fig. 43.3 ). Digital pits are also a characteristic finding ( Fig. 43.4 ). The skin subsequently hardens and develops a taut, shiny appearance (indurated phase). Eventually, there may be gradual thinning of the skin (late atrophic phase). The fingers can develop flexion contractures and ulcers ( Fig. 43.5 ) while involvement of the face can lead to a beaked nose, microstomia and a more youthful appearance.

There are a number of cutaneous changes other than fibrosis in patients with SSc. Dyspigmentation in areas of sclerosis is commonly observed. Some patients develop diffuse hyperpigmentation, 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 ( Fig. 43.6 ). Pigment may also be retained in the skin overlying superficial veins. This leukoderma favors the upper trunk and central face and may overlie uninvolved or sclerotic skin.

Telangiectasias are more common in patients with lcSSc but also occur in patients with dcSSc (see Table 43.3 ). The telangiectasias most often involve the face, lips and palms. These telangiectatic macules are matted or squared-off ( Fig. 43.7 ). Capillary abnormalities in the proximal nail fold are present in more than 90% of SSc patients and can be useful in supporting the diagnosis . Use of an ophthalmoscope or dermatoscope may enhance appreciation of the abnormal nail-fold capillaries. A distinct pattern consisting of capillary loss (“drop out”) alternating with dilated loops is characteristic of SSc.

Calcinosis cutis most commonly develops on the extremities, usually near joints and in distal locations ( Fig. 43.8 ). In addition, the skin is often dry due to decreased sweating, and pruritus can be quite marked. Sclerotic skin may show diminished hair growth, but this is variable; hypertrichosis can also occur, particularly during the recovery phase. Overall, the cutaneous changes are extremely troublesome to patients with SSc. In a questionnaire-based study involving 300 patients with SSc, facial involvement and microstomia were the patients' greatest concerns .

Raynaud phenomenon is characterized by episodic vasospasm of the digital arteries resulting in white, blue and red discoloration of the fingers secondary to cold exposure . Raynaud phenomenon occurs in two settings ( Table 43.4 ). Primary Raynaud phenomenon (Raynaud disease) typically develops in adolescent girls and young women and is not associated with any underlying medical problems . Primary Raynaud phenomenon is common and estimated to affect 3% to 5% of the population. In contrast, secondary Raynaud phenomenon is uncommon and is associated with an underlying medical problem, including SSc ( Fig. 43.9 ; Table 43.5 ). An approach to differentiating primary from secondary Raynaud phenomenon is presented in Fig. 43.10 .

Cutaneous ulcers are common in patients with SSc ( Fig. 43.11 ). 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 (see Fig. 43.5 ). They may also overlie sites of calcinosis cutis. Ulcers can lead to osteomyelitis and even amputation (autoamputation or surgical intervention).

Extracutaneous features

The majority of patients with SSc have internal organ involvement ( Table 43.6 ), which is the major 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. Of note, pulmonary disease has replaced renal crisis as the leading cause of death in SSc. There are two major forms of pulmonary involvement in SSc : (1) interstitial lung disease (ILD); and (2) pulmonary arterial hypertension (PAH). Screening tests for both disorders are outlined in Table 43.6 .

Autoantibodies

Autoantibody testing is useful in confirming the diagnosis of SSc (see Ch. 40 ). Most SSc patients have elevated titers of antinuclear antibodies (ANA) , with the nucleolar or speckled patterns being relatively specific for SSc. Patients with anti-centromere antibodies are more likely to have lcSSc, digital gangrene, and PAH . Patients with antibodies to topoisomerase I (Scl-70) are more likely to have dcSSc with an increased risk of ILD leading to pulmonary fibrosis . Lastly, the subset of patients with anti-RNA polymerase III antibodies is more likely to have rapidly progressive, diffuse skin disease and renal involvement .