Scleroderma is an autoimmune condition characterized by sclerosis of the skin and internal organs. Sclerosis is hardening or thickening as a result of excessive deposition of interstitial collagen and subsequent tissue fibrosis (Bohm & Luger, 2015). Disease pathogenesis involves autoimmunity, inflammation, obliterative vasculopathy, and interstitial fibrosis (Varga, 2017). The estimated prevalence of scleroderma ranges from 20 to 240 per 100,000 persons, and incidence varies from 7 to 489 cases per million per year (Ferreli et al., 2017; Pearson et al., 2018). The disease has a female predominance, with a female-to-male ratio of 4-6:1, and onset is generally between 30 and 50 years old (Ferreli et al., 2017; Pearson et al., 2018). Black patients have a greater prevalence in addition to earlier and more severe cutaneous and systemic disease. Mortality varies by disease subtype and severity of internal organ involvement. Older age at disease onset, pulmonary/renal/cardiac involvement, severe gastrointestinal disease, and multiple organ involvement confer a poor prognosis (Pokeerbux et al., 2019).

Identifying the dermatologic manifestations of scleroderma is key as these are often the presenting features. The modified Rodnan skin score (mRSS) is a quantitative tool to assess severity of skin thickness (Khanna et al., 2017), and a higher skin score has been noted to inversely correlate with survival (Clements et al., 1990, 2000; Kreig & Takehara, 2009). Furthermore, the chronic disfiguring nature of skin disease in scleroderma largely affects an individual's quality of life.

MANIFESTATIONS

Scleroderma is divided into two broad categories: localized scleroderma and systemic sclerosis (SSc). Localized scleroderma is characterized by involvement of the skin and subcutaneous tissues and includes morphea and linear scleroderma (Barnes & Mayes, 2015). SSc is a multisystem disorder with involvement of various organ systems in addition to the skin. Leroy et al. classified SSc into two subtypes based on the extent of skin involvement: diffuse SSc (dcSSc) and limited SSc (lcSSc; LeRoy et al., 1988). lcSSc is characterized by skin induration confined to the face and extremities distal to the knees and elbows, and patients may exhibit Raynaud's phenomenon (RP) and SSc-specific nail fold capillary changes and/or SSc-specific autoantibodies (Hachulla & Launay, 2011). Organ fibrosis is a delayed manifestation and is usually mild to moderate in nature. In dcSSc, skin thickening extends to the trunk and proximal portions of the extremities, and internal organ fibrosis is often more severe (Barnes & Mayes, 2015).

The term systemic sclerosis sine scleroderma is used for lcSSc patients without any cutaneous involvement but with classic SSc characteristic nail fold capillaroscopy abnormalities, specific antinuclear antibodies, and internal organ involvement (Hachulla & Launay, 2011). CREST syndrome is an acronym used to denote calcinosis cutis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia (Hachulla & Launay, 2011; Winterbauer, 1964). These findings can be seen in both lcSSc and dcSSc (although more common in lcSSc).

The characteristic dermatologic manifestation of scleroderma is skin thickening (Figure 1) that is not a result of other precipitating events like exposures, infections, or trauma (Van den Hoogen et al., 2013). Skin thickening is typically bilateral, symmetrical, and nonpitting and may extend proximal to metacarpophalangeal joints (Van den Hoogen et al., 2013). The skin involvement may span over three phases: an initial edematous phase with increasing indurating, followed by a fibrotic phase, and subsequently a fibrotic phase (Ferreli et al., 2017). Facial involvement (Figure 2) results in mask-like facies with sclerosis of the perioral skin, resulting in narrowed oral orifice and radial furrowing around the mouth (Kreig & Takehara, 2009). For calculation of the mRSS, skin thickness is measured by manual palpation at 17 body sites and graded from 0 (normal) to 3 (severe thickening with inability to pinch the skin into a fold; Table 1; Khanna et al., 2017). The sum of these scores yields an mRSS, with a higher score portending a worse disease (Khanna et al., 2017). Note, however, that this method is largely limited by interobserver and intraobserver variability (Khanna et al., 2017).

FIGURE 1. Tightened, indurated skin over digits. Note the flexion contractures, shortened second and third fingers, and deformed nails.

FIGURE 2. Drawn pursed lips, shiny skin over the cheeks and forehead, and atrophy of muscles in the temple, face, and neck. These changes in the face are called "mauskopf" (mousehead).

TABLE 1 Modified Rodnan Skin Score

Digital swelling (Figure 3) is not uncommon and is defined by the American College of Rheumatology as a diffuse, usually nonpitting, increase in soft tissue mass of the digits extending beyond the normal confines of the joint capsule and obliterating the normal contours (Van den Hoogen et al., 2013). Telangiectasias (Figure 4) are visible dilated dermal capillary vessels that blanch upon pressure application. They are typically found on the face but also noted over the neck, upper trunk, extremities, palmar hands, lips, inside of the mouth, and, less frequently, lower trunk and abdomen (Pearson et al., 2018; Van den Hoogen et al., 2013). Calcinosis cutis (Figure 5) is the deposition of calcium hydroxyapatite crystals in the subcutaneous tissue and is seen in nearly 25% of patients with SSc bearing an association with greater disease duration, centromere Ab, PM/Scl Ab, and digital ulcers (Boulman et al., 2005). On examination, whitish firm nodules or papules are noted to involve the extremities and rarely the trunk. These can be complicated by ulceration, infection, and pain, all of which can also contribute to severe disability and morbidity. Clinical diagnosis is typical, although radiologic examination also reveals calcium deposition. A "salt-and-pepper" appearance (termed poikiloderma; Figure 6) can be seen on the face, arms, and trunk and develops because of patches or plaques of hypopigmentation alternating with preserved perifollicular pigmentation (Bohm & Luger, 2015).

FIGURE 3. Swelling of the distal limbs.

FIGURE 4. Facial and mucous membrane telangiectasia characteristic of limited systemic sclerosis.

FIGURE 5. Hard subcutaneous nodules on the forearm, with radiograph showing these nodules as soft tissue calcifications adjacent to the radius.

FIGURE 6. Diffuse hypopigmentation and hyperpigmentation, alopecia, drawn tight lips, and tight, shiny skin over the cheeks and nose with lack of skin folds and muscle atrophy at the corner of the mouth.

Localized scleroderma is divided into the following subtypes: plaque, generalized, and linear localized scleroderma (Figure 7). These patients typically do not have internal organ or vascular involvement, or sclerodactyly. RP is a vascular manifestation of scleroderma characterized by three phases of color change (blanching followed by cyanosis and subsequent blushing) that are triggered by cold or stress exposure (Figure 8). Changes are typically seen in the extremities, including the tips of fingers and toes, ear, and nose. It is present in more than 95% patients with SSc (Pearson et al., 2018). RP may progress to poorly healing digital ulcers on the fingertips and extensor surfaces in 8%-30% of cases of scleroderma with an increased risk of infection (Ennis et al., 2013; Khimdas et al., 2011; Mouthon et al., 2010). Digital pitting may occur secondary to progression of RP, leading to ischemia (Figure 9). Nail fold capillary changes in scleroderma initially include enlarged capillaries (Figure 10) with hemorrhage and disorganization of the microvasculature followed by capillary loss ("dropout") visualized at the nail fold or on the cuticle (Van den Hoogen et al., 2013).

FIGURE 7. Thickening of the scalp with extension onto the face, seen in linear scleroderma. This particular form is often termed

FIGURE 8. Well-demarcated pallor in the fingers of both hands, characteristic of Raynaud's phenomenon.

FIGURE 9. Gangrene in the left fingers, digital pit on the right thumb, and amputation of the distal right index finger.

FIGURE 10. A drop of immersion oil enhanced visualization of the nail fold showing dilated nail fold capillary loops and periungual erythema.

Scleroderma mimics is the term given for conditions that manifest with skin thickening without having autoantibodies, internal organ involvement, nail fold capillary changes, or the RP that is characteristic of SSc (Ferreli et al., 2017). Such mimickers include scleredema, scleromyxedema, eosinophilic fasciitis (Figure 11), nephrogenic systemic fibrosis, and cutaneous sclerosis secondary to chronic graft-versus-host disease in patients who have received bone marrow transplant.

FIGURE 11. Skin of the calf (left image) showing

CLUES TO THE DIAGNOSIS OF SCLERODERMA: INTERNAL ORGAN INVOLVEMENT

Scleroderma is a clinically heterogenous connective tissue disease. In addition to the dermatologic manifestations described above, multisystem disease is not uncommon with a particular emphasis on pulmonary, gastrointestinal system, and renal diseases. Pulmonary involvement is the leading cause of mortality in patients with SSc, with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) accounting for >60% deaths (Steen & Medsger, 2007). ILD and PAH can be present in both lcSSc and dcSSc, although ILD is more common in dcSSc and PAH is more common in lcSSc. Nonspecific interstitial pneumonia is the typical pattern of ILD noted in SSc. Scleroderma renal crisis is a dreaded complication and was historically the most common cause for mortality in SSc (Denton & Ong, 2015). It can present as accelerated hypertension, acute renal failure, pulmonary edema, headache, and encephalopathy. Gastrointestinal involvement may include gastroesophageal reflux disease, esophageal dysmotility, gastric antral vascular ectasia, small bowel dysmotility, and small bowel obstruction (Denton & Ong, 2015). Cardiac involvement can be life threatening but is often difficult to diagnose. Patients may present with arrhythmia, conduction defect, cardiac fibrosis, myocarditis, and systolic or diastolic dysfunction (Denton & Ong, 2015). Musculoskeletal manifestations include inflammatory arthritis, contractures, tendonitis, and myositis (Denton & Ong, 2015).

DIAGNOSTIC EVALUATION

In 2013, the American College of Rheumatology/European League Against Rheumatism released classification criteria for SSc (Table 2). Intended primarily for research purposes, these are not to be used stringently as diagnostic criteria, as patients with early SSc may be missed (Van den Hoogen et al., 2013). A thorough physical examination is vital in establishing a diagnosis of SSc, particularly where the classification criteria purport the single finding of thickening of the skin proximal to the metacarpophalangeal joints of the hands as sufficient to classify a patient as having SSc (Van den Hoogen et al., 2013). These criteria carry a specificity of 91% and a sensitivity of 92% for identifying patients as having scleroderma. Autoantibody testing is a significant component of diagnostic workup as the antibody status bears impact on disease prognosis, is associated with specific manifestations, and impacts treatment (Table 3; Stochmal et al., 2020). Although multiple antibodies can be associated with SSc, those specific to this condition include scl-70 (anti-Topoisomerase I), centromere, RNA polymerase III, nucleolar, U1-RNP (ribonucleoprotein), and PM-Scl (Stochmal et al., 2020).

TABLE 2 ACR-EULAR 2013 Criteria for Classification of SSc

TABLE 3 Antibodies Associated With Scleroderma

Skin biopsy shows thick and homogenized collagen bundles in the dermis and subcutis (Ferreli et al., 2017; Tratenberg et al., 2017). Similar findings are also seen on biopsy of involved internal organs including lungs, gastrointestinal tract, heart, and tendons. In early stages of the disease, inflammatory perivascular infiltrate of lymphocytes, histiocytes, and plasma cells can be seen (Ferreli et al., 2017; Tratenberg et al., 2017). Proliferation and hypertrophy of intimal layer of small- and medium-sized arteries is the most characteristic finding on histopathology. In patients reporting shortness of breath, additional tests are warranted to evaluate for ILD and PAH. These include pulmonary function tests including spirometry, chest x-ray, and echocardiogram. If indicated, high-resolution computed tomography chest and right heart catheterization can be done for better evaluation of pulmonary fibrosis and pulmonary artery pressure, respectively (Denton & Ong, 2015).

TREATMENT

Treatment of SSc is individualized based on organ-specific manifestations. With the exception of antifibrotic medication nintedanib in ILD associated with SSc, there is no other FDA-approved medication for this condition. However, numerous studies have identified the use of methotrexate (MTX), mycophenolate mofetil, cyclophosphamide (CYC), azathioprine, rituximab, and tocilizumab in treating SSc (Fernandez-Codina et al., 2018).

For cutaneous manifestations of SSc, MTX has shown benefit in multiple studies (Fernandez-Codina et al., 2018). In those unable to tolerate MTX or have contraindications or disease progression (mRSS > 32), mycophenolate mofetil, intravenous CYC, and hematopoietic stem cell transplantation have shown benefit (Fernandez-Codina et al., 2018). Steroids as a monotherapy should be avoided as they may worsen renal function and precipitate scleroderma renal crisis. Expert opinion has deemed angiotensin-converting-enzyme inhibitors as gold standard treatment of scleroderma renal crisis (Fernandez-Codina et al., 2018).

Treatment of RP includes lifestyle modifications (keeping both the core and extremities of the body warm). If symptoms progress despite conservative measures, vasodilatory agents including oral calcium channel blockers, phosphodiesterase (PDE5) inhibitors, and topical nitrates can be used. In severe cases, intravenous prostanoids and endothelin receptor antagonist may be used (Fernandez-Codina et al., 2018). Sympathetic nerve blocks have also been studied. In cases of severe digital ischemia and gangrene, amputation may be required.

PAH is treated with PDE5 inhibitors, endothelin receptor antagonists, and prostanoids. For ILD, possible treatments for induction therapy include mycophenolate mofetil, CYC, and rituximab (Fernandez-Codina et al., 2018). Nintedanib is a recently FDA-approved antifibrotic that shows a slowing in the rate of decline in pulmonary function in SSc complicated by ILD (Distler et al., 2019).

Treatment of gastrointestinal manifestations of SSc involves routine management of gastroesophageal reflux disease, dysmotility, or gastrointestinal bleed with additional risk factors and necessary treatment of small intestinal bowel overgrowth or small bowel obstructions occurring as a result of dysmotility. Inflammatory arthritis associated with SSc can be treated with MTX, low-dose glucocorticoids, hydroxychloroquine, and rituximab or tocilizumab (Fernandez-Codina et al., 2018).

CONCLUSION

Scleroderma is an autoimmune condition with multisystemic involvement leading to sclerosis of the skin and internal organs. Skin thickening is a key manifestation of scleroderma, and a timely diagnosis is key to monitor for development of internal organ involvement, which can lead to significant morbidity and mortality.

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