Scleroderma and Other Fibrosing Conditions

Does this patient have scleroderma?

The term scleroderma comes from the Greek “skleros”, meaning hard, and “derma”, meaning skin. Patients with scleroderma experience thickening and hardening of the skin which occurs due to excessive collagen deposition and fibrosis of the skin.

Scleroderma is a term which encompasses several syndromes, and is subdivided into localized scleroderma or systemic sclerosis. Localized forms of scleroderma include morphea, linear scleroderma or en coup de sabre, where involvement is just limited to the skin and subcutaneous tissues without internal organ system involvement. Systemic sclerosis (SSc) is divided into limited and diffuse forms where specific patterns of skin involvement are observed in addition to specific internal organ system (lungs, heart, gastrointestinal tract) involvement. However, similar features of hard and thick skin can be seen in other conditions which are often referred to as “scleroderma mimics”. These mimics include eosinophilic fasciitis, nephrogenic systemic fibrosis, scleromyxedema, and scleredema among others.

This article will focus on the diagnosis and treatment of diffuse cutaneous Systemic Sclerosis (dcSSc), eosinophilic fasciitis (EF), and generalized morphea (GM) as three cutaneous fibrosing syndromes seen with wide-spread skin involvement.

The exact pathogenenic mechanisms for most of these conditions are not well understood. Treatment and prognosis for these conditions vary, and it is important to differentiate among these disorders. Certain clinical features can be used to make the correct diagnosis. These include the clinical presentation, distribution of skin involvement, the presence of Raynaud’s phenomenon (RP) and nailfold capillary abnormalities, and the extent of internal organ involvement. The diagnosis is additionally supported by specific laboratory abnormalities including autoantibodies, radiographic features, and pathology if available.

Systemic Sclerosis – diffuse and limited

SSc is a rare condition occurring in 7-489 persons per million. It affects the population at any age; however, the most common incidence occurs between ages 30-50. It is seen in a female to male ratio of 3:1.

In dcSSc early clinical symptoms include painful and/or puffy swollen hands, RP, and numbness in the fingers. These initial symptoms are frequently followed by progression of skin tightening and involvement of multiple other internal organs. In limited cutaneous (lc) SSc, patients tend to have RP for many years prior to the onset of additional symptoms. Patients with dcSSc by definition have involvement of the skin proximal to the elbows and knees, the face, chest, and abdomen. However, either early or late in the course of the disease, the skin involvement may not include all these areas. In lcSSc the skin thickening is limited to the face and areas distal to the elbows and knees.

Patients with SSc usually have internal organ involvement. Patients can develop scleroderma renal crisis (SRC), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), cardiac disease (including fibrosis and arrhythmia), and gastrointestinal (GI) involvement, which may occur at any point along the GI tract from mouth to anus, and frequently includes symptoms of reflux and dysphagia. Additional symptoms may include weight loss, digital ulceration, development of telangiectasias, skin hyperpigmentation or hypopigmentation. Renal crisis and cardiac involvement are more common in those with the diffuse subtype, but other organ involvement is seen in both subtypes. Musculoskeletal involvement including arthritis, joint contractures, and myopathy can additionally occur.

Physical examination findings are very helpful. In early stages, diffuse puffiness or swelling of the hands is frequently observed. If this is seen in conjunction with RP and nailfold capillary dilatation, a high suspicion for scleroderma should be maintained, although it is possible to see such changes in dermatomyositis and mixed connective tissue disease, and occasionally in SLE, especially if there is an overlap condition. With respect to skin thickening and tightness, it is common for the hands to be involved early on. Associated symptoms are pain, numbness and clumsiness of the hands.

Although most patients who develop SSc have RP, it may be absent early in the course of the disease, especially in those patients with the RNA polymerase III antibody who may develop RP later in the disease course. Additionally nailfold capillary changes are helpful if present but are not always seen. The skin thickening tends to progress from the fingers and hands to the forearms and upper arms, to eventually involve the chest and abdomen. The face is usually involved early at the same time as the hands. Feet and lower extremities are frequently involved as well.

Eosinophilic fasciitis

EF, also known as Schulman syndrome, is an uncommon condition whose true incidence is not known. It occurs in adults from age 20-50 and is seen in a female to male ratio of 1:2. The cutaneous changes associated with EF usually occur rapidly and are seen in association with elevated inflammatory markers, blood and tissue eosinophilia, and hypergammaglobulinemia. Different triggers have been suggested for EF and include preceding trauma, vigorous exercise or infection with Borrelia burgdorferii. Toxic exposure with L-tryptophan or toxic rapeseed oil have previously been reported to produce a self-limited EF-like illness. EF can be seen in association with other immunologic phenomena including immune-mediated cytopenias and morphea. In 10-15% of patients with EF, hematologic disorders including malignancies are discovered.

In general, the clinical onset of EF is rapid, with symmetric and inflammatory skin thickening, followed by edema and dimpling of the skin often referred to as a peau d’orange appearance. Over a period of days to weeks this process develops over the forearms and legs and can progress to include the upper arms, thighs, trunk and neck. Usually the face and hands are spared. The skin becomes progressively indurated and involvement of the deeper fascial layers and muscle can cause puckering and venous furrowing. The epidermis tends not to be involved, and this can be observed with palpation of the skin leading to a wrinkling of the epidermis.

The deep involvement of the subcutaneous structures and fascia can lead to the rapid development of severe flexion contractures and it is important that prompt physical therapy be instituted at the onset of treatment. Raynaud’s phenomenon tends to be absent, and inflammatory arthritis may sometimes be present early in this condition. Systemic symptoms including fatigue, malaise, and weight loss. Internal organ involvement is not generally observed, and, if present, should increase suspicion for SSc.

Generalized morphea

Generalized morphea (GM) is a subtype of localized scleroderma, and is a rare disorder that affects children and adults. Morphea of any type has a yearly incidence of approximately 3/100,000 persons, and GM is estimated to occur in 8% of these cases. There is a female to male predominance of 2.6:1 and more than half the cases are seen in children.

GM usually presents with erythematous, inflammatory, and sometimes pruritic patches on the chest, abdomen, back, and limbs. GM, in contrast to other types of morphea, is defined by the presence of ≥4 morpheaform plaques at 2 or more anatomic sites. The lesions tend to start on the trunk and may spread to involve the limbs centrifugally. The fingers and toes are generally not involved, and this helps distinguish the syndrome from SSc. The plaques later become sclerotic and bound-down. The lesions may also appear hypo-pigmented, hyper-pigmented, or shiny, and hair-loss in these affected areas is common. In pansclerotic morphea, the lesions are deeper, involving the subcutis, are circumferential, and may involve most of the body surface, excluding the fingers and toes. After months to years, the plaques soften and may atrophy.

The joints can be involved in morphea with evidence of arthritis or arthralgias. RP has been reported in a minority of patients, therefore this cannot be used as a point of differentiation from SSc, although RP is vastly more common in SSc than GM. In general, the internal organs are spared in GM. A significant proportion of patients have antinuclear antibody positivity.

What tests to perform?

Laboratory testing

Systemic sclerosis

Autoantibodies are helpful in confirming the diagnosis of SSc and have prognostic value. However, a negative autoantibody profile does not exclude disease. Autoantibodies are seen in approximately 90-95% of SSc patients. It is important to note that certain commercial laboratories’ multiplex antinuclear antibodies (ANAs) miss nucleolar ANAs, and ordering an ANA by immunofluorescence is preferable in this context.

There are at least 7 scleroderma specific autoantibodies, with predictive values for various demographic, clinical, and organ system involvement. The antibodies do not change over the course of the illness. An anti-topoisomerase I (anti-Scl70) antibody occurs in approximately 15-40% of all scleroderma patients, and is associated with diffuse SSc and interstitial lung disease. An anti-centromere pattern, also seen in about 20-40% of SSc patients, is strongly associated with the limited cutaneous SSc subtype, and is associated with pulmonary arterial hypertension. An anti-RNA polymerase III antibody is present in approximately 10% of all patients with SSc and is associated with severe and rapid skin progression, malignancy and an increased likelihood for scleroderma renal crisis. U1RNP is seen in 5% of scleroderma patients, and is also present in patients with mixed connective tissue disease, or with joint and muscle disease.

Although these autoantibodies are specific for SSc they are not sensitive, and their absence does not rule out a diagnosis of SSc. Other autoantibodies (PM-Scl, Th/To, U3RNP) are only available through specialized laboratories. The antibodies are usually mutually exclusive, and if present argue strongly for a diagnosis of SSc in the correct clinical context. Some patients with SSc can have serological and clinical overlap with other connective tissue diseases. Lupus specific autoantibodies (Smith, dsDNA) are seen if there is overlap with other connective tissue disease, and anti-CCP antibodies are seen in overlap with rheumatoid arthritis. Ro antibodies and RF can be seen in scleroderma alone and do not predicate overlap per se. In SSc the presence of anti-B2-glycoprotein 1 antibodies is a risk factor for macrovascular disease.

Eosinophilic fasciitis

Peripheral eosinophilia is present in 80% of cases and can be transient. Also observed are elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hypergammaglobulinemia. Creatine kinase (CK) levels are typically normal. Serum ANAs are typically negative. Hematologic abnormalities should be investigated and association with blood dyscrasias can occur in up to 10% of patients.

Other testing

Systemic Sclerosis

Severity of skin involvement is assessed by the modified Rodnan skin score (MRSS), in which a trained observer measures skin thickness by palpation of 17 areas of skin and grades the skin in severity from 0 (normal) to 3 (severely thickened), where 1 and 2 are mild and moderate thickening, giving a score from 0-51. The MRSS is used in clinical trials to assess response to treatment, but its role in clinical practice has not been delineated.

Specific testing is important in categorizing organ involvement at the time of diagnosis and should be performed periodically in patients with dcSSc. Pulmonary function testing (PFT), trans thoracic echocardiography (TTE) with measurement of pulmonary arterial pressure, electrocardiogram, and high resolution CT of the chest are useful in the evaluation of interstitial lung disease (ILD), pulmonary hypertension (PH), and heart disease. These studies are typically performed at the time of diagnosis.

Annual TTE and PFTs is typically done in every patient. PFTs every 6-12 months can be considered especially in high risk patients and if symptoms develop or progress. Although TTE is frequently utilized to screen for PH, correlation between right ventricular systolic pressure measured by TTE and pulmonary artery pressure measurements on right heart catheterization (RHC) is generally poor. Analysis of B-type natriuretic peptide may help in certain circumstances. Most patients with dcSSc will need these studies performed at least annually.

The evaluation of GI symptoms is driven based on the presence and type of symptoms. This evaluation frequently includes endoscopy and barium swallow and other lower GI studies as indicated based on clinical concerns.

Skin biopsy

Biopsy of the skin is helpful in certain cases of dcSSc if the skin lesions are atypical or if the clinical picture is not clear. A skin biopsy is not required for the diagnosis of dcSSc.

A diagnosis of EF can be made with a full-thickness skin biopsy performed by a dermatologist or general surgeon. It is important that the biopsy is deep enough to include the fascia; this is generally not accomplished by a punch biopsy. There is no pathognomonic finding of EF on biopsy. Typically, the epidermis is spared and often there is dermal-hypodermal sclerosis with fibrotic thickening extending down to the fascia. Inflammatory infiltrates may also be present and include eosinophils. If corticosteroid therapy has been initiated, eosinophils are frequently absent. MRI of the affected areas can also be helpful in the diagnosis of EF, and shows clear involvement of the fascia and deep structures.

In GM, a skin biopsy can be helpful in the diagnosis, but it is not required in the correct clinical context. The biopsy should be performed in such a way that it includes the subcutis, and thus an incisional biopsy is generally superior to a punch biopsy in case of deep tissue involvement.

How should patients be managed?

Systemic sclerosis

There are currently no approved targeted therapies for the treatment of scleroderma. Treatment strategies have focused on traditional immunosuppressive therapies that have proven efficacy in other rheumatic conditions. The treatment of dcSSc depends on specific organ involvement and clinical manifestations.

With respect to RP and digital ulceration, dihydropyridine calcium channel blockers (CCBs) (usually nifedipine or amlodipine) are considered first-line. With nitroglycerin and phosphodiesterase inhibitors considered second-line agents. These agents can be used in combination with CCBs.

Additional agents sometimes employed include aspirin, pentoxifylline and bosentan. Bosentan has been shown to prevent the onset of new digital ulcers in two randomized controlled trials (RCTs), but it was not shown to improve healing of active digital ulcers. Intravenous iloprost, an analog of PGI2 (prostaglandin I2), may be helpful in the case of severe RP and can be given in an outpatient setting (0.5-3 ng/kg per minute for 3-5 consecutive days sequentially), although frequently requires inpatient admission at most centers. It is important to note that this dosing regimen is contraindicated in patients with pulmonary hypertension. Additional approaches with anecdotal benefit include sympathectomy (either via nerve blockade or via a surgical approach).

The two best studied medications in the treatment of SSc, and specifically SSc-ILD, have been cyclophosphamide (CYC) and mycophenolate mofetil (MMF). In the Scleroderma Lung Study (SLS) I, a year of treatment with oral CYC for SSc-ILD was found to be modestly better than placebo in stabilizing FVC at one year. However, in a follow-up study this effect was reduced at 2 years, suggesting a transient benefit. In the recently completed Scleroderma Lung Study II, MMF was compared to CYC for the treatment of SSc-ILD. MMF was found to be non-inferior to CYC with comparable improvements in FVC in both treatment groups at 24 months. Of note, the mRSS improved in both treatment arms with a trend favoring CYC. Based on the results of these two trials, first line treatment for progressive SSc-ILD will likely shift from CYC to MMF given its more favorable side effect profile. MMF has separately been evaluated for the treatment of scleroderma skin disease, albeit in small cohorts and may have beneficial effects on lowering skin score, particularly in patients with early dcSSc. A recent post-hoc analysis of the SLS II showed that both MMF and CYC had statistically significant improvements in mRSS in patients with dcSSc at 24 months.

Other traditional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) have been evaluated in scleroderma. A small randomized, controlled trial compared one year of methotrexate to placebo in patients with early (< 3 years) diffuse scleroderma. Despite the small size of the study, there was a trend towards improvement in the mRSS in the MTX group. The European League Against Rheumatism (EULAR) and European Scleroderma Trial and Research Group (EUSTAR) recommend MTX for skin disease in patients with early dcSSc.

Rituximab, a monoclonal antibody against CD20, used in the treatment of rheumatoid arthritis and ANCA associated vasculitis, has come of interest in the treatment of SSc. A small nested case-control study demonstrated that patients treated with Rituximab versus matched controls had improvement in their mRSS, and prevented further decline of FVC in a small subset of patients with ILD. While Rituximab may be beneficial in SSc, larger studies are needed.

In light of recent advances in the understanding of the pathogenesis of SSc, new antifibrotic agents are currently in development and have entered Phase II and III trials. Some of the newer drugs include fresolimumab, a monoclonal antibody to TGF-beta, an LPA₁ antagonist, SAR100842, tocilizumab, a monoclonal antibody against the IL-6 receptor. These drugs have shown promise in early phase trials with improvement in skin scores.

Two recently approved drugs for idiopathic pulmonary fibrosis, pirfenidone and nintedanib are now being studied in SSc-ILD. A Phase II trial of pirfenidone in SSc-ILD (LOTUSS) was completed and showed acceptable tolerability, even with over 60% of patients concurrently taking MMF. A Phase III trial of nintedanib in SSc-ILD is currently ongoing.

Given the relatively poor prognosis of SSc-ILD and the historic lack of targeted therapies for the disease, autologous hematopoietic stem cell transplant (HSCT) presents a potentially attractive therapeutic option. Three major trials have compared HSCT to CYC in SSc patients with internal organ involvement. ASSIST (Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial), a single center study, found that patients with dcSSc and internal organ involvement treated with HSCT compared to IV CYC for 6 months had improvement in skin scores and FVC at 12 months. The ASTIS (Autologous Stem cell Transplantation International Scleroderma) trial, a multi-center study in Europe and Canada, found that dcSSc patients treated with HSCT had improved event-free and overall survival despite a 10% treatment related mortality in the HSCT group, when compared to one year of IV CYC. The SCOT (Scleroderma: Cyclophosphamide Or Transplantation) trial, a multi-center study in North America, comparing IV cyclophosphamide for 1 year with HSCT, found that there was long-term superiority to myeloablative HSCT with lower transplant related mortality than expected (3%). HSCT may be considered for patients with severe disease who have been refractory to other treatment options.

Pulmonary hypertension is another leading cause of morbidity and mortality in SSc. The WHO (World Health Organization) has developed a functional classification system to categorize PAH according to its clinical symptoms and severity. In general, oral therapy is recommended for patients with functional class (FC) II or higher, and the goal of treatment is to improve functional class. Current therapies for SSc-PAH target the vasoconstrictive and vasodilatory mediators produced by the dysfunctional endothelium. The three main targeted pathways for the treatment of SSc-PAH include the nitric oxide pathway (phosphodiesterase type 5 inhibitors- sildenafil, tadalafil), the endothelin pathway (bosentan, ambrisentan) and the prostacyclin pathway (epoprostenol, iloprost, selexipag). It is important to note that many of the large randomized trials in PAH have not been designed or powered to look at SSc-PAH specifically, and evidence for the use of these medications for SSc-PAH is gathered from subgroup analyses of larger studies or smaller series of SSc patients.

Scleroderma renal crisis is treated with ACE-inhibitors. There is expert agreement that ACE-inhibitor therapy should be maximized in preference to the use of other antihypertensives. There are several retrospective studies that suggest that steroid use greater than 15 mg of prednisone equivalent are associated with a risk for SSc renal crisis, and moderate to high dose steroids should be avoided whenever possible in SSc patients.

Specific scleroderma patients are at higher risk for SRC than others: those with a positive RNA polymerase 3 antibody and those with rapidly progressive early skin involvement. We recommend that these patients, as well as all patients with dcSSc, obtain blood pressure monitors for home use and keep a record of their blood pressure monitoring regularly. We give instructions to notify us if the blood pressure increases by 20-30 points or if it is higher than 140 mm Hg. There is no utility for the prophylactic use of ACE-inhibitors to prevent SRC; however, early treatment of SRC is important to prevent end-stage renal disease, stroke and hypertensive retinopathy.

Scleroderma gastrointestinal disease is an important source of morbidity. Evidence based guidelines for treatment in the form of RCTs are lacking, but proton pump inhibitors should be used for the treatment of gastroesophageal reflux. Promotility agents including Reglan, domperidone and octreotide can be utilized in the treatment of dysmotility, and malabsorption when caused by bacterial overgrowth is treated with antibiotics.

The musculoskeletal manifestations of dcSSc include inflammatory myositis, myopathy related to fibrosis, arthritis, and the development of flexion contractures among others. The treatment of arthritis and inflammatory myositis follows that of other connective tissue diseases. Early and aggressive physical and occupational therapy for the prevention of flexion contractures in scleroderma patients is especially warranted.

Eosinophilic fasciitis

Treatment with high-dose corticosteroids early in the course of EF is associated with a beneficial clinical response. The starting dose of corticosteroid is generally prednisone equivalent of 0.5-1mg/kg daily and this should be maintained until there is evidence of clinical response. Subsequent tapering of prednisone is slow and frequently lasts over 1 year. Combination of immunosuppression with MTX or MMF may allow faster tapering of corticosteroid. Use of hydroxychloroquine has also been reported.

Generalized morphea

Topical therapy with topical steroids or vitamin D analogues, which is frequently effective for other forms of morphea, is usually not sufficient for GM. Phototherapy and/or systemic therapies should be considered. In the case of superficial involvement, a trial of phototherapy, specifically UVA light is prudent. However, if involvement is deep, phototherapy is unlikely to penetrate sufficiently. First line systemic therapy is generally a combination of glucocorticoids and MTX with a target dose of 15-25 mg/weekly by oral or subcutaneous administration. Prednisone 1 mg/kg daily is an appropriate starting dose for patients with rapid progression of disease and deep involvement with a gradual taper. IV pulse methylprednisolone has also been used in severe cases with some efficacy.

Other agents employed for the treatment of morphea include: hydroxychloroquine, MMF, penicillamine, colchicine, cyclosporine, bosentan, and infliximab. There is little evidence to support efficacy for these agents.

What happens to these patients?

Systemic sclerosis

SSc is a chronic condition with a heterogeneous clinical course and no curative therapies to date. The prognosis is primarily dependent on internal organ system involvement and disease subtype (limited versus diffuse).

The overall mortality rate of dcSSc is at least fivefold higher than age and sex adjusted general population. ILD and PH are the leading cause of death in scleroderma.

It is important to note that over the past decade, mortality for patients with SSc has significantly improved owing to improved ascertainment of organ system involvement and directed therapy.

Eosinophilic fasciitis

Many patients with EF can achieve full remission. Some factors that are associated with poor outcome include younger age of onset, presence of morphea lesions, and truncal involvement. Physical therapy is important to combat the disability associated with flexion contractures.

Generalized morphea

The clinical course of GM is variable. The plaques can be uncomfortable and disfiguring and can be associated with musculoskeletal complications including arthritis and joint contractures. Morphea lesions in children can be especially disabling when they interfere with normal growth and development. Over time the plaques tend to soften, but pigmentation abnormalities may persist indefinitely.

How to utilize team care?

• In SSc, specialty consultations are frequently required including pulmonary (ILD and PH expertise), gastroenterology, dermatology, cardiology, renal, and neurology. The role of the rheumatologist is to determine the organ involvement and refer cases as needed. These are generally not required for GM or EF though coordinated care with Dermatology can take place.

• Occupational and Physical Therapy are necessary in the case of SSc, GM and EF. Therapists are essential in the treatment and prevention of contractures which are a large source of disability in this patient population. Referral should be made early, and longer than usual courses of therapy may be of benefit.

• Patients with SSc may develop unique dental issues therefore communication between medical doctors and dental providers is essential.

• A nutrition referral may be of benefit in patients with issues of malabsorption.

Are there clinical practice guidelines to inform decision making?

EULAR/EUSTAR recommendations for the treatment of systemic sclerosis were published in 2009 and revised in 2016, and include 14 different recommendations depending on the clinical problem being addressed. In a survey of members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group, most recommendations were relatively well accepted among SSc experts with some regional disagreement based on access differences.

Given the rarity of EF and GM there are no clinical practice guidelines.

Other considerations

ICD-10 codes

• M34.9 Systemic sclerosis

• M34.1 CREST/Limited scleroderma

• L94.0 Morphea/Localized scleroderma

• M72.9 Eosinophilic fasciitis

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