Rheumatology

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, including localized forms of scleroderma (morphea), where involvement of skin and subcutaneous tissues without internal organ system involvement is seen, and systemic sclerosis (SSc), where specific patterns of skin involvement are observed in addition to specific organ system involvement. However, similar features of hard and thick skin can be seen in other conditions which are sometimes referred to as “mimics” of SSc. 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 pathogenetic mechanisms for most of these conditions are not well understood. Treatment and prognosis for the 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 context, distribution and type of skin involvement, the presence of Raynaud’s phenomenon (RP) and nailfold capillary abnormalities, and the presence and type of internal organ involvement. Specific laboratory abnormalities including autoantibodies, radiographic features, and pathology can additionally be helpful as well.

Systemic sclerosis - diffuse and limited

SSc is a rare condition occurring in 7-489 persons per million population. It can affect patients of 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 complaints include painful and/or puffy hands, RP, and numbness in the fingers or sometimes the carpal tunnel syndrome. These initial symptoms are frequently followed by progression of skin fibrosis and symptoms related to multiple other internal organs. In limited cutaneous (lc) SSc, patients tend to have Raynaud’s phenomenon 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 which can include the chest, abdomen, back and upper and lower legs. However, either early or late in the course of the disease process, the skin involvement may not include these areas. In lcSSc the skin thickening is distal to the elbows and knees only and includes the face as well.

Patients with SSc usually have internal organ involvement. This includes scleroderma renal crisis, interstitial lung disease (ILD), pulmonary arterial hypertension, 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 reflux and esophageal dysfunction. Additional symptoms may include weight loss, digital ulceration, development of telangiectasia, 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, contracture, and myopathy is important as well.

Physical examination findings are very helpful in this diagnosis. In a very early setting diffuse puffiness 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 also in dermatomyositis and mixed connective tissue disease, and also occasionally in SLE, especially if there is some overlap involved. 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 Raynaud’s phenomenon, it is possible for this symptom to 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 chest and abdomen. The face is usually involved early at the same time of the hands. Feet and lower extremities are frequently involved as well.

Eosinophilic fasciitis

EF, also known as Schulman’s syndrome, is a very rare condition whose true incidence is not known. It tends to occur in adults in 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 associated with EF and include preceding trauma, vigorous exercise or infection with Borrelia burgdorferii. Toxic exposure with L-tryptophan or toxic rapeseed oil have produced self-limited EF-like illnesses historically. 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 found.

In general, the clinical onset of EF is rapid, with symmetric and inflammatory skin thickening. and with edema and dimpling often referred to as a peau d’orange appearance. Over a period of days to weeks this process occurs 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 layers of fascia and muscle can cause puckering and venous furrowing. One important point is that 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 for prompt physical therapy to be instituted at the onset of treatment. Nailfold capillary examination will be normal even if Raynaud’s phenomenon is present, although Raynaud’s tends to be absent. Inflammatory arthritis may be present in the early inflammatory phase as well. Systemic complaints including fatigue, malaise, and weight loss can be observed. Internal organ involvement is not generally observed, and, if present, should increase suspicion for SSc.

Generalized morphea

Generalized morphea (GM) is a subtype of morphea or localized scleroderma, and is quite rare. Morphea of any type has a yearly incidence of approximately 3/100,000 persons, and GM is estimated to occur in 8% of cases. There is a female to male predominance of 2.6 :1, and the mean age of incidence is 33, although morphea is seen in all ages with up to half of cases occurring in children.

GM usually presents with erythematous, inflammatory, and sometimes pruritic patches on the chest, abdomen, back, and limbs. The lesions tend to start on the trunk and then may spread to involve the limbs centrifugally. The fingers and toes are generally not involved and this point serves to help distinguish this clinical syndrome from SSc, although not from eosinophilic fasciitis. 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. GM, in contrast to other types of morphea, is defined by the presence of ≥4 morpheaform plaques at 2 or more anatomic sites. In pansclerotic morphea, the lesions are deeper, involving the subcutis, circumferential, and may involve most of the body surface, but, again, excluding the fingers and toes. After months to years, the plaques soften and may become atrophic.

The joints can be involved in morphea with arthritis or arthralgia and the development of flexion contractures. Raynaud’s phenomenon has been reported in a minority of patients, so the presence or absence of Raynaud’s phenomenon cannot be used as a strict point of differentiation, although it is vastly more common in SSc vs GM. In general, there is no involvement of any internal organs in GM. Very severe skin restriction can lead to pulmonary or gastrointestinal disorders in a strict minority of patients. A significant proportion of patients have concomitant autoimmune disease including antinuclear antibody positivity.

What tests to perform?

Autoantibody testing

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 point out 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 various demographic, clinical, and organ system predictive value. The antibodies do not change over the course of the illness and are usually seen in isolation (i.e., it is exceedingly rare to have more than one antibody). An anti-topoisomerase (or anti-Scl70) antibody occurs in approximately 20% of all scleroderma patients, and is associated with diffuse SSc and interstitial lung disease. An anti-centromere antibody, also seen in about 20% of SSc patients, is seen in strong association with the limited cutaneous SSc subtype and is associated with pulmonary hypertension and protection from renal disease. An anti-RNA polymerase III antibody is positive in approximately 10% of all patients with SSc and is associated with severe and rapid skin progression, as well as with an increased likelihood for scleroderma renal crisis. U1RNP is seen in 5% of scleroderma patients, and is also seen in connection with the mixed connective tissue disease, and 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 not available commercially. 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 mostly if there is overlap with other connective tissue disease, and antiCCP 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-glycoprotein1 antibodies is a risk factor for macrovascular disease.

Eosinophillic fasciitis

Peripheral eosinophillia is present in 80% of cases. Also observed are elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hypergammaglobulinemia, and elevated creatine kinase (CK), and aldolase. An isolated elevated aldolase (with normal CK) has been reported with some frequency and may relate specifically to fascial involvement. An ANA is not usually positive although it can be, but scleroderma specific antibodies including the antiScl70, anti-RNA polymerase 3 and anticentromere antibodies are negative. Hematologic abnormalities should be investigated and association with blood dyscrasia is not uncommon.

Specific tests are important in categorizing organ involvement at the time of diagnosis and should be performed periodically in patients with dcSSc. Pulmonary function testing (PFT), echocardiography 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.

Performing such studies at the time of diagnosis is frequently done. Repeating echocardiography annually and PFTs every 6-12 months can be considered especially in high risk patients and especially if symptoms should develop. Although echocardiography is frequently utilized to screen for PH, correlation between right ventricular systolic pressure measured by trans thoracic echocardiography (TTE) and pulmonary artery pressure measurements on right heart catheterization is generally poor with an r as low as 0.31. Using the 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 tests as indicated based on clinical concerns.

Severity of skin involvement can be assessed by use of the modified Rodnan skin score (MRSS), in which a trained observer grades 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.

Biopsy

In SSc, biopsy of the skin is helpful in certain cases or if the skin lesions are atypical or the clinical picture is not clear. A skin biopsy is not required for the diagnosis of dcSSc. In EF, diagnosis can made with a full-thickness skin biopsy which can be performed by a dermatologist or more frequently a general surgeon. It is important for the biopsy to get deep enough to include fascia which is generally not accomplished by a punch biopsy.

Under the microscope the epidermis will be spared, fibrosis will be seen extending down to fascia and in association with an inflammatory infiltrate. This infiltrate may include eosinophils, but eosinophils are frequently absent especially if corticosteroid therapy has been initiated.

Additionally helpful in diagnosis of EF is MRI of the affected areas. MRI can show clear involvement of fascial areas and deep structures. In GM, a skin biopsy can be helpful in the diagnosis of morphea, 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 so, again, an incisional biopsy is generally superior to a punch biopsy in the case of deep involvement.

How should patients with scleroderma be managed?

Systemic sclerosis

The treatment of dcSSc depends on organ involvement and clinical manifestations. With respect to RP and digital ulceration, dihydropyridine calcium channel blockers (CCBs) (usually nifedipine but other peripheral acting CCBs are also effective) are considered first-line.

Additional agents sometimes employed include aspirin, nitroglycerin, phosphodiesterase inhibitors, and pentoxifylline. Bosentan has been shown to prevent the onset of new digital ulcers in two high quality randomized controlled trials (RCTs), but it was not shown to improve healing of active digital ulcers. Intravenous iloprost may be helpful in the case of severe RP and can be given in an outpatient setting (0.5-3ng/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). Oral formulations of prostaglandin agonists are not yet available in the United States.

The treatment of SSc related skin involvement can be very challenging. Two RCTs showed modest benefit of methotrexate, and this is frequently employed, especially as there is the greatest amount of published experience with the use of methotrexate. In practice, methotrexate is frequently not sufficient for many patients.

In recent years, a greater amount of experience with mycophenolate mofetil (MMF) has developed and it is used with increased frequency. The published data on its use is mostly retrospective, and to date has not been proven effective in an RCT. Cyclophosphamide has been shown in an RCT to improve the MRSS, but because of its side effects, it is not generally used for the treatment of skin disease in the absence of internal organ involvement. Azathioprine and cyclosporine have also been used but have been studied less extensively.

More recently there have been open-label investigations looking at B-Cell depleting therapies, and there may be utility of rituximab in the treatment of skin disease. Imatinib is a tyrosine kinase inhibitor which has shown some beneficial effect on skin thickness in some open-label studies, but was not clearly effective in others. Additional study of this approach is underway. D-penicillamine and oral collagen were not found to be effective in RCTs, but the former is still used in a case by case basis in certain situations.

In the treatment of scleroderma related interstitial lung disease (ILD), there is data from 2 high quality RCTs that indicates a modest degree of benefit from cyclophosphamide. Unfortunately, this benefit has not been seen to be durable following cessation of treatment; however, its utility in a given patient should still be considered. Study is ongoing assessing the utility of MMF and autologous hematopoetic stem cell transplant (HSCT).The use of HSCT has been shown to result in improvement of skin thickening and functional ability as well as stabilization of major organ function in some carefully selected patients. This is being further studied in phase 3 studies in the US and Europe. There is some data for the use of rituximab in this context as well, and this is an area of intense study.

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 steroids greater than 15mg 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 skin involvement especially early in the course of their illness. We recommend that these patients, as well as all patients with dcSSc, obtain blood pressure monitors for home use and check blood pressure regularly and record it. We give instructions to notify us if the blood pressure increases by 20-30 points or if it is higher than 140mmHG. There has not been found to be a 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 in these patients. Evidence based guides to treatment in the form of RCTs are especially 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 rotating 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 is borrowed from that of other connective tissue disease. A strong point to be made is the need for early and aggressive physical and occupational therapy for the prevention of flexion contractures in scleroderma patients.

Eosinophillic fasciitis

Treatment with high-dose corticosteroids early in the course of EF is associated with beneficial clinical response. The starting dose of corticosteroid is generally prednisone equivalent of 0.5-1mg/kg daily which 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 methotrexate or mycophenalate mofetil may allow faster tapering of corticosteroid. Use of hydroxychloroquine, D-penicillamine, and other therapies have 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 is prudent. However, if involvement is deep, phototherapy is unlikely to penetrate sufficiently. First line systemic therapy is generally a combination of glucocorticoids and methotrexate. Varying dosages have been used. In general the target Methotrexate dose will be 15-25mg/weekly by oral or subcutaneous administration with 1-2 years of treatment. Prednisone 1 mg/kg daily is an appropriate starting dose especially for patients with rapid progression of disease and deep involvement with a taper. IV pulse methylprednisolone has also been used in severe cases with some efficacy.

Other agents employed for the treatment of morphea include: hydroxychloroquine, mycophenolate mofetil, penicillamine, colchicine, cyclosporine, bosentan, and infliximab. A case report by Loupasakis and Derk (2010) has described the use of mycophenalate mofetil specifically and has observed treatment responses with this medication titrated up to 3g/daily divided bid in recalcitrant cases. There is a single case in the literature of the successful use of imatinib in this setting as well.

What happens to patients with scleroderma?

Systemic sclerosis

SSc is a chronic condition and is without a cure at the present time. Patients with SSc have heterogeneous clinical courses. Much of the determinant of prognosis depends on internal organ system involvement, and disease subtype (limited versus diffuse) is also extremely important with respect to prognosis.

There is an increase in mortality for patients with both lcSSc and dcSSc with a Standardized Mortality Rate (SMR) of 2.7 (95% CI 2.14-3.38) in men with SSc and SMR 3.81 (CI 3.41-4.25) for women seen in 168 patients in a Scottish study from 2003.

The overall mortality rate of dcSSc is at least fivefold higher than an age and sex adjusted general population. Interstitial lung disease and pulmonary hypertension are the most common causes of death related to scleroderma recently, as well as cardiac causes. In the past, scleroderma renal crisis had been the leading cause of death.

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.

Eosinophillic 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. Although the prognosis of EF is frequently favorable, this may require a prolonged course of treatment and the possibility of treatment related toxicity.

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 contracture. Morphea lesions occurring 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, gastroenterology, dermatology, cardiology, renal, and neurology. One of the roles of the rheumatologist is to determine the organ involvement and refer as needed in the case of dcSSc. These are generally not required for GM or EF.

  • 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. Communication is essential between medical doctors and dental providers.

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

Are there clinical practice guidelines to inform decision making?

Systemic sclerosis

EULAR/EUSTAR recommendations for the treatment of scleroderma were published in 2009 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.

Eosinophillic fasciitis and generalized morphea

Given the rarity of EF and GM, with the literature based in case reports and case series, no clinical practice guideline were found.

What is the evidence?

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