The changing face of scleroderma (systemic sclerosis)

A diagnosis of scleroderma (systemic sclerosis) traditionally conjures up an image of a patient with a rapidly progressive, frequently fatal disease for which no treatments are effective. However, with earlier diagnosis, recognition of the wide spectrum of this illness, the emergence of specialty clinics and more effective treatments, this view is now unduly pessimistic.

The last two decades have witnessed significant breakthroughs in understanding the pathogenesis of this disease, leading to more targeted therapies. Although a more optimistic prognosis is warranted, challenges naturally remain.

However, with the upsurge of interest in this condition by medical researchers and the pharmaceutical industry, the future looks brighter. This article addresses some new developments in the treatment of scleroderma and the changing prognosis of this condition.

Epidemiology

The annual incidence of scleroderma is estimated to be 10–20 cases per one million persons.¹ This figure is probably an underestimation as scleroderma encompasses a wide spectrum of problems, ranging from limited cutaneous and oesophageal involvement, to widespread systemic disease resulting in diffuse fibrosis and major internal organ failure.  

Clinical features

The most common subsets of scleroderma are limited cutaneous (60%), where skin thickening is restricted to areas distal to the elbows and knees; and diffuse cutaneous (40%), which affects the proximal limbs and/or trunk. The term CREST (Calcinosis, Raynaud’s, Esophagus, Sclerodactyly and Telangiectasia) associated with limited scleroderma is now outdated. This is because many patients do not fulfil all the criteria for this syndrome, and furthermore it is not discriminating as all these features also occur in diffuse disease.

Figure 1: Chest x-ray showing changes of interstitial lung disease.		Figure 2: High resolution CT scan showing interstital lung disease in a patient with scleroderma.

Treatment

Systemic treatment

Multiple immunomodulatory and antifibrotic therapies have been trialled in scleroderma. Antifibrotic therapies such as low dose D-penicillamine² showed promise in early trials. However a subsequent large randomised study comparing high with low dose D-penicillamine failed to demonstrate improvement in survival. This treatment has largely gone out of vogue. Combination cyclophosphamide and glucocorticoid therapy modestly improved pulmonary outcomes.³ Cyclosporine,⁴ methotrexate⁵ and mycophenolate mofetil⁶ have all shown benefit in open studies. However, the significant side effects of these agents must be weighed against their potential therapeutic benefit.

Better understanding of the pathogenesis of scleroderma has now also raised the possibility of targeted therapy. For example, a recent case study has shown promise with imatinib mesylate⁷ (a tyrosine kinase inhibitor usually used in the treatment of chronic myeloid leukaemia).  The selective inhibition of tyrosine kinase interferes with the signalling of both platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta, two mediators pivotal in the development of fibrosis.

The use of combinations of anticytokine therapies, for example using agents directed against both TGF-beta and connective tissue growth factor (CTGF), are also being explored.

Immunoablative therapy followed by autologous haematopoietic stem cell infusion remains experimental but has been used with some success in patients with severe scleroderma. However, mortality rates are significant, with a progression free five-year survival mortality of 64%.⁸ Several randomised trials of autologous stem cell transplantation are underway.

Vascular disease

Raynaud’s phenomenon is the most common manifestation in scleroderma, and when associated with scleroderma, can lead to digital ischaemia, ulceration and gangrene. Raynaud’s can effectively be managed by avoiding triggers, keeping the whole body warm, using warm gloves and the cessation of smoking. For more refractory cases, calcium channel blockers⁹ (e.g. nifedipine), topical nitrates, angiotensin receptor blockers (losartan) and antiplatelet therapy may be useful.¹⁰ Raynaud’s complicated by digital ischaemia can be managed by the "off-label" intravenous use of the prostacyclin analogue iloprost.¹¹ This treatment is expensive and requires special access scheme approval, and an admission to hospital for several days. Sympathectomy (cervical or localised digital), may be considered in severe cases but its role is not well established.

Scleroderma renal crisis (SRC)

Scleroderma renal crisis (SRC) occurs in 10% of patients with diffuse cutaneous disease. Prior to the introduction of angiotensin converting enzyme inhibitors (ACEIs), this was the most common fatal complication of scleroderma. Patients usually develop SRC within the first three years of their disease. Risk factors include rapidly progressive disease, corticosteroid dose > 15 mg/day, and the anti-RNA-polymerase antibody. Patients develop sudden onset of hypertension, often followed by oliguric renal failure, proteinuria, microangiopathic anaemia and microscopic haematuria. Early recognition and aggressive introduction of ACEIs to reverse the hypertension are critical to preserving renal function. Since their introduction, mortality has fallen appreciably (from 85% at 1 year, to 24% at 1 year in a single centre).¹²  Home monitoring of blood pressure and early review of elevated pressures facilitate early detection and improve management. A persistent increase of 20 mmHg systolic blood pressure or a 10 mmHg rise in diastolic blood pressure should trigger further evaluation.

Pulmonary manifestations

Scleroderma lung complications include interstitial lung disease (ILD) and pulmonary hypertension (PHT).

ILD occurs in approximately 40-50% of patients with diffuse scleroderma and 30% of patients with limited scleroderma. The clinical course varies from mild and asymptomatic to severely debilitating. High resolution CT scans and pulmonary function tests (including diffusing capacity) are the investigations of choice. With the recent development of effective treatment for fibrosing alveolitis, modest preservation of lung function (FVC) and improved health-related outcomes (skin thickening, quality of life, dyspnoea and function) may be achieved if instigated early.^13,14

Significant B cell infiltration has been demonstrated within pulmonary lesions and suggests that B cell depletion therapies (rituximab) are an appealing avenue of investigation for scleroderma lung disease. These are now being investigated.

Lung transplantation is an option for patients with severe ILD that is not responsive to pharmacologic interventions and when carefully selected (no cutaneous ulcers, recurrent episodes of aspiration, renal failure, or left ventricular dysfunction) have a four year survival of approximately 70%.¹⁵ Autologous haematopoietic stem cell transplantation, as discussed below, is another alternative treatment option in rapidly progressive lung disease.

PHT (mean pulmonary artery pressure > 25 mmHg on right heart catheterisation) is more common in patients with limited scleroderma. This may be either due to a primary obliterative pulmonary arteriopathy or secondary to ILD. Dyspnoea on exertion is the earliest symptom, but occurs relatively late when the disorder is moderately advanced. Routine screening with lung function tests (particularly diffusing capacity) and echocardiography enable earlier detection, and now new treatments have significantly improved morbidity and mortality. Bosentan and, more recently, the selective type A endothelin-1 receptor antagonists ambrisentan (US) and sitaxsentan (Europe) have dramatically improved patient survival (1 year 68% to 86% and 2 year 47% to 73%).¹⁶ Sildenafil (Viagra, Revatio), a phosphodiesterase type 5 inhibitor, has also shown promise in short term studies. Trials adding this to endothelin receptor antagonist treatment are currently underway.

Gastrointestinal manifestations

Gastro-oesophageal reflux disease (GORD) and dysphagia are almost universal in patients with scleroderma, although the majority of patients are asymptomatic. Proton pump inhibitors are the mainstay of treatment. Promotility agents (metoclopramide, domperidone) may be useful in patients with intestinal dysmotility, and antibiotics/probiotics may be used to treat malabsorption secondary to bacterial overgrowth.

Changing prognosis

The future is looking brighter for patients with scleroderma. New developments have significantly improved the morbidity and mortality associated with complications such as renal crisis, interstitial lung disease and pulmonary hypertension. Multidisciplinary clinics specialising in the treatment of this multisystem disease are leading to earlier detection of complications and therefore prompt instigation of treatment. Intense research and the development of drugs targeted at specific pathways are already underway and we eagerly await the results of these new, promising agents.

Table 1: New developments in scleroderma

Kindly written by:

Professor Leslie Schrieber MBBS (Hons) MD FRACP; Associate Professor of Medicine, University of Sydney; Department of Rheumatology, Royal North Shore Hospital, NSW;  Editorial Advisory Board Member: Virtual Rheumatology Centre.

Dr Bethan Richards MBBS (Hons) MMed; Senior Rheumatology Registrar, Department of Rheumatology, Royal North Shore Hospital, NSW.

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