Scleroderma

Published on 18/03/2015 by admin

Filed under Dermatology

Last modified 22/04/2025

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Scleroderma

Sameh S. Zaghloul, Najat A.Y. Marraiki and Mark J.D. Goodfield

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Systemic sclerosis (SSc), often called scleroderma, is a rare multisystem disease characterized by skin fibrosis, autoantibody production, and vascular abnormalities often leading to visceral disease. It can affect any organ system, particularly the gastrointestinal tract, kidney, heart, and lungs. Patients typically present with cutaneous sclerosis or Raynaud phenomenon (RP). The degree of skin involvement defines the clinical subset of the disease. Diffuse cutaneous SSc (dcSSc) involves the skin proximal to the neck, elbows, or knees, whereas involvement distal to these sites is known as limited cutaneous SSc (lcSSc); some authors include an intermediate group. Localized scleroderma, or morphea, is a different condition.

Management strategy

Limited cutaneous and dcSSc, with different severities and survivals, have been recognized as distinct subsets. Some authors have suggested an intermediate cutaneous form with intermediate survival.

In most cases cutaneous lesions and RP precede systemic involvement. The face and hands are typically involved, with patients displaying a characteristic shiny appearance of the skin and complaining of increased skin stiffness or rigidity. To date, no treatment has proved uniformly effective in modifying the course of the disease and there is no specific therapy for the skin, although dry skin should be cared for daily using emollient creams. Topical 0.025–0.05% tretinoin may improve the perioral radial furrows and facial tightening.

UVA phototherapy (PUVA and UVA1) has been reported to be effective in reducing skin thickness. Vasodilators such as nifedipine reduce vasospasm and improve peripheral blood flow. Also, losartan, an antagonist of angiotensin II receptor type I, has been found to be effective in reducing the severity and frequency of attacks of RP. Parenteral prostacyclin analogs such as iloprost also improve both the severity and frequency of RP. Both low-dose prednisolone 20 mg/day and methotrexate 15–25 mg/week have been shown to reduce skin thickness scores. Cyclosporine 3–4 mg/kg/day may improve skin induration but has no effect on internal organ involvement. It should be used with caution as renal involvement with SSc is not uncommon. Mycophenolate (0.5–1.5 g bid) is of value for both skin and lung involvement. Cyclophosphamide 1–2 mg/kg/day is of proven value in reducing skin scores and preventing the development of lung fibrosis and other complications, and pulsed therapy with cyclophosphamide is also effective and possibly safer.

Biologics, including rituximab, infliximab, basiliximab and imatinib, have all been investigated with varying success. Trials of stem cell transplantation show promising efficacy, but have significant side effects. Respiratory complications of SSc develop in roughly 30% of patients. Pulmonary hypertension (PAH) may occur and should be confirmed by appropriate investigation. Iloprost infusions have also been shown to reduce PAH. Angiotensin-converting enzyme (ACE) inhibitors are particularly effective in reducing the renal complications of the disease, and early treatment may prevent the onset of renal failure. Proton pump inhibitors treat esophageal disease effectively. Recent randomized controlled trials have suggested that oral minocycline and D-penicillamine are not effective in SSc. Although SSc carries a high case-specific mortality, there have been significant advances in the management of skin, renal, and pulmonary complications. The identification of novel signaling pathways and mediators that are altered in SSc and contribute to tissue damage allows their selective targeting. This in turn opens the door for novel therapeutic strategies using novel compounds, or innovative ways of using already approved drugs.

Specific investigations

First-line therapies

image Nifedipine A
image Iloprost A
image ACE inhibitors B

Second-line therapies

image Methotrexate A
image Cyclophosphamide B
image Prednisolone B
image Losartan B
image Acitretin C
image Colchicine C
image UVA C
image Mycophenolate C

The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis.

Calguneri M, Apras S, Ozbalkan Z, Ertenli I, Kiraz S, Ozturk MA, et al. Clin Rheumatol 2003; 22: 289–94.

In this study 27 patients with early diffuse SSc were treated with oral cyclophosphamide (1–2 mg/kg/day) plus oral prednisolone (40 mg every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. There was a significant improvement in the skin score, maximal oral opening, flexion index, predicted forced vital capacity, and carbon monoxide diffusing capacity in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group.

Third-line therapies

image Extracorporeal photochemotherapy B
image Imatinib B
image Cyclosporine C
image Rituximab C
image Autologous non-myeloablative hemopoietic stem-cell transplantation C
image Thalidomide D
image Etanercept D
image Minocycline F

Other: internal organ involvement

Interstitial lung disease associated with systemic sclerosis: what is the evidence for efficacy of cyclophosphamide?

Berezne A, Valeyre D, Ranque B, Guillevin L, Mouthon L. Ann NY Acad Sci 2007; 1110: 271–84.

Since 1993, the beneficial effect of oral or intravenous cyclophosphamide in the treatment of SSc-related ILD has been reported in retrospective studies, one showing improvement of pulmonary function test scores and/or chest CT at 1 year, and improvement of survival at 16 months. The results of two controlled trials were recently reported. The Scleroderma Lung Study, a prospective randomized placebo-controlled trial, included 158 patients, of which 145 completed at least 6 months of treatment. The course of forced vital capacity (primary outcome) adjusted at 1 year was significantly better in the group treated with oral cyclophosphamide (p<0.03), although the effect of cyclophosphamide was minor.

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