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Scleroderma (systemic sclerosis)
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Systemic sclerosis (SSc), sometimes referred to as scleroderma, is a rare, multisystem disease characterized by cutaneous sclerosis, autoantibody production, and vascular abnormalities, often leading to visceral disease. It can affect any organ system, particularly the skin, 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) . A small subset of patients known as systemic sclerosis sine scleroderma have no detectable skin involvement but have other clinical features along with autoantibodies specific to SSc. In some cases, older patients with late-onset disease and anti-RNA polymerase III antibodies may present with systemic sclerosis as a paraneoplastic phenomenon. Localized scleroderma, or morphea, is a distinct condition, with differing prognosis and treatment.
Management Strategy
Prognosis differs between lcSSc and dcSSc and is largely influenced by the degree of visceral involvement. Notably, patients with both lcSSc and dcSSc need to be evaluated for systemic disease. To date, there is no treatment that has proven uniformly effective in modifying disease course; however, increasing data supports the use of various therapeutic agents in SSc. Treatment should be tailored for each patient, taking into consideration disease subset, severity, and organ involvement.
In most cases, cutaneous lesions and RP precede systemic involvement. The face and hands are typically involved, with patients reporting increased skin stiffness/rigidity and skin displaying a characteristic shiny appearance. Patients should be counseled on gentle skin care practices. Topical tretinoin may improve perioral radial furrows and facial tightening. Hyaluronidase treatment may improve microstomia . Antihistamines may help itch; however, severe pruritus may require systemic therapy. Calcinosis cutis may require surgical removal, and intralesional sodium thiosulfate is occasionally justified.
For the treatment of RP, vasodilators such as nifedipine reduce vasospasm and improve peripheral blood flow. Losartan has been found to be effective in reducing the severity and frequency of attacks of RP. Phosphodiesterase type 5 (PDE-5) inhibitors, selective serotonin reuptake inhibitors (SSRIs), pentoxifylline, and α-blockers are other treatment options. Digital ulcers are a frequent problem in SSc and may become infected. Recalcitrant ulcers may respond to sildenafil . Endothelin receptor antagonists may improve digital perfusion. Palmar sympathectomy and botulinum toxin may be valuable. Parenteral prostacyclin analogs also improve the severity and frequency of RP.
Both psoralens and ultraviolet A (PUVA) photochemotherapy and ultraviolet A1(UVA1) phototherapy have been reported to improve skin thickness. Most SSc experts currently use mycophenolate at doses of 2–3 g/day as first-line therapy as it has demonstrated benefit in both skin and lung involvement and has a favorable risk profile. Cyclophosphamide (1–2 mg/kg/day) can reduce cutaneous sclerosis and prevent development of lung fibrosis . Pulsed therapy with cyclophosphamide is effective and possibly safer. Both low-dose prednisolone and methotrexate 15–25 mg/week have been shown to reduce skin thickness scores. However, corticosteroids at doses >15 mg/day is a risk factor for the development of scleroderma renal crisis (SRC). Ciclosporin 3–4 mg/kg/day may improve skin induration but has no effect on internal organ involvement.
Various biologics ( rituximab, infliximab, basiliximab, imatinib ) have been investigated with varying success. Stem cell transplantation shows efficacy in progressive dcSSc with a poor prognosis, but has significant treatment-related morbidity and mortality. Patient selection is critical and must take into account the degree of organ involvement.
Respiratory involvement develops in roughly 60%–80% of SSc patients, with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) being the most frequent types. Iloprost infusions have been shown to reduce PAH. Angiotensin-converting enzyme (ACE) inhibitors are particularly effective in the treatment of SRC. Proton pump inhibitors treat esophageal disease. Prokinetic dopamine agonists may help dysphagia and reflux. Intermittent broad-spectrum antibiotics may diminish bacterial overgrowth and blind loop syndrome.
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 for their selective targeting. This in turn opens the door for therapeutic strategies using novel compounds or innovative ways of using already approved drugs.
Specific Investigations
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Antinuclear antibody negative systemic sclerosis
Salazar GA, Assassi S, Wigley F, et al. Semin Arthritis Rheum 2015; 44: 680–6.
The majority (90%–95%) of patients with SSc have antinuclear antibodies (ANA). ANA-negative SSc disproportionally affects males and tends to have less vasculopathy (decreased PAH, digital ulcers, telangiectasias) and possibly more frequent lower gastrointestinal involvement.
Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies
Reveille JD, Solomon D. Arthritis Rheum 2003; 49: 399–412.
Anti-Scl-70 and anticentromere (ACA) antibodies are very useful in distinguishing SSc patients from healthy controls, patients with other connective tissue diseases, and unaffected family members. Among SSc patients, antiScl-70 positivity is associated with higher risk for diffuse cutaneous involvement and radiographic pulmonary fibrosis while ACA positivity is more likely to have limited skin involvement and less likely to have radiographic pulmonary fibrosis.
Once a patient is determined as being antiScl-70 or ACA-positive or negative, there is no justification for serial determinations.
Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening
Shah AA, Casciola-Rosen L. Curr Opin Rheumatol 2015; 27: 563–70.
Studies have demonstrated that SSc patients with anti-RNA polymerase III antibodies have a significantly increased risk of cancer within a few years of disease onset. Epidemiologic data demonstrate that patients developing SSc at older ages also have a short cancer–scleroderma interval, suggestive of paraneoplastic disease.
Calcium channel blockers for primary and secondary Raynaud’s phenomenon
Rirash F, Tingey P, Harding S, et al. Cochrane Database Syst Rev 2017; 12.
Calcium channel blockers led to a relative reduction of 44% in frequency of Raynaud episodes compared with placebo and also decreased pain and severity of attacks.
Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo controlled SEDUCE study
Hachulla E, Hatron P-Y, Carpentier P, et al. Ann Rheum Dis 2016; 75: 1009–15.
This prospective, randomized, double-blind, placebo-controlled study of 83 SSc patients showed sildenafil to significantly reduce the number of digital ulcers by week 8 compared with the placebo group, reflecting a higher healing rate in the sildenafil group.
Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis-related pulmonary artery hypertension and cutaneous vascular complications
Kumar U, Sankalp G, Sreenivas V, et al. Rheumatol Int 2013; 33: 1047–52.
A prospective, open-label, uncontrolled pilot study in 17 patients with scleroderma and PAH treated with sildenafil showed statistically significant improvement in 6-min walk test, World Health Organization (WHO) class of dyspnea, severity of RP, and mean pulmonary artery pressure (mPAP) from their pretreatment values. Additionally, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing.
Iloprost for the treatment of systemic sclerosis
Hachulla E, Launay D, Hatron P-Y. Presse Med 2008; 37: 831–9.
Intravenous iloprost, a stable analog of PGI 2 , is effective in the treatment of SSc-RP, reducing the frequency and severity of attacks. It also appears useful for the treatment of digital ulcers and improves kidney vasospasm.
Losartan therapy for Raynaud’s phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial
Dziadzio M, Denton CP, Smith R, et al. Arthritis Rheum 1999; 42: 2646–55.
In this trial, 25 patients with primary RP and 27 patients with SSc-RP were treated with either losartan or nifedipine. Losartan reduced the frequency and severity of RP and its clinical benefit was greater in patients with primary RP.
The therapeutic efficacy of botulinum toxin in treating scleroderma-associated Raynaud’s phenomenon
Bello RJ, Cooney CM, Melamed E, et al. Arthritis Rheumatol 2017; 69: 1661–9.
Forty patients with SSc-RP received 50 units of botulinum toxin type A in one randomly selected hand compared with sterile saline in the opposite hand. Patient reported outcomes (hand function, cold, pain sensitivity scores) were better in the Botox-treated hand but did not reach statistical significance.
Therapeutic management of acral manifestations of systemic sclerosis
Meyer MF, Daigeler A, Lehnhardt M, et al. Med Klin 2007; 102: 209–18.
Calcium channel antagonists, α 1 -adrenergic blockade with prazosin, losartan (angiotensin II receptor inhibitor), fluoxetine (SSRI), and prostacyclin analogs have been beneficial in the treatment of SSc-RP.
Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial
Tashkin DP, Roth MD, Clements PJ, et al. Lancet Respir Med 2016; 4(9): 708–19.
In total, 142 SSc patients with ILD were randomized to receive treatment with mycophenolate mofetil (MMF) for 2 years or cyclophosphamide (CYC) for 1 year. Both treatments resulted in significant improvement in lung function over the 2-year course of the study. Skin improvement, measured by a decrease in mRSS, was seen in most patients irrespective of treatment (73.6% subjects on CYC, 71.7% subjects on MMF). MMF was better tolerated and had less toxicity.
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