BSR and BHPR guideline for the treatment of systemic sclerosis

SSc is a complex, multi-organ disease that requires a comprehensive multidisciplinary guideline. This is a short summary of the guideline, which is available in full as supplementary material at Rheumatology Online. Each recommendation is graded for level of evidence (I-IV) and strength (A-D). Patients are classified as having SSc based on current classification criteria (ACR/EULAR 2013 [1]). Other scleroderma spectrum diseases are not included in this document. Figure 1 summarizes a general approach to management of SSc. Overview of management of SSc The principles of current management of SSc are summarized. Once a confirmed diagnosis is established, all patients can be designated as either lcSSc or dcSSc subset based upon the extent of skin thickening. Proximal skin involvement, involving skin of trunk or proximal limbs, is designated diffuse. Cases with overlap disease should be identified so that overlap features may be treated concurrently with SSc. All patients require symptomatic treatment, and both limited and diffuse cases should be treated for vascular manifestations. Active, early dcSSc requires immunosuppressive treatment. In all cases of SSc, vigilant follow-up to determine significant organ-based complications is mandatory. dcSSc: diffuse cutaneous SSc; lcSSc: limited cutaneous SSc; GI: gastrointestinal. Management of early diffuse cutaneous SSc (dcSSc) should occur within the framework of a multidisciplinary team. Early recognition and diagnosis of dcSSc is a priority, with referral to a specialist SSc centre (III, C). Patients with early dcSSc should be offered an immunosuppressive agent: MTX, MMF or i.v. CYC (III/C), although the evidence base is weak. Some patients might later be candidates for autologous haemopoietic stem cell transplant (ASCT; see below). D-Pen is not recommended (IIa/C). ASCT may be considered in some cases, particularly where there is risk of severe organ involvement, balancing concerns about treatment toxicity (IIa/C). Skin involvement may be treated with either MTX (II, B) or MMF (III, C). Other options include CYC (III, C), oral steroid therapy (in as low a dose as possible to suppress symptoms, and with close monitoring of renal function; III, C) and possibly rituximab (III, C). AZA or MMF should be considered after CYC to maintain improvement in skin sclerosis and/or lung function (III, C). RP is almost universal and can be treated by vasodilators, but benefit must be balanced against side-effects. Around half of patients with SSc report a history of digital ulceration that reflects more structural vasculopathy. Severe digital ulcers (DUs) are those causing or threatening tissue destruction or when three or more occur in 1 year. These should be considered for advanced therapy, such as sildenafil, iloprost or bosentan [2]. First-line treatments are calcium channel blockers (Ia, A) and angiotensin II receptor antagonists (Ib, C). Other treatments that may be considered are: selective serotonin reuptake inhibitors, α-blockers and statin therapy (III, C). Phosphodiesterase type 5 inhibitors are being used increasingly for SSc-related RP (IIa, C). Intravenous prostanoid (e.g. iloprost; Ia, B) and digital (palmar) sympathectomy (with or without botulinum toxin injection) should be considered in severe and/or refractory cases (III, D). DUs require integrated management by a multidisciplinary team; management includes local and systemic treatment (III, C). Oral vasodilator treatment should be optimized, analgesia optimized and any infection promptly treated (III, C). Sildenafil should now be used before considering i.v. prostanoids and bosentan, in line with the current National Health Service (NHS) England Clinical Commissioning policy [3] (I, A). In severe active digital ulceration, patients should receive i.v. prostanoid (Ia, B). In patients with recurrent, refractory DUs, a phosphodiesterase type 5 inhibitor (IIa, B) or i.v. prostanoid (Ia, B) and an endothelin receptor antagonist (including bosentan; Ia, B) should be considered. Digital (palmar) sympathectomy (with or without botulinum toxin injection) may also be considered in severe and/or refractory cases (III, D). Up to 80% of SSc patients will develop interstitial lung disease, but this may be mild and stable. Immunosuppression should be considered when extensive or progressive disease is confirmed. All SSc cases should be evaluated for lung fibrosis. Treatment is determined by the extent and severity and the likelihood of progression to severe disease (I, A). CYC by i.v. infusion is recommended (I, A/B), and MMF may also be used as an alternative or after CYC (II, B). For patients living in England, treatments are initiated through a designated Pulmonary Hypertension Centre (see NHS England A11/S/a) according to the national commissioning policy for treatment of pulmonary arterial hypertension (PAH; NHS England/A11/P/b and NHS Commissioning Board (NHSCB)/A11/P/a), reflecting expert recommendations [4]. Diagnosis should be based upon results of full evaluation of PAH, including right heart catheterization and evaluation of concomitant SSc-related cardiac or lung disease (I, A). Therapies licensed for PAH should be used in the UK Pulmonary Hypertension Centres, taking account of the agreed commissioning policies (I, A/B). Gastro-oesophageal reflux is near universal and needs treatment. Other gastrointestinal (GI) manifestations include constipation, bloating, small intestinal bacterial overgrowth, altered bowel habit and anorectal incontinence (overall management covered elsewhere [5]). The following therapeutic approaches and drugs are considered by experts to be of value in treatment of GI tract complications of SSc. Proton pump inhibitors and histamine H2 receptor antagonists are recommended for treatment of gastro-oesophageal reflux and dysphagia and may require long-term administration (III, C). Prokinetic dopamine antagonists may be used for dysphagia and reflux (III, C). Parenteral nutrition should be considered for patients with severe weight loss refractory to enteral supplementation (III, C). Intermittent broad-spectrum oral antibiotics (e.g. ciprofloxacin) are recommended for intestinal overgrowth, and rotational regimes may be helpful (III, C). Anti-diarrhoeal agents (e.g. loperamide) or laxatives may be used for symptomatic management of diarrhoea or constipation that often alternate as clinical problems (III, C). SSc renal crisis (SRC) causes severe hypertension and acute kidney injury and without treatment is often lethal. It affects 5–10% of SSc patients, predominantly the diffuse subset. Patients at risk of SRC should be followed closely and their blood pressure monitored at least weekly (III, C). Prompt recognition of SRC and initiation of therapy with an angiotensin-converting enzyme inhibitor offers the best opportunity for a good outcome (III, C). Other anti-hypertensive agents may be considered for management of refractory hypertension in conjunction with an angiotensin-converting enzyme inhibitor in SRC (III, C). Clinically evident cardiac involvement includes diastolic or systolic heart failure, arrhythmia and conduction disturbances and has a significant mortality. Although the published evidence base is limited, experts have recommended the following treatment approach for cardiac complications of SSc. Consider immunosuppression with or without a pacemaker (IV, D). Consider the potential benefit of an implantable cardioverter defibrillator (III, D). Angiotensin-converting enzyme inhibitors and carvedilol. Selective β-blockers may be considered, but consider aggravation of RP (IV, D). Diuretics, including spironolactone and furosemide (IV, D). Calcium channel blockers have been shown to reduce the frequency of systolic heart failure in SSc with investigational evidence of cardiac abnormalities (III, D). Treatment of skin thickening, assessed by modified Rodnan skin score, is central to management of dcSSc treatment, and pruritus is common and troublesome in early stage disease. Practical approaches to ensure adequately moisturized skin are essential, especially moisturizers that are lanolin based (III, C). Antihistamines are often used for itch (III, C). Current treatment options for telangiectasia include skin camouflage and laser or intense pulsed light therapy (III, C). There is a very limited evidence base (mainly case reports and small series) to guide clinicians on the management of calcinosis in patients with SSc. Calcinosis complicated by infection should be recognized early and treated with appropriate antibiotic therapy (III, D). Surgical intervention should be considered for severe, refractory calcinosis, which is severely impacting upon functional ability and quality of life (III, D). Musculoskeletal involvement includes tendinopathy, joint contractures and, in some cases, overlap arthritis. Musculoskeletal manifestations of SSc may benefit from immunomodulatory treatments given for other complications, such as skin disease (III, C). When arthritis or myositis is more severe, generally in the context of an overlap SSc syndrome, management is in line with similar clinical conditions occurring outside the context of SSc (III, C). Haematopoietic stem cell transplant registry data, several case reports and pilot studies in the USA and Europe in dcSSc demonstrated a rapid clinical improvement, but with important treatment-related mortality [6]. Current evidence supports use of ASCT in poor-prognosis diffuse SSc where patients do not have severe internal organ manifestations that render this treatment option highly toxic (Ib, B). Although the evidence base is limited, non-drug interventions may have merit and are well tolerated. Specialist experience of SSc cases is likely to make non-drug interventions more effective, and these approaches are popular with patients and can be expected to impact positively on the disease. More research is needed in this area (III, D). SSc should be diagnosed promptly, investigated appropriately and managed within an integrated system of primary, secondary and tertiary level care. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: C.P.D. has been a consultant to Actelion, GlaxoSmithKline, Bayer, Inventiva, Takeda and Roche and received research grants from CSL Behring, Novartis and Actelion. J.v.L. has been a consultant for MSD, Pfizer, Roche, BMS and Eli Lilly. A.L.H. has been a consultant to Actelion and Apricus, has spoken at meetings sponsored by Actelion and received research funding from Actelion. All other authors have declared no conflicts of interest. Detailed diagram of table 1.