The updated EULAR recommendations for treatment of systemic sclerosis, according to the organ involvement, including strength of the recommendations and the results of internal evaluation within the task force group
| Organ involvement | Recommendation | Strength of recommendation | Results of internal evaluation |
|---|---|---|---|
| I. SSc-RP | A meta-analysis of RCTs on dihydropyridine-type calcium antagonists indicates that nifedipine reduces the frequency and severity of SSc-RP attacks. A meta-analysis of RCTs indicates that PDE-5 inhibitors reduce the frequency and severity of SSc-RP attacks. Dihydropyridine-type calcium antagonists, usually oral nifedipine, should be considered as first-line therapy for SSc-RP. PDE-5 inhibitors should also be considered in treatment of SSc-RP. | A | 8.19 |
| A meta-analysis of RCTs on prostanoids indicates that intravenous iloprost reduces the frequency and severity of SSc-RP attacks. Intravenous iloprost should be considered for severe SSc-RP. Experts recommend that intravenous iloprost should be used for treatment of SSc-RP attacks after oral therapy. | A | 8.29 | |
| One small study indicates that fluoxetine might improve SSc-RP attacks. Fluoxetine might be considered in treatment of SSc-RP attacks. | C | 6.06 | |
| II. Digital ulcers in patients with SSc | Two RCTs indicate that intravenous iloprost is efficacious in healing digital ulcers in patients with SSc. Intravenous iloprost should be considered in the treatment of digital ulcers in patients with SSc. | A | 8.39 |
| A meta-analysis of RCTs and results of an independent RCT indicate that PDE-5 inhibitors improve healing of digital ulcers in patients with SSc. Moreover, the results of one small RCT indicate that PDE-5 inhibitors may prevent development of new digital ulcers in SSc. PDE-5 inhibitors should be considered in treatment of digital ulcers in patients with SSc. | A | 8.03 | |
| Bosentan has confirmed efficacy in two high-quality RCTs to reduce the number of new digital ulcers in patients with SSc. Bosentan should be considered for reduction of the number of new digital ulcers in SSc, especially in patients with multiple digital ulcers despite use of calcium channel blockers, PDE-5 inhibitors or iloprost therapy. | A | 8.19 | |
| III. SSc-PAH | Based on the results of high-quality RCTs including heterogeneous population of patients with PAH, including CTD-PAH, several ERA (ambrisentan, bosentan and macitentan), PDE-5 inhibitors (sildenafil, tadalafil) and riociguat have been approved for treatment of PAH associated with CTDs. ERA, PDE-5 inhibitors or riociguat should be considered to treat SSc-related PAH. | B | 8.32 |
| One high-quality RCT in patients with SSc indicates that continuous intravenous epoprostenol improves exercise capacity, functional class and haemodynamic measures in SSc-PAH. Intravenous epoprostenol should be considered for the treatment of patients with severe SSc-PAH (class III and IV). | A | 8.10 | |
| Based on the results of high-quality RCTs including heterogeneous population of patients with PAH, including CTD-PAH, other prostacyclin analogues (iloprost, treprostinil) have also been registered for treatment of PAH associated with CTDs. Prostacyclin analogues should be considered for the treatment of patients with SSc-PAH. | B | ||
| IV. Skin and lung disease | Two RCTs and their re-analysis have shown that methotrexate improves skin score in early diffuse SSc. Positive effects on other organ manifestations have not been established. Methotrexate may be considered for treatment of skin manifestations of early diffuse SSc. | A | 7.42 |
| In view of the results from two high-quality RCTs and despite its known toxicity, cyclophosphamide should be considered for treatment of SSc-ILD, in particular for patients with SSc with progressive ILD. | A | 7.84 | |
| Regarding HSCT, two RCTs have shown improvement of skin involvement and stabilisation of lung function in patients with SSc and one large RCT reports improvement in event-free survival in patients with SSc as compared with cyclophosphamide in both trials. HSCT should be considered for treatment of selected patients with rapidly progressive SSc at risk of organ failure. In view of the high risk of treatment-related side effects and of early treatment-related mortality, careful selection of patients with SSc for this kind of treatment and the experience of the medical team are of key importance. | A | 8.03 | |
| V. SRC | Several cohort studies showed benefit in survival with use of ACE inhibitors in patients with SRC. Experts recommend immediate use of ACE inhibitors in the treatment of SRC. | C | 8.52 |
| Several retrospective studies suggest that glucocorticoids are associated with a higher risk of SRC. Blood pressure and renal function should be carefully monitored in patients with SSc treated with glucocorticoids. | C | 8.10 | |
| VI. SSc-related gastrointestinal disease | Despite the lack of large, specific RCT, experts recommend that PPI should be used for the treatment of SSc-related GERD and prevention of oesophageal ulcers and strictures | B | 8.58 |
| Despite the lack of RCTs in patients with SSc, experts recommend that prokinetic drugs should be used for the management of SSc-related symptomatic motility disturbances (dysphagia, GERD, early satiety, bloating, pseudo-obstruction, etc). | C | 7.97 | |
| Despite the lack of RCTs in patients with SSc, the experts recommend the use of intermittent or rotating antibiotics to treat symptomatic small intestine bacterial overgrowth in patients with SSc. | D | 8.10 |
CTD, connective tissue disease; ERA, endothelin receptor antagonists; EULAR, European League against Rheumatism; GERD, gastro-oesophageal reflux disease; HSCT, haematopoietic stem cell transplantation; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5; PPI, proton pump inhibitor; RCTs, randomised controlled trials; SRC, scleroderma renal crisis; SSc, systemic sclerosis; SSc-RP, Raynaud's phenomenon in patients with SSc.