Rapamycin versus methotrexate in early diffuse systemic sclerosis: Results from a randomized, single‐blind pilot study

Abstract

Objective. To assess the safety and efficacy of rapamycin in the treatment of diffuse systemic sclerosis (SSc; scleroderma).Methods. Eighteen patients with diffuse SSc of <5 years duration were randomized to receive rapamycin or methotrexate (MTX) in a single-blind, 48-week study. Abnormalities in clinical and laboratory parameters were compared between the 2 treatment groups. The potential efficacy of the study drugs was evaluated by comparing results of the baseline and 48-week assessments, including the modified Rodnan skin thickness score (MRSS) and the Health Assessment Questionnaire disability index.Results. The baseline characteristics of the patients were similar in both groups (n ‫؍‬ 9 in each). One patient in the rapamycin group who never received the study drug was excluded from the analysis. Three patients in each group withdrew from the study; 2 of the withdrawals were treatment-related (severe hypertriglyceridemia associated with rapamycin, and pancytopenia associated with MTX), and 4 were SSc-related. Hypertriglyceridemia was the most notable side effect associated with rapamycin, but it was generally well tolerated and treatable. The incidence and severity of other adverse drug reactions were comparable between the 2 groups. Within each group, the MRSS improved significantly from baseline. In the rapamycin group, the patient's global assessment showed a significant improvement from baseline, while forced vital capacity values declined from baseline. The disease activity scores at 48 weeks and the changes in these scores from baseline were not significantly different between the 2 groups.Conclusion. Rapamycin has a reasonable safety profile in a select group of patients with scleroderma. Larger trials are needed to assess the efficacy of rapamycin in patients with early diffuse SSc.

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

“…As mentioned previously, mTORC1 activation also contributes to type I collagen production by fibroblasts, the process that leads to fibrosis in SSc skin lesions 11,12 and is inhibited by rapamycin 13 . In a pilot study of patients with progressive SSc, rapamycin was safe, although it had limited efficacy 15 . TGFβ also activates mTORC2 in skin fibroblasts, as evidenced by increased phosphorylation of AKT at Ser473 154 , and mTORC2 activity also contributes to kidney fibrosis 155 .…”

“…Beyond its effects on T cells in SLE, rapamycin blocks fibroblast proliferation, collagen production and dermal fibrosis in the skin 11,12 and holds promise for the treatment of patients with SSc 15 (TABLE 1). Interestingly, mTORC2 mediates kidney fibrosis 155 , which could explain the limit ed efficacy of mTORC1 blockade by rapamycin in this setting, and suggests that dual ATP-competitive mTOR inhibitors might show improved efficacy (TABLE 1).…”

“…In patients with systemic sclerosis (SSc), mTOR activation contributes to type I collagen production by dermal fibroblasts 11,12 , and rapamycin improves skin fibrosis 13 and reduces osteopenia in a mouse model of the disease 14 . A pilot study of rapamycin in patients with SSc showed limited efficacy, but the treatment was determined safe 15 . Rapamycineluting endovascular stents have also been used to treat large-vessel vasculitis, aortitis 16 and Takayasu arteritis 17 , but the drug has limited clinical efficacy in patients with granulomatosis with polyangiitis (GPA) 18 , despite lowering titers of myeloperoxidase and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) 19 .…”

Implementation von Leitlinien für eine Therapie der systemischen Sklerose (Sklerodermie)

“…Eine kürzlich publizierte randomisierte, einzeln-blinde Studie untersuchte die Wirkung von Rapamycin (Sirolimus; 5-15 ng/ml Spiegel) im Vergleich zu Methotrexat und zeigte einen positiven Effekt auf die globale Gesundheitseinschätzung durch die Patienten, aber keinen Effekt auf die Lungenfunktion [17]. Die Ergebnisse größerer Studien bleiben abzuwarten, um möglicherweise einen evidenzbasierten Einsatz dieser Substanzklasse bei der systemischen Sklerose zu begründen.…”

Systemic sclerosis: Current concepts in pathogenesis and therapeutic aspects of dermatological manifestations

“…d-penicillamine was found effective at a median dose of 750 mg.[71] Rapamycin, a drug that blocks the response of T cells to cytokines including IL-2, was found to be as effective as methotrexate. [6972] Topical application of 0.01% of halofuginone reduced skin scores in a pilot study. [73]…”