Background Psoriatic arthritis (PsA) is a systemic, inflammatory disease. The chronic inflammatory nature of psoriasis and PsA predisposes patients to cardiovascular diseases and metabolic syndrome (MetS). MetS is associated with systemic inflammation and proinflammatory cytokines. Biochemical evidence suggests that methotrexate (MTX) and metformin (MET) may share a common cellular target, the AMP-activated protein kinase. Clinical observations and experimental results argue for an anti-inflammatory and immunosuppressant property of MET.
Objectives A randomized placebo-controlled trial was conducted to evaluate the efficacy and safety of metformin as add-on therapy to MTX compared to MTX after 24 weeks in patients with PsA.
Methods The study randomized 56 patients with a diagnosis of PsA defined by the classification criteria for psoriatic arthritis group. Patients with a history of a cardiovascular event and diabetics were excluded. Of the 56 patients, 28 were active. Active disease defined as ≥6 tender joints, ≥6 swollen joints, psoriasis area and severity index score (PASI) ≥10, erythrocyte sedimentation rate (ESR) >28 mm/hr and C-reactive protein (CRP) ≥10mg/dl. Body mass index (BMI) and classic cardiovascular risk factors were recorded. Blood samples were analysed for glucose, lipid profile, ESR, hsCRP, proinflammatory cytokines; tumour necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and IL-17. The homeostasis model assessment model for insulin resistance (HOMA-IR) was used. The patients were randomized in a 1:1 ratio to receive 500mg/day retarded formulation of metformin (n=29) or placebo (n=29). Continuation of stable doses of MTX (25mg/week), NSAIDs, and/or corticosteroids (prednisone <10 mg/day) was permitted. Metformin drug pause on the day of MTX was given. Folic acid supplementation was given to both groups. The primary clinical endpoint was the ACR 20% (ACR20) response at 24 weeks. Secondary endpoints included reduction in PASI score, Health Assessment Questionnaire- Disability Index (HAQ-DI) and Psoriatic arthritis response criteria (PsARC) score.
Results More metformin- treated (12 of 29 [41%]) than placebo-treated (6 of 29 [21%]) patients achieved ACR20 at 24 weeks (p<0.001). Greater proportions of metformin- than placebo-treated patients had clinically meaningful improvements in HAQ- DI at week 24, p<0.005. Significantly more MET- treated patients achieved PASI75 response at week 24 compared to the placebo group, P<0.001. More patients treated with metformin achieved an improvement in PsARC than placebo (55% vs 31% (p<0.001)). There was a significantly greater reduction in proinflammatory cytokines in the metformin group compared to the placebo group. Furthermore, BMI and HOMA improved significantly in the intervention group as compared to the placebo group. The proportion of patients with adverse events were similar in the metformin and placebo groups.
Conclusions Metformin as add-on therapy to MTX in PsA achieved greater improvements in all clinical outcomes measured compared to MTX use alone. Metformin had an anti-inflammatory effect. Metformin may thus be a valid therapeutic addition in PsA. Suppression of the inflammatory signalling pathways that play a role in PsA and contribute to the development of co-morbidity such as cardiovascular risk, obesity and diabetes mellitus may be prevented or dampened by metformin.
Disclosure of Interest None declared
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