Is it beneficial to combine etanercept and methotrexate in the treatment of psoriatic arthritis?

Current treatment options for PsA

Early diagnosis and treatment of psoriatic arthritis (PsA) can prevent joint function damage and deformities caused by its destruction. PsA therapy includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and tumor necrosis factor inhibitors (TNFi). Among these is etanercept, a dimeric fusion protein that inhibits the activity of TNF-α and TNF-β. Other options include inhibitors of the interleukin pathways 12/23 and 17, Janus kinases, or phosphodiesterase 4.

The combination of methotrexate and TNFi has been shown to be beneficial in patients with rheumatoid arthritis. However, until now, there has not been a comparative study to verify the benefit of combining methotrexate with TNFi for patients with PsA.

Methodology and course of the study

The double-blind clinical study SEAM-PsA (Study of Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) lasted 48 weeks in terms of active treatment, followed by 30 days of observation. The study included patients over 18 years old with active PsA who were naïve to etanercept and other biological treatments, and whose PsA had not been previously treated with methotrexate. Previous methotrexate treatment for psoriasis was allowed only if it was discontinued at least 6 months before the study began and not due to intolerance or toxicity. Entry criteria included at least 3 tender joints, 3 swollen joints, and active psoriasis (lesions at least 2 cm in diameter). Patients using non-steroidal anti-inflammatory drugs or corticosteroids had to be on a stable dose for at least 2 weeks before starting the treatment (at least 4 weeks for corticosteroids). 

Patients were randomized into 3 groups in a 1:1:1 ratio, with treatment administered once weekly: oral methotrexate (target dose 20 mg) + placebo subcutaneously; oral placebo + subcutaneous etanercept (50 mg); oral methotrexate + subcutaneous etanercept. After 24 weeks, patients with an inadequate response were given rescue therapy with combined treatment. 

Results

A total of 851 patients were enrolled in the study, with 81.2% completing it. The average age was 48.4 ± 13.1 years. The majority of participants (56%) had PsA for less than 2 years.

Rescue therapy at week 24 was given to 24.3% of patients in the methotrexate + placebo group, 16.2% in the etanercept + placebo group, and 12.7% in the methotrexate + etanercept group. 

Response to therapy

The parameters of symptom improvement by 20% (ACR20 score) and minimal disease activity (MDA) at week 24 were significantly higher in the etanercept + placebo group compared to the methotrexate + placebo group (ACR20: 60.9 vs. 50.7% patients; p = 0.029; MDA: 35.9 vs. 22.9%; p = 0.005).

Similarly, in the etanercept + methotrexate group, ACR20 and MDA values were significantly higher compared to the methotrexate + placebo group (ACR20: 65.0 vs. 50.7% patients; p = 0.005; MDA: 35.7 vs. 22.9%; p = 0.005).

Consistent differences between groups were observed in secondary response indicators (50% and 70% symptom improvement scores [ACR50, ACR70], the number of patients achieving very low disease activity, and PsA disease activity scores). Patients in both etanercept groups showed less radiographic disease progression at week 48 compared to the methotrexate + placebo group.  

Conclusion

Monotherapy with etanercept and combination therapy using etanercept and methotrexate show higher efficacy than monotherapy with methotrexate in patients with PsA. However, the combination of etanercept and methotrexate did not further enhance the efficacy of etanercept. 

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Source: Mease P. J., Gladman D. D., Collier D. H. et al. Etanercept and methotrexate as monotherapy or in combination for psoriatic arthritis: primary results from a randomized, controlled phase III trial. Arthritis Rheumatol 2019; 71 (7): 1112−1124, doi: 10.1002/art.40851.