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10-07-2019 | Psoriatic arthritis | Highlight | Article

Methotrexate versus etanercept as first-line therapy for psoriatic arthritis

Authors: Deepak R Jadon, Jobie Evans, William Tillett



There is a substantial body of evidence showing that early diagnosis and effective intervention improve clinical outcomes in patients with psoriatic arthritis (PsA). A significant proportion of patients with PsA experience structural damage, translating to altered physical function within the first few years of disease. Taken together, these factors indicate a “window of opportunity” for improving outcomes in PsA, as we have seen in rheumatoid arthritis (RA), and therefore lead to greater pressure on clinicians to instigate the “best” first-line treatment.

Choosing the most appropriate treatment for PsA must be balanced against comorbidities, including: current or past malignancy; severe or recurrent infections such as hepatitis B and C, tuberculosis, disseminated zoster, and HIV; congestive cardiac failure; and demyelinating disease. Cumulative phototherapy dose for skin psoriasis should also be considered. Lifestyle choices such as smoking, alcohol, and obesity also have differential impact on the appropriateness of therapy choice. Not only should the patient’s current status be taken into account, but also their likely future status based on the patient’s immediate environment and wider demographic. These factors all preclude or hamper the use of tumor necrosis factor (TNF) inhibitor therapy, but not necessarily methotrexate use.

Two recent publications, the American College of Rheumatology (ACR)/National Psoriasis Foundation (NPF) guidelines for the treatment of PsA and the SEAM-PsA clinical trial, have refocused our attention on the positioning of methotrexate and etanercept in the treatment paradigm. This article will debate the clinical reasons relating to efficacy, safety, and practicality for using etanercept or methotrexate as first-line therapy for PsA.

The case for etanercept as first-line therapy in PsA

Author: William Tillett

The recent ACR/NPF guidelines recommend TNF inhibitor therapy over oral small molecule therapy (sulfasalazine, methotrexate, leflunomide, apremilast) for treatment-naïve patients with PsA on the basis of efficacy, and in the absence of contraindications such as infections, congestive cardiac failure, or demyelinating disease. These guidelines cite five randomized controlled trials where a direct comparison was made between methotrexate and TNF inhibitors, and seven with indirect comparisons using the Baucher adjusted indirect method.

In the SEAM-PsA trial, Mease et al set out to examine the efficacy of methotrexate monotherapy relative to etanercept monotherapy, and the value of combining methotrexate and etanercept in patients with PsA. In this double-blind study, 851 patients with PsA were randomized to weekly treatment comprising oral methotrexate 20 mg plus placebo (n=284), etanercept 50 mg plus placebo (n=284), or etanercept 50 mg plus oral methotrexate 20 mg (combination therapy; n=283). The results showed superiority of etanercept over methotrexate monotherapy in terms of ACR20 response and minimal disease activity (MDA) response at week 24, with rates of 60.9 versus 50.7% (p=0.029) and 35.9 versus 22.9% (p=0.005), respectively. The corresponding rates for combination therapy compared with methotrexate monotherapy were 65.0 versus 50.7% (p=0.005) and 35.7 versus 22.9% (p=0.005).

The use of the ACR20 and MDA endpoints in the SEAM-PsA trial is interesting. The ACR20 indicates that etanercept is superior for articular disease, while the MDA, as a modern PsA-specific measure, shows that etanercept is superior in multiple domains including joint disease, skin disease, and enthesitis. In addition to the clinical outcomes, the etanercept arms also showed less radiographic progression compared with methotrexate monotherapy at week 48.

In summary, there is conclusive evidence from the SEAM-PsA trial that etanercept is superior to methotrexate in PsA and therefore, on the basis of efficacy alone and in the absence of contraindications, should be used first-line in PsA. This view is supported by the ACR/NPF guidelines.

The case for methotrexate as first-line therapy in PsA

Authors: Deepak R Jadon, Jobie Evans

Despite not being licensed for the treatment of PsA, methotrexate has been the anchor DMARD in patients with PsA for over 20 years. Methotrexate’s status is reflected by its inclusion in numerous international recommendations for the management of PsA, including the ACR/NPF, EULAR, and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines. The EULAR and the GRAPPA recommendations for the management of peripheral PsA and enthesitis-predominant PsA both position methotrexate before the use of TNF inhibitor medications, with the option to expedite to TNF inhibitor therapy if poor prognostic markers are present.

The Methotrexate in Psoriatic Arthritis (MIPA) clinical trial randomized treatment-naïve patients with PsA to either methotrexate or placebo. At week 24, there were no statistically significant differences between the two treatment groups in terms of the primary endpoint of ACR20 response rate or DAS-28. However, methotrexate was associated with a statistically significant reduction in patient and physician global assessment scores and skin scores. Nevertheless, many in the clinical and research community believe the results of this trial do not reflect what is observed in clinical practice owing to the study’s high attrition rate, submaximal methotrexate target dose of 15 mg/week, preponderance of patients with oligoarticular PsA (which limited the power of analyses), and failure to address the effect of treatment on dactylitis or enthesitis.

The open-label Tight Control in Psoriatic Arthritis (TICOPA) trial, in which 101 out of 206 patients received at least 15 mg/week of methotrexate in the first 12 weeks of the trial, demonstrated a significant proportion of patients achieving ACR20 (40.8%), ACR50 (18.8%), ACR70 (8.6%), MDA (22.4%), and PASI75 (27.2%) response criteria, as well as marked reductions in tender joint count, swollen joint count, dactylitis, and enthesitis scores.

Even with the advent of biosimilars, the price differential between etanercept and methotrexate will, in most countries, still be more than 40-fold. There is a need for robust evidence demonstrating that the gains in efficacy attained by etanercept over methotrexate are both financially and societally justified, especially in countries where provision of healthcare is state-funded.

We have decades of experience and familiarity using methotrexate safely in rheumatic disease; the power of this should not be underestimated. Many clinicians still consider PsA to be a mild disease that can be managed with NSAIDs alone. To replace methotrexate with etanercept in the treatment paradigm might result in them holding that position. Methotrexate should remain first-line in the majority of patients with PsA, as it will achieve remission in up to 25% of patients, is inexpensive, and less immunosuppressive in those with comorbidities.


More data are needed directly comparing etanercept and methotrexate in terms of patient acceptability, drug persistence, sustained (>5–10 years) structural damage alteration, immune modulation, health economics including work productivity, and prognosis modulation before there is a global paradigm shift to using etanercept rather than methotrexate as the first-line treatment of PsA. Research into some of these topics is underway; however, numerous unmet needs still remain.

About the authors

Deepak Jadon

Deepak Jadon is a consultant rheumatologist, Director of the Rheumatology Research Unit, and lead for psoriatic arthritis (PsA) at Addenbrooke’s Hospital, Cambridge, UK. Disclosures

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Jobie Evans

Jobie Evans is a specialist registrar and clinical research fellow in rheumatology at Addenbrooke’s Hospital, Cambridge, UK. Disclosures

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William Tillet

William Tillett is a consultant rheumatologist at the Royal National Hospital for Rheumatic Diseases, Bath, UK, and senior lecturer in the Department of Pharmacy and Pharmacology at the University of Bath. Disclosures

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