A study from the University of Leeds, Leeds, England, showing an association between first-line anti-TNF therapy in early rheumatoid arthritis (RA) and a significantly lower rate of difficult-to-treat (D2T) disease at 5 years was highlighted as one of last year’s notable studies in RA at the 2026 Rheumatology Winter Clinical Symposium (RWCS) in Maui, Hawaii.

“Difficult-to-treat disease is our Achilles heel,” said Jack Cush, MD, who teaches at the Anne Burnett Marion School of Medicine at Texas Christian University in Fort Worth, Texas, and serves as the editor of RheumNow.com. “Early TNF inhibition produced an advantage [in this cohort analysis], especially when it came to reducing the number who went on to develop difficult-to-treat RA. The study makes the case for, ‘use your best drug first.’”

The finding, which was first presented at the American College of Rheumatology 2025 Annual Meeting by Task Toyoda, MBBS, is unsurprising, but “no one has ever shown this as clearly as the Leeds group did,” Cush said in an interview after the RWCS meeting.

Healthcare utilization data favorable for early anti-TNF therapy in the cohort will be reported in the published paper, senior investigator Kulveer Mankia, BMBCh, DM, told Medscape Medical News in an interview. But already, he said, the idea of first-line TNF inhibition is “gaining traction” among experts in the UK who provide guidance for the National Health Service (NHS).

Researchers at the University of Leeds identified patients with early RA in their inflammatory arthritis cohort who were naive to disease-modifying antirheumatic drugs (DMARDs) and treated with an anti-TNF agent as first-line induction therapy for 12 months as part of a clinical trial. The patients were matched with 228 other others who received usual care with treat-to-target conventional synthetic (cs) DMARDs.

At 5 years of follow-up, only 0.9% of 114 patients in the anti-TNF induction group met the European Alliance of Associations for Rheumatology (EULAR) definition of D2T RA compared with 7% of the usual-care/control group (odds ratio [OR], 0.11; P = .033). Additionally, rates of drug-free remission were significantly higher in the anti-TNF group at 5 years (13.2% vs 6.1%; OR, 2.25; P = .049).

The 2021 definition of D2T disease has three components: failure of ≥ 2 biologic or targeted synthetic (b/ts) DMARDs with different mechanisms of action; signs of active disease, inability to taper glucocorticoid treatment, rapid radiographic progress or symptoms causing reduced quality of life; and management that is perceived as problematic by the rheumatologist and/or patient.

At 10 years of follow-up — for which 88% of patients had data available — there remained a trend toward less D2T disease, but it was no longer statistically significant. However, notably, Cush said, significantly fewer anti-TNF-treated patients required two or more bDMARDs at 10 years compared with the csDMARD control individuals (27.7% vs 12.5%; OR, 2.64; P = .006), and a higher proportion achieved sustained remission.

Baseline characteristics, including median seropositivity, symptom duration, and baseline DAS28-ESR (Disease Activity Score in 28 joints using erythrocyte sedimentation rate), were similar in the two groups.

Moving the Needle on Routine Use of First-Line TNF Inhibition

Mankia, professor of clinical and translational rheumatology at the University of Leeds, said in the interview that several previous studies have already indicated that first-line anti-TNF therapy produces faster disease remission compared with usual treat-to-target care. 

But even though “the burden of symptoms and inflammation is reduced early” with TNF inhibition, guidelines from the National Institute of Clinical Excellence, which guides the NHS, have restricted first-line biologic use in early RA because “some studies have shown that [with time], the treat-to-target methotrexate group catches up and achieve similar rates of remission,” he said.

Now, however, there are new forces at play: For one, the availability of TNF inhibitor biosimilars has significantly changed the economic equation, and so has attention paid in recent years to the treatment-resistant state of D2T disease. Therapies currently being developed to treat this state of disease, “such as CAR-T therapy and other cellular therapies,” would be expensive, he said.

“The concept is, why don’t we use a better up-front strategy with a well-established safety profile, which is now more economically attractive and that patients would much rather have, and doctors would much rather prescribe?” Mankia said.

The needle appears to be moving. “We’re looking to move toward routine use of first-line TNF inhibition [for patients with early RA and a poor prognosis] in our center,” he explained, and experts at NHS England have provided positive feedback regarding implementing this approach to the rheumatology team at Leeds.

Regarding national policy, “discussions are underway,” he said. “It may be that a shift in guidance is rolled out initially in early RA patients with a poorer prognosis…such as [those with] positive autoantibodies, higher levels of disability, raised inflammatory markers, and erosions.”

Meanwhile, the Leeds researchers are currently analyzing data from the recently completed TEEMS clinical trial that assessed the use of stratified first-line TNF inhibitor in patients with early RA according to CD4 T-cell subset frequency.

Patients with an abnormal naive T-cell frequency were randomized to receive first-line etanercept with methotrexate or methotrexate alone. Those with a normal T-cell frequency received standard care with methotrexate. The primary outcome is the proportion of patients in remission at 6 months.

Previous work at Leeds showed that a reduced frequency of CD4 naive T cells were predictive of a poor response to first-line methotrexate in patients with early RA, Mankia said, noting that the team hopes to present its TEEMS trial findings at EULAR 2026.

Current guidelines in the US suggest early anti-TNF therapy, but “only after methotrexate or other DMARDs, and they often lump multiple b/tsDMARDs as similar second-line choices,” Cush said. “The research [on frequency of D2T disease] suggests that TNF inhibitors should be or could be first-line DMARD therapy,” he said, pending future prospective studies.

In most RA cohorts, D2T disease has been shown to affect at least 10% of patients, he said.

This study was partially funded by the NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust. At ACR 2025, Mankia disclosed being a consultant for and receiving speaker fees or honoraria from AbbVie, ALLIn Bio, AstraZeneca, DeepCure, Lilly, Serac Healthcare, UCB, and Zura Bio. He also reported receiving grant/research support from several companies.

Cush disclosed at the RWCS meeting serving as a consultant to AbbVie, Novartis, BMS, UCB, and Sanofi.