Tocilizumab with or without MTX for acute RA: Does combo work better than mono?

Subcutaneous tocilizumab, used either as a monotherapy or in combination with methotrexate (MTX), shows greater efficacy than MTX alone in Chinese patients with active rheumatoid arthritis (RA) who have not adequately responded to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).

This was the finding from a large-scale phase III trial hailed as the first to investigate subcutaneous tocilizumab in a purely Chinese population with RA.

“Subcutaneous tocilizumab, given alone or in combination with MTX, had clinically significant efficacy compared with MTX monotherapy in Chinese patients with moderate-to-severe active RA,” said the authors led by Dr Tian Liu from the Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China.

Liu’s team conducted the trial at 19 clinical sites in China between July 2017 and August 2022. The study sought to evaluate the efficacy of subcutaneous tocilizumab, administered alone or combined with MTX, in 340 patients with moderate-to-severe active RA (mean age 47.5 years, 86.5 percent women). [JAMA Netw Open 2025;8:e2511095]

The patients had confirmed RA for ≥6 months, had received MTX for at least 12 weeks, and experienced treatment failure with at least one csDMARD (including MTX). They presented with at least six swollen joints and eight tender joints, and had either a high-sensitivity C-reactive protein level of ≥4 mg/L or an erythrocyte sedimentation rate of ≥28 mm/hr.

The study included a 24-week double-blind treatment phase, followed by a 24-week extension phase and an additional 8 weeks of safety follow-up.

Tocilizumab alone or with MTX

During the double-blind treatment phase, patients were randomly assigned to receive tocilizumab monotherapy (n=136), MTX monotherapy (n=68), or tocilizumab-MTX combination therapy (n=136) for 24 weeks. Tocilizumab (162 mg) was administered subcutaneously once every 2 weeks, and oral MTX (10-25 mg) was administered once weekly.

Patients who achieved a Disease Activity Score in 28 joints (DAS28) of ≤3.2 after 24 weeks continued their randomly assigned treatment for an additional 24 weeks, whereas those with a score >3.2 switched to unblinded tocilizumab-MTX treatment.

The primary efficacy endpoint was the proportion of patients who achieved a ≥20 percent improvement in the American College of Rheumatology (ACR20) response criteria at 24 weeks, with long-term efficacy analysed at 48 weeks and safety monitored for 56 weeks.

Week 24 ACR20 response rate higher with combo therapy

At Week 24, the ACR20 response rate was higher in the tocilizumab-MTX combination therapy (52.9 percent) and tocilizumab monotherapy (50 percent) groups compared with the MTX monotherapy group (25 percent), with significant differences of 27.9 and 25 percentage points, respectively (p<0.001 for both).

The ACR50 response rate at Week 24 was significantly higher in the tocilizumab-MTX (23.5 percent) and tocilizumab alone (21.3 percent) groups than in the MTX alone group (7.4 and 7.3 percent), with differences of 16.1 and 14 percentage points, respectively. The ACR70 response rate was not significantly different between the tocilizumab groups and the MTX group.

Efficacy improved or sustained at 48 weeks

A long-term efficacy analysis at 48 weeks demonstrated either improved or sustained efficacy in patients continuing with tocilizumab monotherapy or tocilizumab-MTX combination therapy, along with an improved disease status in those who switched to unblinded tocilizumab-MTX treatment at 24 weeks.

“Among patients who did not achieve DAS28 low disease activity (LDA) at week 24, switching to tocilizumab-MTX during the extension phase improved disease activity in all groups, possibly because of prolonged tocilizumab exposure,” the authors reported.

In those who achieved a DAS28 LDA at week 24, continuation of tocilizumab from baseline improved disease activity and ACR20, ACR50, and ACR70 response rates through week 48. Continuation of tocilizumab-MTX stabilised disease activity and ACR20, ACR50, and ACR70 response rates.

“Consistent with previous studies, our findings suggest that long-term tocilizumab treatment, alone or in combination with MTX, can further improve disease activity, maintain LDA or remission,” said the authors. “The study provides solid evidence for subcutaneous tocilizumab.”

In terms of safety, tocilizumab was well tolerated, both as a monotherapy and in combination with MTX, with no new safety signals observed in the study.

Major milestones in Chinese population

Treatment options are needed for patients with RA who experience inadequate response to csDMARDs. “Our findings suggest that subcutaneous tocilizumab, both as monotherapy and combination therapy, is a viable treatment option for Chinese patients with acute RA,” the authors said.

“To our knowledge, this is the first extensive multicentre clinical trial directly comparing subcutaneous tocilizumab monotherapy, subcutaneous tocilizumab in combination with MTX, and MTX monotherapy for treating RA,” they noted. “It is also the first clinical trial we are aware of that assessed subcutaneous tocilizumab in Chinese patients.”

The authors asserted that further research involving ethnically and regionally diverse populations is necessary to confirm the efficacy and safety of subcutaneous tocilizumab, particularly when used as a monotherapy.

A debilitating autoimmune disease

RA is a chronic, systemic autoimmune disease that primarily affects the lining of synovial joints, resulting in damage to diarthrodial joints. [Bone Res 2018;6:15; Rheumatol Autoimmun 2023;3:67-69]

The pro-inflammatory cytokine interleukin-6 (IL-6) is elevated in the serum and synovial fluid of patients with RA and is associated with active disease.

Tocilizumab is a recombinant humanised monoclonal antibody that acts as an IL-6 receptor antagonist. It is approved in several countries for the treatment of adults with moderate-to-severe RA. [Drugs 2017;77:1865-1879]

Treat RA early

“Pharmacotherapy is essential to abrogate inflammation, reduce progressive structural damage, and prevent adverse clinical outcomes,” said the authors. “Treatment should be initiated as early as possible in the course of RA, with sustained remission or low disease activity as an established target.”