Patients with rheumatoid arthritis (RA) and large joint involvement (LJI) are known to experience higher disease burden, more severe functional impairment, and poorer long-term outcomes compared with those without LJI. Involvement of major joints such as the shoulders, hips, knees, and ankles is often associated with higher disease activity scores and accelerated structural damage. Several studies have suggested that conventional tumour necrosis factor (TNF) inhibitors may show suboptimal efficacy in this subgroup, highlighting an unmet therapeutic need.
A recent post hoc analysis published in Rheumatic and Musculoskeletal Diseases Open evaluated the efficacy of ozoralizumab in RA patients stratified by LJI status. The analysis included data from 246 Japanese patients who received ozoralizumab 30 mg every four weeks for 52 weeks across two randomized clinical trials: OHZORA and NATSUZORA. The OHZORA trial enrolled 152 patients receiving concomitant methotrexate, including 111 with LJI and 41 without, while the NATSUZORA trial included 94 patients treated without methotrexate, comprising 72 patients with LJI and 22 without.
At baseline, patients with LJI demonstrated significantly higher Clinical Disease Activity Index (CDAI) scores, reflecting more active and severe disease. Notably, this difference resolved as early as day 3 following initiation of ozoralizumab therapy and remained absent at most subsequent time points throughout the 52-week treatment period. Improvements were consistent across patient-reported outcomes, physician global assessments, and functional measures, including Health Assessment Questionnaire scores. Trial completion rates were similar between patients with and without LJI, indicating comparable tolerability and treatment adherence.
Biomarker analyses further supported the clinical findings. Patients with LJI showed sustained reductions in inflammatory markers, including interleukin-6 and matrix metalloproteinase-3, throughout the treatment duration, suggesting effective suppression of synovial inflammation and joint degradation. Radiographic assessment using changes in the modified Total Sharp Score at week 24 in the OHZORA trial demonstrated comparable inhibition of structural joint damage in patients with and without LJI, indicating that ozoralizumab effectively prevented radiographic progression irrespective of large joint involvement.
Ozoralizumab is a next-generation, trivalent NANOBODY® therapeutic designed to overcome limitations of conventional TNF inhibitors. It lacks an Fc region and consists of two anti-human TNFα variable heavy-chain (VHH) antibody domains and one anti-human serum albumin (HSA) VHH antibody. This unique structure provides potent TNF neutralisation while extending systemic half-life through albumin binding. Its small molecular size (38 kDa) enables rapid and efficient penetration into inflamed joint tissue, including large joints. Moreover, the absence of Fc-mediated immune complex formation reduces Fcγ receptor–dependent immune activation, which may contribute to a lower risk of injection-site reactions and other Fc-related adverse effects.
These findings position ozoralizumab as a promising and clinically relevant therapeutic option for RA patients with large joint involvement, a population often associated with refractory disease and poorer outcomes. By demonstrating rapid, sustained disease control and comparable protection against joint destruction regardless of LJI status, this study suggests that ozoralizumab may help address an important gap in RA management. The results have potential implications for future treatment algorithms and may inform biologic therapy selection based on patterns of joint involvement, supporting more individualized and effective care strategies for patients with rheumatoid arthritis.
References
- Ebina K, Okamoto S, Kyuuma M, Horiuchi N, Matsumoto R, Etani Y, Noguchi T, Tanaka Y, Takeuchi T. Efficacy of ozoralizumab in rheumatoid arthritis patients with large joint involvement: a post hoc analysis of OHZORA and NATSUZORA trials. RMD Open. 2025 Dec 11;11(4):e006218.
- Tanaka Y. Ozoralizumab: first Nanobody® therapeutic for rheumatoid arthritis. Expert Opin Biol Ther. 2023 Jul-Dec;23(7):579-587.
- Thakare DR. Ozoralizumab in rheumatoid arthritis: a novel Fc-free anti-TNF agent with serology-independent efficacy. Rheumatology (Oxford). 2025 Oct 9:keaf526.