Adding the B-cell depleting agent rituximab (Rituxan) to methotrexate slowed joint damage progression in patients with rheumatoid arthritis (RA) regardless of the level of disease activity, Austrian researchers reported.
At 1 year, patients with low disease activity receiving rituximab in combination with methotrexate had a change in joint damage scores of 0.38, according to Daniel Aletaha, MD, and colleagues from the Medical University of Vienna.
Similar changes were seen among those with moderate and high disease activity (0.39 and −0.05, respectively, P=0.5 for all), the researchers reported in the January Annals of the Rheumatic Diseases.
In contrast, patients receiving methotrexate alone had more pronounced changes in joint damage scores, at a mean of 0.40 with low disease activity, 1.04 for moderate activity, and 1.31 for high activity, differences that approached statistical significance (P=0.058).
The natural history of rheumatoid arthritis involves the gradual accrual of irreversible joint destruction, which can occur within a year or two of disease onset.
In addition, in patients receiving suboptimal therapy, joint damage closely tracks disease activity and is primarily driven by joint swelling and acute phase reactants such as C-reactive protein (CRP).
Previous research has demonstrated that cytokine-directed biologic therapy, particularly using agents targeting tumor necrosis factor (TNF) and interleukin-6, can uncouple this destructive parallel process.
"Both TNF and IL-6 blockers inhibit proinflammatory cytokines which are believed to play a major role in the pathways leading to osteoclast and chondrocyte activation, the pivotal populations responsible for bony and cartilage damage," Aletaha and colleagues wrote.
However, whether cell-depleting therapies could have similar effects has not been explored, so the researchers conducted a retrospective analysis of data from the IMAGE trial, which was a phase III trial comparing rituximab plus methotrexate with methotrexate alone in patients with RA who had not previously received either agent.
The current analysis included 188 patients on methotrexate monotherapy and 204 receiving methotrexate plus rituximab.
After a year of treatment, significant differences were seen between the methotrexate monotherapy and combination groups on multiple endpoints, including tender joint counts, patient and physician global assessments, pain, CRP, erythrocyte sedimentation rate, disease activity scores in 28 joints, and health assessment questionnaire (P<0.001 for all).
When the researchers analyzed patients' x-ray changes in relation to disease activity, they found little difference between the two treatment groups for patients with low disease activity, with scores differing by only 0.02 points.
However, for the moderate and high disease groups, there were "remarkable differences" of 0.65 (P=0.003) and 1.36 (P=0.05), respectively, they reported.
A change in score greater than 0.25 was considered "unequivocal progression," they noted.
They also looked at the two components of the overall joint damage scores, and found that for erosions, changes in the methotrexate monotherapy group at 1 year ranged from 0.37 in the low disease group to 0.85 in the high disease group, while the corresponding numbers in the rituximab group were 0.26 and −0.02.
For joint space narrowing, scores in the methotrexate group were 0.03 in the low disease group and 0.46 in the high disease group, while scores in the rituximab group were 0.12 and −0.02 in the low and high disease activity groups, respectively.
Because swollen joints and CRP correlate well with disease damage, the researchers also looked at radiographic outcomes according to these endpoints.
They found that with rituximab treatment, even patients in the highest tertile of swollen joints had only minimal progression in joint damage at 1 year compared with those in the lowest tertile (0.31 versus 0.28, P=0.97).
In contrast, patients receiving methotrexate alone in the highest tertile of swollen joints had significantly more x-ray changes compared with those in the lowest tertile (1.33 versus 0.32, P=0.009).
Similar results were seen when patients were classified according to levels of CRP at 1 year, with the greatest differences again being seen for the highest level of CRP.
These results suggest that B-cell depletion with rituximab can have effects on decoupling disease activity from damage similar to the benefits reported for the TNF inhibitors and other cytokine-targeting treatments.
"Aletaha and colleagues have demonstrated a similar dissociation between clinical and structural outcomes in patients treated with rituximab, suggesting that the mechanisms explaining this dissociation are not unique to anti-TNF drugs," observed Edith Villeneuve, MD, and Boulos Haraoui, MD, of the University of Montreal, in an accompanying editorial.
Among the possible mechanisms for the effects of B-cell depletion in preventing damage are reductions in autoantibodies and immune complexes that in turn can limit the production of inflammatory cytokines, the researchers explained.
Limitations of this analysis included its exploratory and retrospective design and the inclusion of only patients who had not previously received methotrexate.
The lead author and one co-author advise and speak for Roche, and the co-author also receives grants and research support from the company.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Annals of the Rheumatic DiseasesSource Reference: Aletaha D, et al "Rituximab dissociates the tight link between disease activity and joint damage in rheumatoid arthritis patients" Ann Rheum Dis 2013; DOI:10.1136/annrheumdis-2012-201970.
Annals of the Rheumatic DiseasesSource Reference: Villeneuve E, Haraoui B "Uncoupling of disease activity and structural damage. Does it matter clinically?" Ann Rheum Dis 2013; DOI: 10.1136/annrheumdis-2012-202650.