Session Information
Session Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy: Safety Issues
Session Type: Abstract Submissions (ACR)
Background/Purpose: In the United Kingdom (UK), rituximab (RTX), an anti-CD20 monoclonal antibody, is currently used to treat patients with rheumatoid arthritis (RA) who have failed initial anti-tumor necrosis factor (TNF) therapy. There is a concern over whether B-cell depletion and potential resultant hypogammaglobulinaemia may result in an increased risk of serious infections (SI). The aim of this study was to determine if RTX influences the risk of SI when used in routine clinical practice.
Methods: The British Society for Rheumatology Biologics Register-RA is an ongoing national prospective cohort study of subjects with RA recently started on biologic therapy. To date, over 20000 subjects have been recruited. Patients who had failed a first anti-TNF and were switched to either a second anti-TNF or RTX between 2001-2012 were identified from the study cohort. All patients were followed by physician and patient questionnaires every six months for the first three years and annual physician questionnaires thereafter, in which data on drug therapy and serious adverse events were reported. Deaths were identified by flagging with UK National Health Service Information Centre. SIs were defined as those requiring intravenous antibiotics and/or hospitalization, or those resulting in death. Subjects were followed until 01/31/2013, first serious infection, death or treatment discontinuation allowing for a lag window (90 days after first missed dose of anti-TNF and 12 months following each course of RTX), whichever came first. The rates of SI in both cohorts (anti-TNF switched to another anti-TNF vs anti-TNF switched to RTX) were compared using Cox proportional hazards model adjusted using inverse probability of treatment weighting (IPTW) (see variables included in table).
Results: In total, 525 subjects experienced at least one SI (448 in 4048 anti-TNF treated subjects and 77 in 1433 RTX treated subjects) occurred during 14155 and 2621 person-years (pyrs) of observation respectively (incidence rate 31 versus 29 per 1000 pyrs) (Table). After adjustment using IPTW, there was a lower overall risk of SI for patients receiving rituximab than for those receiving a second anti-TNF: hazard ratio (HR) for RTX 0.50 (95% CI 0.33, 0.76). However, the median time to first SI was shorter in the RTX cohort. Analysis limited to patients who initiated their second biologic after RTX approval in 2006 gave similar results.
| Second anti-TNF (n=4048) | Rituximab (n=1433) | |
| Age (years), mean (SD) | 56.4 (12.3) | 59.5 (11.8) |
| Gender: n (%) female | 79.3 | 77 |
| RA disease duration (years), Median (IQR) | 14 (8, 21) | 15 (9, 22) |
| DAS28 score at switch, mean (SD) | 5.4 (1.5) | 5.9 (1.3) |
| HAQ at switch, mean (SD) | 1.9 (0.6) | 1.9 (0.6) |
| Steroid use (%) | 57 | 68 |
| Past serious infection on initial anti-TNF therapy: n (%) | 342 (8.5) | 198 (19.9) |
| Follow-up (pyrs) | 14155 | 2621 |
| Median follow-up (pyrs; IQR) | 2.7 (0.8, 6) | 1.5 (0.8, 2.5) |
| Number of first serious infections | 448 | 77 |
| Median time to infection (years; IQR) | 1.4 (0.4, 3.2) | 0.5 (0.2, 1.4) |
| Crude incidence rate of SI per 1,000 pyrs (95% CI) | 31 (28, 34) | 29 (23, 36) |
| Unadjusted HR (95% CI) | Referent | 0.62 (0.49, 0.80) |
| Age and gender adjusted HR (95% CI) | Referent | 0.56 (0.44, 0.72) |
| Fully adjusted by IPTW HR (95% CI)* | Referent | 0.50 (0.33, 0.76) |
| *IPTW HR adjusted by age, disease duration, Disease Activity Score (DAS)-28 score and Heath Assessment Questionnaire (HAQ) when initiating the second biologic, gender, smoking, use of steroids before switching to a second biologic, reason for stopping first anti-TNF, previous serious infection, number of prior disease modifying anti-rheumatic drugs (DMARDs) used before initiating biologic treatment, diabetes, lung involvement, heart disease, liver disease, renal disease, previous cancer, tuberculosis and year of starting first biologic drug. |
Conclusion: The rate of SI in patients starting a second biologic is similar to that previously observed for a first anti-TNF therapy although our data suggest patients selected to switch to RTX may have a lower risk of SI compared to patients who switch to a second anti-TNF.
Disclosure:
L. Silva-Fernández,
None;
M. Lunt,
None;
A. S. Low,
None;
K. D. Watson,
None;
B. Control Centre Consortium,
None;
D. P. Symmons,
None;
K. L. Hyrich,
None;
O. B. O. T. BSRBR,
Pfizer Inc,
2,
MSD,
2,
Abbott Immunology Pharmaceuticals,
2,
UCB,
2,
Roche Pharmaceuticals,
2,
SOBI,
2.
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