A North American-based team of researchers has reviewed 8 years of registry data and concluded that the risk of infection does not increase when patients with rheumatoid arthritis (RA) are switched from rituximab to another biologic agent. The team, led by Leslie Harrold, MD, MPH, of the University of Massachusetts Medical School, asserted that the importance of such research was to determine the safety of switching between biologic therapies – especially between biologic agent classes – because of the inherent increased risk of infection in patients taking disease-modifying antirheumatic drugs (DMARDs) for prolonged periods of time.

The study used patient data from the CORRONA registry, an independent observational cohort of patients with RA who were recruited from more than 160 sites across the US. Dr Harrold and colleagues included those who were diagnosed with RA between March of 2006 and March 2014. Other inclusion criteria were: first-time use of rituximab was within CORRONA enrollment; subsequent use of non-rituximab biologic after rituximab (with no other intervening biologics); 1 or more follow-up appointments within 12 months of non-rituximab biologic agent initiation; and available data on rituximab infusion dates to calculate time duration for switch to no-nrituximab biologic.

The researchers established infection rates and time to infection as the primary outcomes for the study, with secondary outcomes including the effect of rituximab treatment frequency and time from initiation of second biologic. This meant categorizing the patients by duration  of time between their last rituximab infusion and being switched to a second biologic agent (grouped into either ≤5 months, 6 to 11 months, or ≥12 months). 


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The study objective was to determine whether the time between a patient’s last rituximab infusion and a switch to a different class of biologic agent altered the risk of infection “in a real world clinical setting” of patients with RA.

A total of 215 patients qualified for analysis. Of these, 104 patients switched from rituximab to another biologic agent at ≤5 months, with an infection rate per patient-year of 0.34 (95% confidence interval [CI], 0.22 to 0.52). Sixty-seven patients switched between 6 and 11 months, with an infection rate per patient-year of 0.30 (95% CI, 0.17 to 0.52), whereas those who switched to a second biologic agent at ≥12 months had an infection rate per patient-year of 0.41 (95% CI, 0.22 to 0.77). 

Furthermore, the entire study group experienced 37 total infections, only 7 of which were considered “serious,” defined as those requiring intravenous antibiotics or hospitalization.

The researchers used Cox regression models to determine unadjusted hazard ratios (HRs) for risk of infection in each patient subgroup. The analysis found HRs of 0.92 (0.46 to 1.84) and 1.20 (0.57–2.55) in the 6- to 11-month and ≥12-month groups, respectively, when compared with the ≤5-month group.  

After adjusting for age, sex, RA disease duration, smoking status, pain, presence of subcutaneous nodules, modified Health Assessment Questionnaire scores history of cardiovascular disease, history of serious infection, number of prior DMARDs, and number of prior biologic agents excluding rituxumab, HRs for infection were 0.94 (0.42–2.10) and 1.09 (0.43–2.76) in the 6- to 11-month and ≥12-month groups, respectively.

The results indicated “that there was no association between time to the switch and infection,” the authors concluded. Moreover, “Addition of the number (0, 1, or 2) and/or rate of rituximab re-treatment prior to initiation of the subsequent biologic agent to the models did not impact these results.”

Summary and Clinical Applicability

These results suggest there is no higher risk of infection for patients with RA who switch between two biologic agents within a short time period.  “For patients needing to switch from rituximab, these data suggest that switching to another biologic agent with the potential for suppression of disease activity is a valid approach,” the researchers wrote. “Providers should therefore be encouraged to optimize therapy according to disease activity levels after an inadequate response to rituximab, rather than delay initiation of another biologic agent due to concerns regarding residual immunosuppressive effects of rituximab and the risk of infection.”

“Clearly, how the patient is responding to the medication is an important factor,” Dr. Harrold wrote in an email to Rheumatology Advisor. “Clinicians should consider switching biologics if patients have not achieved the desired disease activity target after an adequate trial of rituximab or if they are having an adverse event.”

Limitations and Disclosures

  • Smaller sample sizes available for analysis, limited follow-up duration, and wide 95% CIs

  • Recall bias of actual date for qualifying infection may have influenced the results

  • B cell depletion status was not measured but may be necessary for future studies “to determine whether the peripheral B cell level after rituximab treatment affects the safety of subsequent biologic agents,” the authors noted

Dr Harrold is an employee of and owns stock options in the CORRONA registry; has received grant funding from Pfizer; and has received consultancy fees from Roche. Dr Kremer is a shareholder and employee of CORRONA; has received research support from Genetech; and has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Genetech, GlaxoSmithKline, Eli Lilly, MedImmune, Pfizer, and Sanofi. Dr. Greenberg is an employee and shareholder of CORRONA, and he has received consulting fees from Novartis, Genetech, Janssen, Eli Lilly, and Pfizer.

Over the past 2 years, the CORRONA registry has received support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo, Genetech, Horizon Pharma, Janssen, Eli Lilly, Novartis, Pfizer and UCB through contracted subscriptions. 

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References

Harrold LR, Reed GW, Karki C, et al. Risk of infection associated with subsequent biologic agent use after rituximab: results from a national rheumatoid arthritis patient registry. Arthritis Care Res 2016;68(12):1888–1893. doi:10.1002/acr.22912

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