Infectious Risk of Rituximab in Combination with Other Biologics

Rigby WF, et al. Safety of Rituximab in Combination with Other Biologic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: An Open-label Study. J Rheumatol. 2013 Apr 1. [Epub ahead of print]

As rheumatologists, we have become fairly comfortable with the safety profile of rituximab and other biologics when used as monotherapy, but probably have never used biologics in combination, fearing infectious complications.


about 20%–40% of patients do not achieve an adequate clinical response to biologic DMARD [monotherapy] treatment

Despite these inadequate responses, data to help choose the optimal biologic therapy are limited given the limited number of RCTs comparing biologic DMARDs.

This was an open label study of 176 patients looking at the combination of rituximab plus one other biologic (adalimumab, etanercept, abatacept, or infliximab). 58/178 (33%) patients were also on MTX.

The rate of serious infections were of highest concern in this study, but results were rather reassuring:

Four serious infections were reported over 48 weeks (2.7 events/100 patient-yrs, 95% CI 1.0–7.2).

Over the 48-week study period, 104 (59.1%) of patients, did experience some type of infection.

Although there was no control group in this study, the authors noted that these findings were similar to previous data:

it is striking that no evidence of an increased safety signal was observed

Also pointing out that:

This safety profile should be considered in the context of this treatment-refractory patient population

While combinations of biologic medications are a potential next step to study, I would expect this data to only very slowly emerge. Before the practice of using rituximab with other biologics becomes more mainsteam, much better data is certainly needed.

With the above study in mind, another paper that provides some useful data on which patients might be at higher risk of infections while receiving rituximab:

Gottenberg JE, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry Arthritis Rheum. 2010 Sep;62(9):2625-32. doi: 10.1002/art.27555.

Which points out risk factors for infection such as:

  • low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6–15.2], P = 0.005)

  • chronic lung disease and/or cardiac insufficiency (OR 3.0 [95% CI 1.3–7.3], P = 0.01)

  • RA-related extraarticular involvement (OR 2.9 [95% CI 1.3–6.7], P = 0.009)

The authors suggest checking IgG levels prior to subsequent cycles of rituximab.

The Ig concentrations should also be assessed before each new cycle of RTX, given the cumulative risk of decreased Ig levels with repeated treatments with RTX