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Juvenile Idiopathic Arthrits

Systemic Sclerosis

Rheumatic Disease and Pregnancy

Psoriatic Arthritis

Osteoarthritis

Opioids

Morbidity from DMARDs

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.

Unfortunately:

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

Maintenance, reduction, or withdrawal of etanercept in RA

Smolen JS, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Lancet. 2013 Mar 16;381(9870):918-29. doi: 10.1016/S0140-6736(12)61811-X. Epub 2013 Jan 17.

Many patients will ask how long they need to continue taking certain medications. The PRESERVE trial is the first RCT looking at reduction or withdrawl of TNF inhibitors in RA.

This study is 52-week extension of an initial 36-week open-label trial of methotrexate plus etanercept 50mg weekly, and included only those patients who achieved sustained low disease activity.

participants were eligible for randomisation when they had completed the open-label stage (36 weeks) and achieved sustained low disease activity (mean DAS28 ≤3·2 from weeks 12 to 36 and DAS28 ≤3·2 at week 36).

604 patients were randomized 1:1:1: to:

  • 50 mg etanercept plus methotrexate
  • 25 mg etanercept plus methotrexate
  • Placebo injection plus methotrexate

The primary endpoint was the proportion of patients with low disease activity at week 88

Percentage of patients acheiving primary endpoint:

  • 50 mg etanercept + MTX: 82·6%
  • 25 mg etanercept + MTX: 79·1%
  • Placebo + MTX: 42·6%

No differences were noted in adverse events, specifically infections.

After acheiving remission, it appears that reducing the dose of etanercept to 25mg weekly is a viable option, and as the authors point out, potentially an economical option as well.