Data from a large prospective German cohort found a greater risk for lower intestinal perforation (LIP) with tocilizumab (TCZ) as compared with conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy for rheumatoid arthritis (RA).1 Despite this increased risk, LIPs remained relatively uncommon, with an incidence of 2.7 per 1000 patient years (PYs). These results were reported in the Annals of the Rheumatic Diseases.

The use of DMARD pharmacotherapy was expected to result in significant reductions in required glucocorticoid (GC) doses, thereby decreasing rates of gastrointestinal tract complications. Data from the TCZ clinical development program identified GI perforation as a notable side effect; however, limitations secondary to early escape trial designs limited the number of PYs available to estimate the significance of the finding.2  Thus, researchers in Germany aimed to identify risks factors for LIP in the context of TCZ, GC, and nonsteroidal antiinflammatory drug (NSAID) use.



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High Yield Data Summary

  • The crude incidence rate of LIP was increased in patients with RA taking TCZ (2.7/1000 patient years) as compared with other DMARDs (0.2-0.6/1000 patient years) 
  • Though the absolute incidence of LIP remained low, 30-day mortality rates when LIP occurred were high (46%)

The German register Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) is a large prospective, observational cohort study of patients with RA who begin treatment with a bDMARD or csDMARD after failure with csDMARD therapy. 

Patients were prospectively observed, with data collected at time of enrollment, 3 months, and then every 6 months, for a period of 5 years regardless of treatment changes. They were also given the option to extend observation for an additional 5 years at conclusion. 

Data collected at each time point included clinical status, disease activity score based on 28 joints (DAS28), pharmacotherapy type and dose, and adverse events occurring since last data evaluation. For the purposes of this study, primary outcome was defined as the incidence of LIPs that occur in patients exposed to either TCZ, csDMARDs, tumor necrosis factor inhibitor (TNFi), abatacept, or rituximab. Secondary outcomes were defined as the development of clinical signs or symptoms of LIP.

A total of 13,310 patients were enrolled in the RABBIT register up until October 2015. Chronic gastrointestinal (GI) disease was least prevalent in the csDMARD-treated group and most prevalent in those patients treated with abatacept. None of these patients with baseline chronic GI disease developed an intestinal perforation during this study.

One hundred forty one adverse effects possibly related to GI perforations were identified in 53,972 patient years (PYs) of follow-up. Medical review confirmed that 44 of these incidents to be GI perforation. Of these cases, 37 were localized to the lower intestine (32 in the colon/sigma). Only 2 of these patients had a history of preexisting diverticulitis.

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The crude LIP incidence rate was increased in the TCZ treatment group (2.7/1000 PYs) as compared with the treatments examined (0.2−0.6/1000 PYs). The adjusted hazard ratio, referenced to csDMARDs, in the TCZ group was 4.48 (95% CI 2.0 to 10.0), in tumor necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3), and in other biologic DMARDs 0.33 (0.1 to 1.4).

Treatment with TCZ, cumulative GCs and NSAIDs, and increased age were identified as being associated with LIP in univariate and multivariate analysis. In this group of patients, TCZ exposure was associated with 4.5 times higher risk for LIP (95% CI 2.01 to 9.99). This association was not found for use of TNFi, abatacept, or rituximab.

“Biological mechanisms may also support the increased risk of LIP in patients treated with TCZ: the interleukin 6 (IL-6) receptor targeted by TCZ seems to have an important function of the intestinal barrier. It is hypothesized that locally accumulated fat tissue may cover inflamed diverticula, similar to creeping fat in Crohn’s disease which covers inflamed intestinal segments and where IL-6 is predominantly found,” the authors explained. 

Summary and Clinical Applicability

In the first real-world study comparing rates of LIP with various DMARDs for the treatment of RA, researchers found a 2.7/1000 PYs LP rate with TCZ treatment for RA. This represents an increased rate compared with csDMARDs and other biologics. Of note, most patients who experienced LIP while taking TCZ did not have a prior history of diverticulitis, and had relatively mild symptoms on presentation. 

“Rheumatologists should be aware that IL-6 inhibition can be associated with an increased risk of LIP in patients with prior diverticulitis… [and should] be advised to observe signs and symptoms of LIP carefully and to inform non-specialized doctors that CRP, in their case, cannot be interpreted as a marker of diverticular inflammation,” the authors concluded.

Limitations and Disclosures

  • Preexisting diverticulitis was likely underreported at time of registry enrollment
  • Low numbers of LIPs included in the register limited the number of  Cox regression covariates
  • Exact doses, start/stop dates of NSAIDs prior to study enrollment were not captured by RABBIT, so long-term effects of NSAIDs on LIP may not have been adequately estimated 

The German Biologics Register RABBIT is supported by an unconditional grant sponsored by AbbVie, Bristol-Myers Squibb, Celltrion, Hospira, MSD Sharp & Dohme, Pfizer, Roche and UCB.

Multiple study authors report receiving consulting, speaker, and personal fees from the pharmaceutical industry.

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References

  1. Strangfeld A, Richter A, Siegmund B, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2016; Published online ahead of print July 12, 2016. doi:10.1136/annrheumdis-2016-209773.
  2. Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011;13:1–13. doi:10.1186/ar3455.