Does bDMARD Exposure Change Mortality Risk in Septic RA Patients?

Data from a study recently published in the Annals of the Rheumatic Diseases suggest that patients taking biologic disease-modifying antirheumatic drugs (bDMARDs) at time of developing a serious infection (SI) have a decreased risk of fulminant sepsis and mortality as compared to those not exposed to bDMARDs.  Researchers posit that bDMARD immunosuppression may play a role in down-regulating the host response to microbial pathogens, thus decreasing sepsis development.

The Rheumatoid Arthritis oBservation of BIologic Therapy (RABBIT) biologics register, an ongoing observational cohort in Germany, was used to identify patients with active rheumatoid arthritis (RA) who were started on either a bDMARD or conventional synthetic DMARD (csDMARD) after failing at least 1 prior csDMARD.  DMARD type and dose, treatment duration, adverse effects, RA disease activity quantified by the 28-joint-count (DAS28), disease comorbidities, and physical function were reported by rheumatologists to the RABBIT registry. 

The primary outcome selected by study authors was development of serious infection, defined by the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

SIs were subsequently analyzed by a units of investigation model-based analysis, incorporating overall mortality rates to account for possible undetected septic cases resulting in mortality.

Nine hundred forty seven patients out of a total of 12,097 registry-eligible patients were identified as having developed a SI.  These patients tended to have longer RA disease duration, higher DAS28 scores, and more comorbidities as compared with patients who did not develop a SI.

Incomplete SI information excluded 88 patients from being included in data analyses. Of the remaining 1017 patients who developed SIs, pneumonia, bone/joint infection, and respiratory infections were most frequently reported (28.4%, 11.2%, and 10.3% respectively).  One hundred thirty five cases of sepsis occurred within 30 days of initial report of SI, with 85 cases resulting in patient death.

Calculation of the adjusted risk of sepsis development showed that increasing age and concurrent chronic kidney disease were associated with sepsis risk.  (Table 1) 

Treatment with bDMARDs of any type was found to be protective against mortality with sepsis. The risk factors for sepsis-associated fatality were older age, high-dose glucocorticoid use, and history of heart failure. (Table 1)

“Adverse outcomes of SI (sepsis and death) were more likely in biologic-naïve patients than in patients exposed to bDMARDs at the time of SI which could indicate a protective effect of bDMARDs. This double-edged effect of bDMARDs has been described very recently as the ‘dual’ role of TNFi regarding septic arthritis,” the authors noted.

Summary and Clinical Applicability

Patients with rheumatoid arthritis exposed to bDMARDs had a significantly lower risk of developing sepsis as compared to those who did not receive bDMARDs pharmacotherapy.  Furthermore, mortality-associated with sepsis was also decreased in patients receiving bDMARDs. 

Limitations and Disclosures

• Potential differential distribution of SI subtypes
• Suspicious bias may be a confounder, with patients being treated with bDMARDs being hospitalized earlier than those being treated with csDMARDs after presenting with signs of SI

Dr Schneider disclosed receiving financial support from Abbvie, Actelion,  Chugai, Merck Serono, Pfizer, Roche, UCB. Dr Kaufman disclosed receiving financial support from Abbvie, Amgen, Chugai, MSD, Pfizer, Roche,  UCB, Chugai, Roche, MSD, Pfizer, UCB.  Dr Zink disclosed receiving financial support from BMS, Merck-Sharp & Dohme, Pfizer, Roche, and UCB.  Dr Strangfeld disclosed receiving financial support from BMS, Merck-Sharp & Dohme, Pfizer, Roche, and Sanofi-Aventis.

Table 1.  Risk of Sepsis and Death After Serious Infection According to Generalized Estimating Equation Multinomial Regression 

	Sepsis (n=137)		Death (n=53)
	Adjusted OR	95% CI	Adjusted OR	95% CI
Age	1.41	1.15 to 1.74	2.47	1.61 to 3.79
Chronic kidney disease	1.93	1.19 to 3.14	1.51	0.72 to 3.17
Exposure to csDMARD
TNFi	0.64	0.42 to 0.97	0.48	0.24 to 0.95
Other bDMARD	0.45	0.25 to 0.80	0.16	0.05 to 0.54
CI: confidence interval; OR: odds ratio (adjusted); csDMARD: conventional synthetic disease-modifying antirheumatic drug; TNFi: tumor necrosis factor inhibitor

Reference

Richter A, Listing J, Schneider M, et al. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(9):1667-73 doi:10.1136/annrheumdis-2015-207838.

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