Biologics Seem to Protect Against Sepsis in RA

Sepsis risk spikes with discontinuation of biologics.

Patients with rheumatoid arthritis (RA) who were being treated with biologic therapies and developed serious infections had a lower risk of sepsis than if they were on conventional agents, German researchers reported.

Among patients on biologics at the time of the infection, the risk of sepsis was almost halved, with an odds ratio of 0.56 (95% CI 0.38 to 0.81), according to Anja Strangfeld, MD, of the German Rheumatism Research Center in Berlin, and colleagues.

Sepsis results from a dysregulation of the inflammatory response following exposure to an infectious agent. It “is a major concern in patients with serious infections because it results in a case fatality rate of 30 to 50%. Older patients are particularly susceptible to sepsis because of hospitalization, comorbidity, and impaired physical function,” the researchers wrote in the September Annals of the Rheumatic Diseases.
Patients with RA are at increased risk of infections, and this is further elevated by the use of immunosuppressive therapies — including biologics — as well as disease comorbidities and complications of joint surgeries.
Several decades ago it was shown that tumor necrosis factor (TNF) was a key player in the cascade of events comprising sepsis, but early clinical trials using TNF inhibitors found no survival benefit, until an animal study suggested that the timing of anti-TNF exposure was crucial for ensuring survival following infection.
None of the earlier trials examined whether being on TNF inhibition at the time of serious infection influenced progression to sepsis, either aiding in recovery or worsening the risk. Therefore, Strangfeld and colleagues analyzed outcomes from the German biologics register, which had enrolled more than 12,000 patients on biologics or conventional disease-modifying anti-rheumatic drugs (DMARDs) by 2013.
Among the cohort, 1,017 serious infections were reported, with the most common being pneumonia, in 28.4%, bone and joint infections in 11.2%, and respiratory tract infections other than pneumonia in 10.3%.

A total of 11.7% progressed to sepsis within 1 month, and the case fatality rate was 63%. Among the patients whose infections did not lead to sepsis, the fatality rate was 6.2%.
Compared with the register cohort in general, patients who developed serious infections were older, had longer duration of disease and greater disease activity, as well as more comorbidities.
In a generalized estimating equations model, older age was associated with a higher risk of both sepsis (OR 1.41 for each 10 years, 95% CI 1.15 to 1.74) and death (OR 2.47, 95% CI 1.61 to 3.79). Underlying chronic renal disease also was associated with an increased risk of sepsis (OR 1.93, 95% CI 1.19 to 3.14), while heart failure was linked with a significantly higher mortality risk (OR 3.56, 95% CI 1.73 to 7.33).
Compared with conventional DMARDs, treatment specifically with a TNF inhibitor at the time of infection lowered the risk of sepsis (OR 0.64, 95% CI 0.42 to 0.97) and death (OR 0.48, 95% CI 0.24 to 0.95). Treatment with other biologic agents also was protective against sepsis (OR 0.45, 95% CI 0.25 to 0.80) and mortality (OR 0.16, 95% CI 0.05 to 0.54).
“The effective immunosuppression via biologic DMARDs may prevent an unregulated host response to serious infection and the development of sepsis,” Strangfeld and colleagues stated.

The researchers then compared outcomes among patients who had not previously received a biologic at the time of the infection (n=134), those who were on a biologic (n=517), and those who had been on a biologic but stopped it more than a month before (n=212).
There were 133 serious infections in the biologics-naive group, 515 in the current biologics group, and 211 in the biologics-discontinued group. Sepsis developed in 17.3% of the biologics-naive group and in 18.4% of the biologics-discontinued group, compared with 11.3% of patients currently on biologics.
After adjustment for age, sex, steroid dose, physical function, and comorbidities, the odds ratios for sepsis (OR 0.97, 95% CI 0.56 to 1.70) and death (OR 0.96, 95% CI 0.42 to 2.17) among those who had discontinued biologics did not differ from those who had never received a biologic.
In contrast, the adjusted risk for sepsis (OR 0.57, 95% CI 0.34 to 0.97) and death (OR 0.34, 95% CI 0.15 to 0.80) was significantly lower for those currently receiving a biologic compared with those never given biologics.
The impact of discontinuation of biologic therapy on sepsis was an important finding of the study, according to the authors.

“It is common knowledge that initiation of biologic DMARD therapy increases the risk of serious infections. Further, discontinuation of biologic DMARDs is supposed to decrease the risk of serious infection,” they wrote.
“Our results suggest a different mechanism: adverse outcomes of serious infections (sepsis and death) were more likely in biologics-naive patients than in patients exposed to biologic DMARDs at the time of serious infection, which could indicate a protective effect of biologic DMARDs,” they explained. But that protective effect was lost when biologics had been stopped, they pointed out.
“Discontinuation of biologic DMARDs seems to shift the risk from an increased susceptibility to serious infections to more severe outcomes,” they observed.
However, the results of this study need to be confirmed.
A limitation of the study was the possibility of “suspicion bias,” with patients on biologic therapies possibly being hospitalized more quickly and followed more closely if they developed serious infections.

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