Prescribing two biologics or one with a JAK inhibitor comes with risk, but some are riskier than others.
Combining two biologics, or a biologic and a JAK inhibitor, appears to be as safe as monotherapy overall in people with immune-mediated inflammatory diseases – with some exceptions, according to new French research.
“The combination of different biological and targeted synthetic DMARDs (i.e., combotherapy) has recently emerged in the management of immune-mediated inflammatory diseases,” the authors wrote, noting that real-world data on its use was lacking.
The authors analysed data from 42,000 subjects with immune-mediate inflammatory diseases (IMIDs) across multiple sites in France, and found 131 combotherapy types among 125 patients. Patients were included if they had taken combotherapy for at least 90 consecutive days.
The most common IMIDs in the sample were inflammatory bowel disease (48.8 %), connective tissue diseases (23.2 %), inflammatory myopathies (14.4 %) and vasculitis (11.2 %). The median age was 36 and 58% of the participants were female. Patients were matched with 251 control patients on monotherapy.
After a median follow-up of 15 months, one in four patients had severe infections, 4% had cancer, 3.2% had venous thromboembolism, 2.4% had acute coronary syndromes and 5.6% had died.
There was a one-year cumulative incidence of 29% for serious adverse events and 24% for severe infections. But there was no significant difference between combotherapy and monotherapy in SAEs, severe infections or survival after the researchers accounted for confounding variables.
Severe adverse events were more common with specific combinations, according to their multivariate analyses: abatacept + JAKi combinations had a seven-fold higher risk, anti-IL-1-based combinations had a five-fold higher risk and anti-CD20-based combinations had a four-fold higher risk.
“Seven deaths were identified; four (57%) under JAKi/abatacept, two under rituximab/complement inhibitor (eculizumab), and one under rituximab/infliximab combinations,” the authors wrote.
“Beyond mortality, the association of JAKi/abatacept was the one with the greatest safety concerns, with 73% of patients presenting at least one SAE, and all acute coronary syndromes occurring within this group.”
The underlying condition did not appear to affect the risk of serious adverse events. Factors that did increase the risk were a history of previous cancer, previous severe infections, underlying connective tissue diseases, auto-inflammatory diseases and age. Protective factors were underlying IBD and spondylarthritis.
Connective tissue diseases, inflammatory myopathies and systemic vasculitis represented nearly half of the combotherapy indications in the study population, and a third of patients had overlapping IMIDs.
The authors found it noteworthy that 68% of patients had no severe adverse events with combotherapy, even though over two-thirds were also on glucocorticoids and a quarter were also on csDMARDs.
Severe adverse events during combotherapy were more commonly reported in rheumatological studies than inflammatory bowel disease ones, they added.
“This could be explained by regimens preferentially containing the anti-integrin vedolizumab in the latter, which has a specific intestinal immunosuppressive effect and a better safety profile than other agents used in rheumatology.”
Because this study was based on a database analysis, it’s possible that events occurring outside of hospitals were underreported.
“Overall, the risk of SAE does not seem to be greatly increased under combotherapy as compared to their monotherapy counterpart, but particular attention should be given to certain agents, notably JAKi in terms of MACE and cancer, and TNFi with respect to severe infections.
“Notably, the composition of the combotherapy, rather than the clinical condition, seems central in predicting the safety of the treatment to be prescribed. Although prospective and controlled studies are still needed to better clarify the subject, our data should help clinicians from a wide range of specialties in the management of such complex patients,” the authors wrote.
