Biologics might have revolutionized treatment for rheumatoid arthritis, but existing research also points out that using these medications can increase the risk of serious infections or hospitalizations in some patients.
According to registry and observational studies, risk levels for infection are highest during the first six months of tumor necrosis factor inhibitor biologics treatment with a plateau hitting between 24-to-36 months.
A new study published in Current Rheumatology Reports reviewed key studies into these rheumatoid arthritis-related negative incidents, finding risk is greater with tumor necrosis factor inhibitor biologics than with traditional disease-modifying anti-rheumatic drugs.
To highlight this difference in risk, researchers discussed several existing studies that address individual questions of how biologic treatments affect rheumatoid arthritis in an attempt to help clinicians and patients make the most informed decisions about therapies.
The biologics, which inhibit key cytokines and cytokine pathways, most often used to treat rheumatoid arthritis are etanercept, infliximab, golimumab, certolizumab pegal, adalimumab, anakinra, tocilizumab, abatacept, and rituximab. Despite their benefits, patients and providers worry both about injection site reactions, as well as infections.
Role of Disease in Risk
According to one study, it’s the altered immune system response present with rheumatoid arthritis that increases the infection risk. These patients have a greater chance of failing traditional disease-modifying anti-rheumatic drugs, making them candidates for biologics. However, if a patient has active rheumatoid arthritis, as well as a serious infection, it’s difficult to identify whether biologics are truly responsible for the infection.
Comparing biologics patients with those receiving other treatments, such as methotrexate, can help providers and patients better understand the risk. This data comes from observational studies, but it’s limited by confounding bias, channeling bias, differential follow-up, detection bias, and follow-up loss.
Rheumatoid Arthritis Role in Infections
Overall, rheumatoid arthritis patients have a higher ratio for developing infections than patients that don’t have rheumatoid arthritis.
A study of 609 rheumatoid arthritis patients and 609 non-rheumatoid arthritis patients, all over age 18, revealed rheumatoid arthritis patients have higher rates in 11 infection categories (95% CI, 1.41 to 1.65). Only two categories – urosepsis/pyelonephritis and gastroenteritis – didn’t pose a higher risk level.
Hospitalized Infection Risk
Rheumatoid arthritis patients have a two-fold increased adjusted risk of hospitalized infections when compared to those without rheumatoid arthritis. A retrospective cohort study performed with 1999-2006 claims data revealed the risk of hospitalized infections with a rate ratio of 1.88 (95% CI 1.71 to 2.07).
Rheumatoid Arthritis and Hospitalized Infections
Higher disease activity in rheumatoid arthritis patients does correlate to an increased rate of hospitalized infections.
Based on data from the Consortium of Rheumatology Researchers of North America, culling data from 16,242 patients, researchers identified 2,282 infections during 7,290 patient-years of follow-up. Of those incidents, 59 became hospitalized infections.
Every 0.6 increase in the disease activity score 28 used to assess clinical disease activity was associated with a 25% increased rate of infections that led to hospitalizations. These results, researchers said, indicate that controlling rheumatoid arthritis disease activity as best as possible could not only improve function and quality of life, but it could also lower infection risk rates.
Biologics and DMARD Differences
Patients using tumor necrosis factor inhibitor biologics do experience a greater infection risk during their first six months of treatment (95% CI 1.3 to 2.6). According to researchers, the risk is higher compared to traditional disease-modifying anti-rheumatic drugs by 1.2 to 1.8 times for up to 24 months following the beginning of biologics therapy (95% CI 0.6 to 1.3).
Using data from the British Society for Rheumatology Biologics Register, investigators compared serious infections between 11,798 biologics-treated patients and 3,598 disease-modifying anti-rheumatic drugs. Of those patients 1,808 developed at least one serious infection with incidence rates of 42/1,000 patient years of follow-up with biologics (95% CI 40 to 44) and 32/1,000 patient years of follow-up with disease-modifying anti-rheumatic drugs (95% CI 1.1 to 1.5).
Serious infection risk rates didn’t differ much for the three biologics examined – adalimumab, etanercept, and infliximab.
Do Biologics Differ?
For those using biologics therapy, serious infections are defined as ones needing hospitalization, intravenous antibiotic therapy, life-threatening, or ones that lead to significant disability. However, biologic therapies aren’t all the same when facing these negative events, such as pneumonia and cellulitis.
In a study using data from the Dutch Rheumatoid Arthritis Monitoring registry, researchers discovered the adjusted risk of serious infections was significantly lower with etanercept than with infliximab (HR=0.49, 95% CI 0.29 to 0.83) or with adalimumab (HR=0.55, 95% CI 0.44 to 0.67). Among this group, lower respiratory infections were the most common.
A study examining serious infections in the first 12 months of biologic and disease-modifying anti-rheumatic drug therapy supported those findings. Among rheumatoid arthritis patients, infliximab was linked to a significant increase in serious infections compared to etanercept (HR=1.26, CI 95% 1.07 to 1.45) and adalimumab (HR=1.23, 95% CI 1.02 to 1.48). Based on these results, glucocorticoid use was associated with dose-dependent infection increases.
In addition, a study of 11,466 patients with psoriasis or psoriatic arthritis examined serious infection risks with four biologics: infliximab, adalimumab, ustekinumab, and etanercept. The cumulative incidence rate was 1.45 per 100 patient years (323 serious infections), and the respective rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient years for ustekinumab, etanercept, adalimumab, and infliximab, respectively. By comparison, rates for non-methotrexate/non-biologics were 1.05 and 1.28 per 100 patient years for methotrexate/non-biologics.
Biologics and Hospitalized Infection Risk
Overall, research shows using biologics increases the risk of hospitalized infections compared to traditional disease-modifying anti-rheumatic drugs. However, there are no studies directly comparing biologics and corticosteroids.
Biologics Risk Increase as a Group
In a group of rheumatoid arthritis patients, pneumonia and urinary tract infections were the most common infections. Study data showed current biologic use was linked with significantly higher hospitalized infection risks (relative risk 1.21; 95% CI 1.02 to 1.43). Methotrexate and hydroxychloroquine use were associated with lower risk – 0.81 (95% CI 0.70 to 0.93) and 0.74 (95% CI 0.62 to 0.89), respectively.
Biologics Differences and Hospitalized Infection Risks
When compared, adjusted hospitalized infection rates for etanercept, adalimumab, abatacept, and rituximab were similar. However, the rate was increased for infliximab (HR 2.3, 95% CI 1.3 to 4.0).
According to study data, hospitalization risks were greater with older patients and those with chronic obstructive pulmonary disease. Prednisone doses of >7.5 mg/day and chronic inflammation were also linked to an increased hospitalized infection risk.
Biologics, Hospitalized Infections, and Concomitant Use
Based on existing research, the verdict is still out on whether concomitant use of biologics is effective. In a study comparing denosumab and zoledronic acid, investigators found the rate of hospitalized infections was comparable (HR=0.89, 95% CI 0.69 to 1.15).
Although the study demonstrates concomitant use of denosumab might be safe, these results cannot be generalized to other concomitant biologic use for rheumatoid arthritis treatment. In fact, other studies show concomitant biologics use in rheumatoid arthritis patients increases infection rates without improving efficacy.
Infection Risk and Switching Biologics
When assessing the risk of hospitalized infections for rheumatoid arthritis patients, the overall crude incidence rate was 15.3 per 100 patient years (95% CI 14.7 to 15.9), ranging from 13.1 per 100 patient years for abatacept to 18.7 per 100 patient years for rituximab. The results also showed that infection risks were greater for infliximab and etanercept than they were for abatacept.
Another study looking at switched biologic therapy for rheumatoid arthritis patients determined the hazard rate for all infections was significantly higher for adalimumab, etanercept, and infliximab. Rates were not higher for abatacept. When compared to rituximab, severe infection risk was significantly higher for infliximab, but not for abatacept, adalimumab, or etanercept.
Curr Rheumatol Rep. 2016 Oct;18(10):61. doi: 10.1007/s11926-016-0609-5. “Infections With Biologics in Rheumatoid Arthritis and Related Conditions: a Scoping Review of Serious or Hospitalized Infections in Observational Studies.” Singh JA. https://www.ncbi.nlm.nih.gov/pubmed/27613285