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Do Biologics Have a Negative Effect on Infection Risk?—An association between biologic drug use and an increased risk of serious infection in RA has been debated, but a new analysis provides

a more comprehensive perspective.

By Angela M. Incassati, PhDReviewed by David Fernandez, MD, Fellow, Adult Rheumatology, Hospital for Special Surgery, New York, NY

Rheumatoid arthritis (RA) is a chronic, pathological condition caused by systemic inflammation. Rampant activation and infiltration of immune cells into the joints often leads to

debilitating pain and swelling and, if left uncontrolled, joint destruction as well. Years of research have identified a number of immune cells and their signaling pathways critical to the

pathogenesis of the disease, including tumor necrosis factor α (TNF α ) and interleukins (ILs)-1ß, -6, -12, and -23, among others, leading to the development of therapeutic biological drugs,

or biologics, targeting these pathways.1

rheumatoid arthritis is associated with an increased risk of serious infections.A recent comprehensive analysis of 106 randomized controlled trials of approved biologic therapies sheds new

light on the topic, identifying scenarios where an association is detected and where one isn’t.New comprehensive analyses on the safety of biologic drugs overall, and in specific

subpopulations of patients, provide updated information to physicians and patients alike to consider when discussing treatment options.

There are currently numerous approved biologic therapies for the treatment of RA in the U.S. and the European Union, including monoclonal antibodies, antibody fragments, and fusion proteins.

Each of these therapies targets and neutralizes a specific immune pathway, effectively reducing the inflammatory response and improving symptoms of disease and overall outcome.2,3

Old concerns resurface

Therapeutically inhibiting the immune response carries with it the potential for unwanted side effects, including interfering with the body’s natural ability to respond to infection. The

risk of developing serious infections—defined as infections resulting in hospitalization, treatment with intravenous antibiotics, or death—associated with the use of biologics has been a

concern since the initial randomized controlled trials (RCTs) investigating the efficacy and safety of the drugs.3 The issue continues to be a complex one for many reasons. Though RCTs

remain the highest benchmark for assessing and evaluating the efficacy and safety of a drug, they’re often underpowered to detect rare adverse events.2,3

To determine whether a particular treatment is associated with an increased risk of a rare event, data from multiple clinical trials may be assessed in systematic reviews and

meta-analyses--powerful tools that allow results to be examined across studies. Several systematic reviews and meta-analyses have been performed over the past decade with respect to risk of

serious infection with the use of biologics. The analyses examined data from multiple clinical trials that included patients who had or hadn’t been previously exposed to disease-modifying

anti-rheumatic drugs (DMARDs) and patients with early stage or with longer-term established RA, as well as different treatment scenarios, including variations in treatment drug, dose, and

duration.3

The results from these analyses were mixed: 1 found an association between biologic use and the risk of serious infection; 1 reported an increased risk in developing serious infections only

with higher doses of drug and shorter durations of trials; and 3 found no association between standard-dose biologic use and risk of serious infection.3-8

Casting a wider research net

In an attempt to provide greater clarity to the situation, Singh and colleagues have performed a comprehensive systematic review of the literature, including traditional and network

meta-analyses, to compare data from the varying subpopulations of patients across clinical trials.8 All randomized trials of adult patients with RA treated with any of the approved biologics

as monotherapy or combination therapy as compared to each other, placebo, or traditional DMARDs were included. In all, 106 published trials including 42,330 patients were included in the

analyses.

In the traditional meta-analysis, the authors found a significant 27% increase in the risk of serious infection with the use of standard-dose biologics (with or without traditional DMARDs)

as compared to the risk observed in patients taking only traditional DMARD monotherapy. Interestingly, the risk increased to 42% in patients who had previously been treated with methotrexate

and decreased to essentially no risk at all in those who were methotrexate-naïve. Similar trends were revealed with the network meta-analyses of standard- and high-dose biologic therapies

with or without traditional DMARDs. Low-dose biologic therapy with or without traditional DMARDs wasn’t associated with an increased risk of serious infection in the combined population or

in the subpopulations stratified by methotrexate use, while the use of combination biologics with or without traditional DMARDs was associated with in a greater increase in risk.8

The authors also calculated the absolute annual risk of serious infection with biologic use per subpopulation. The median absolute reported serious infection risk was 20 cases per 1000

patients annually on traditional DMARD therapy. In comparison to that, the absolute increase in the number of serious infections was an additional 6 per 1000 patients among those on

standard-dose biologic therapy (with/without a traditional DMARD), an extra 17 among patients on high-dose biologic therapy (with/without a traditional DMARD), and 55 per 1000 patients

receiving combination biologics. Overall, the findings support that standard- and high-dose biologic use, as well as combination biologic drug use, with or without traditional DMARDs in RA

are associated with an increased risk of serious infection as compared to the use of traditional DMARDs alone, and that prior exposure to methotrexate may be a significant contributing

factor to that risk.8 (Note that FDA-approved RA dosages for almost all biologics would be considered “standard” or “low-dose.” Exceptions in certain circumstances might be infliximab or

rarely, adalimumab. High-dose adalimumab and golimumab regimens exist, but only for inflammatory bowel disease and hidradenitis suppurativa.)

The data continue to be mixed

While the findings from Dr. Singh’s research team offer one of the most comprehensive analyses to date regarding the association between biologic use and risk of serious infection in RA, the

data are limited to RCTs that include small, controlled populations of patients who were often treated over short periods, which may not be entirely reflective of real-world patients in

clinical practice.2,8 As such, data from global biologics registries are, and will continue to be, increasingly important to monitor, especially as greater numbers of patients are included

each year.2

Initial analyses on risk of serious infections associated with biologics of anti-TNF-α agents varied across registries, with some reporting an association and others not. Cumulative findings

are pointing to an increased risk early in treatment (within the first 6 months), followed by a decrease in risk over time. This is attributed to a number of factors, including high-risk

patients stopping therapy, functional improvement over time, and less glucocorticoid use after that point. Non-anti-TNF-α biologics have yet to amass similar registry data, though the number

of registries for such agents is rising.6,9-11

As with any therapy, the potential benefits garnered from using a biologic drug should be weighed against the potential risks. The study by Singh and colleagues offers new comprehensive

analyses on the safety of biologic drugs overall and in specific subpopulations of patients, providing updated information to doctors and patients alike to consider when discussing treatment

options.

Published: December 03, 2015

References

1. Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford). 2014;53:1560-1569. 2. Codreanu C,

Damjanov N. Safety of biologics in rheumatoid arthritis: data from randomized controlled trials and registries. Biologics. 2015;9:1-6. 3. Lahiri M, Dixon WG. Risk of infection with biologic

antirheumatic therapies in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2015;29:290-305. 4. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in

rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA.

2006;295:2275-2285. 5. Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of

serious adverse events. Ann Rheum Dis. 2009;68:1136-1145. 6. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid

arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis. 2009;68:25-32. 7. Thompson AE, Rieder SW, Pope JE. Tumor necrosis factor therapy and the risk of serious

infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum. 2011;63:1479-1485. 8. Singh JA, Cameron C,

Noorbaloochi S, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386:258-265. 9.

Cobo-Ibáñez T, Descalzo MÁ, Loza-Santamaría E, et al. Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or

rituximab: data from the Spanish registry BIOBADASER 2.0. Rheumatol Int. 2014;34:953-961. 10. Dixon WG. Rheumatoid arthritis: biological drugs and risk of infection. Lancet.

2015;386:224-225. 11. Salmon JH, Gottenberg JE, Ravaud P, et al. Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common

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