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Study: Increasing Biosimilar Use in RA Requires Greater Disease Management Knowledge


Biosimilar availability will expand treatment of rheumatoid arthritis (RA) to more patients and earlier disease settings, so it's important to understand the potential complications.

Increased availability of biosimilars for treatment of rheumatoid arthritis (RA) is expected to result in greater access for patients and earlier treatment in the disease cycle, leading to increased risk of immunosuppression and an increased risk of infection. Therefore, the authors of a review of available evidence argue, it is important to better understand the management of RA to mitigate the risk of overtreatment with tumor necrosis factor (TNF) inhibitors and immunosuppression.

“While the contemporary clinical treatment goal is to achieve remission, the ideal immunological treatment goal is to achieve an immune homeostasis, such that the immune system can respond dynamically and appropriately to the environment,” the authors wrote.

Based on their review of literature from the past 6 years, the authors concluded that it is important to consider comorbidities when making treatment decisions for patients with RA. Not just infection risk but also cardiovascular disease and cancer risks are increased in patients with RA. Both the immune dysfunction associated with RA and medications used to treat RA may affect risk of these conditions, they wrote.

The authorization of biologics targeting TNF more than 20 years ago dramatically improved treatment options, but the costs of originator drugs limited access for many patients prior to the availability of less expensive biosimilars, the authors wrote. As treatment options expand, information on comorbidities could support the assessment of benefits and risks of each therapy.

The authors cited reports indicating the most common comorbidities in patients with RA are depression, asthma, cardiovascular events, solid-organ malignancies, and chronic obstructive pulmonary disease. They focused on cardiovascular disease (CVD), infections, and malignancies because these conditions “may lead to an increased risk of mortality” and “are also impacted by at least 1 of the therapeutic options currently available for the treatment of RA.”


The authors discussed studies that revealed elevated risks of heart failure, myocardial infarction, stroke, and coronary artery calcification and other conditions in patients with RA compared with control populations.

The elevated CVD risk associated with RA is thought to be due to a combination of traditional CVD risk factors, systemic inflammation associated with the RA disease process, and potentially adverse events from RA medications. The prevalence of CVD risk factors, such as smoking, hypertension, diabetes, hyperlipidemia, and obesity, is often higher among patients with RA compared with the general population, the authors noted, and current recommendations support CVD risk management as part of the overall clinical management of patients with RA.

According to the authors, the available evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) “should be used with caution” in patients with CVD or related risk factors, and the dose of glucocorticoids (GCs) should be minimized for prolonged use, as these treatments have been linked to increased risk of CVD in patients with RA.

On the other hand, they cited evidence suggesting inhibition of TNF offers risk reduction, as chronic inflammation can be a signal of the body’s attempt to control cardiovascular disease. Anti-TNF biologics used to treat RA include infliximab, adalimumab, and etanercept. Methotrexate also is associated with reduced risk of CVD in patients with RA.

Regarding newer drug classes, the interleukin-6 inhibitor tocilizumab has raised concerns over elevated lipid levels, although an increase in clinical risk has not been shown. The authors cited a small number of studies that have suggested tocilizumab or abatacept (which inhibits T-cell activation) may have cardiovascular advantages compared with anti-TNF biologics. This possible disconnect between lipids and cardiovascular risk “remains to be fully elucidated,” according to the authors.


Patients with RA are at increased risk of serious infections and infections overall. The authors discussed literature suggesting 3% to 8% of patients with RA experience infections, the most frequent being infections of the respiratory or urinary tracts, tuberculosis, and sepsis.

Like CVD, the increased infection risk in patients with RA is thought to be dependent on a number of factors, attributed to a combination of the immune dysregulation associated with RA, immunocompromising comorbidities, and immunosuppressive therapy. Additionally, they said, “there is evidence suggesting that the inflammatory processes underlying RA may also drive the development of infections,” as numerous studies have linked disease activity to risk of infection.

For GCs, the authors said, the “benefit-to-risk ratio of this treatment remains precarious,” as increasing susceptibility to serious infections and associated mortality associated with these drugs is “supported by numerous studies.”

For conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, the evidence suggests no increased risk for serious infection or serious infection-associated mortality, according to the authors.

Biologics overall are associated with an increased risk of infection compared with csDMARDs, and the association may be dose-dependent; however, the authors said, there is conflicting evidence. For example, the duration of biologic use in one study was associated with increased risk of serious infection, whereas another showed decreased risk of sepsis and lower mortality risk with biologics compared with csDMARDs.

Anti-TNF biologics in particular are associated with an increased risk of infection in patients with RA, the authors wrote, “although the magnitude of this risk is a topic of debate.” Whether any specific TNF inhibitor differs from another in serious infection risk remains unclear based on the authors’ review of the research. The authors said limited evidence suggests that patients treated with TNF inhibitors vs other biologics may have an increased risk of hospitalization due to infections compared with those treated with abatacept.

GC, csDMARD, and biologic therapies have been linked to reactivation of hepatitis B virus (HBV) infection. As such, there is a boxed warning regarding HBV reactivation in the prescribing information for rituximab, a monoclonal antibody targeting CD20 used to treat lymphoma and RA. The authors noted that medical organizations recommend screening for HBV prior to initiating immunosuppressive therapies or vaccinating patients with rheumatic diseases against HBV.

According to the authors’ review of literature, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), including recently introduced Janus kinase (JAK) inhibitors, as of yet “have an unclear association with infection risk.” Existing data suggest a link between JAK inhibitor use and herpes zoster (HZ) infection and “support the HZ vaccination of patients with RA, particularly if patients are to receive JAK inhibitors,” they wrote.

There are limited data regarding any increased risk of COVID-19 outcomes associated with RA therapies; however, the authors discussed early studies suggesting a lower risk of hospitalization associated with TNF inhibitors and a greater risk associated with GCs compared with other treatments.


Patients with RA have increased risk of developing lymphoma. Although the relationship is not fully clear, the authors wrote there is “strong evidence that the inflammatory processes underlying RA may also drive the development of lymphoma.”

The authors noted there is “no compelling evidence” suggesting an association between the csDMARD methotrexate and an increased risk of lymphoma in patients with RA.

They discussed the black box warning issued by the FDA in 2009 for the risk of non-Hodgkin lymphoma associated with TNF inhibitors. This warning, according to the authors, was based on limited data, and newer data have called these earlier observations into question, as “a recent overview of systematic reviews and meta-analyses of malignancy risk with TNF inhibitors noted no increase in lymphoma risk in patients with RA.”

Patients with RA also appear to be at greater risk of nonmelanoma skin cancer compared with the general population. Anti-TNF therapy is associated in particular with squamous cell carcinoma, and “further studies are required to explore the factors that underlie this increase.” The authors advised that “regular skin examination is desirable for patients with RA treated with TNF inhibitors.”

Optimizing Benefit-to-Risk Ratio of Treatments

The authors concluded that ”dysregulated systemic inflammatory responses” are associated with the development of comorbidities in RA. Responsibly managing RA, they said, requires weighing the potential contribution of each treatment option with comorbidities and risks.

With TNF inhibitors in particular, the authors argued, the risks of overtreatment must be weighed against the potential cardiovascular benefits. This is especially important because access to biosimilars is expected to rapidly lead to wider use of these agents. Conversely, the improved access and lower costs associated with biosimilars could also lead to earlier initiation of treatment, which the authors suggested could improve control of systemic inflammation, leading to prevention of cardiovascular complications in patients with RA.

To mitigate the risk associated with overtreatment and immunosuppression, the authors advised that “for those patients achieving prolonged and sustained disease remission, step-down approaches may be appropriate.” They added that “a shared decision-making approach will be critical” to responsibly managing RA.


Taylor PC, Atzeni F, Balsa A, Gossec L, Müller-Ladner U, Pope J. The key comorbidities in patients with rheumatoid arthritis: a narrative review. J Clin Med. 2021;10(3):509. doi:10.3390/jcm10030509

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