The Impact of Biologic Therapies on Rheumatoid Arthritis Comorbidities

A study published in Arthritis Research & Therapy determined the impact of biologic disease modifying anti-rheumatic drugs (bDMARDs) on comorbidities in patients with rheumatoid arthritis (RA).

Research suggests that multiple comorbidities are a result of the high cumulative burden of systemic inflammation. The authors hypothesized that better disease control could be achieved through new, more potent treatments that may reduce comorbidity. However, comorbidities in patients with RA may be an adverse event of medication, meaning bDMARDs might be associated with an increased incidence of some diseases.

For the study, the investigators evaluated whether there was an association between biologic use and a change in the following comorbidities: infections, cardiovascular disease (CVD), malignancy, gastrointestinal disease, depression, and osteoporosis.

The investigators examined tumor necrosis factor inhibitors (TNFi), because they were the first bDMARD to enter clinical practice, and are the most widely studied biologic drugs.

Serious infections (SIs) often lead to hospitalization, intravenous antibiotics, or death, and individuals with RA have an increased risk of SIs. Glucocorticoids and conventional synthetic DMARDs (csDMARDs) have broad immunosuppressive properties and predispose to SIs, according to the study.

Observational data suggests the baseline risk in biologic-naïve patients with RA is approximately double that of the general population. Since bDMARDs target key cytokines and other cells involved in maintaining inflammation and fighting infection, it is likely bDMARDs will only increase the risk of SI. However, long-term use of bDMARDs may reduce the risk of infection by lowering the patient’s need for glucocorticoids, the authors wrote.

Although individual, early randomized controlled trials (RCTs) of TNFi did not show a statistically significant increased risk of SI, a meta-analysis of 9 RCTs of adalimumab (ADA) and infliximab (INF), showed a doubled risk of SI compared with the controls.

The most recent systematic review and meta-analysis of 106 RCTs of 9 biologic therapies revealed an OR of 1.31 for a standard dose of bDMARDs compared with csDMARDs. These findings translated to an additional 6 SIs per 1000 person-years in patients taking bDMARDs compared with csDMARDs alone, according to the authors. No differences in risk were observed between bDMARDs.

The latest systematic review of observational data found 9 studies of SI in patients treated with TNFi. The authors found the highest risk of SIs are within the first 6 months of therapy, with a gradual decline thereafter that is comparable to RA patients treated with csDMARDs. Approximately two-thirds of the decline can be attributed to “depletion of susceptibles,” and one-third can be attributed to improved physical function, and decreased steroid dosage. The most common area of SIs were in the lower respiratory tract, followed by skin, and soft tissue.

In patients treated with monoclonal antibodies INF and ADA, investigators identified an increased risk of tuberculosis (TB), and other granulomatous diseases. A majority of TB cases occurred within the first 6 months of starting INF, which suggests the reactivation of latent TB.

Another study reported 40 cases of TB in patients with RA who were given TNFI, of whom, 62% were extra-pulmonary, with 10 cases resulting in death. Although rates were higher in INF- and ADA-treated patients, cases did occur in patients treated with etanercept (ETN), according to the authors.

Data from the RCTs suggest an increased risk of TB in patients treated with certolizumab pegol and golimumab.

Although a systemic review and meta-analysis found a 1.6-fold increase in risk of herpes zoster (HZ), a different study of 36,212 participants with RA saw no difference in the risk of HZ in patients who initiated TNFi compared with those initiating csDMARDs. An increase in age and a dose of glucocorticoid greater than 10-mg daily was an additional risk factor for HZ.

In general, patients with RA have an increased risk of CVD. A systematic review and meta-analysis of observational cohort data showed a 54% reduction in the risk of CVD events in TNFi users compared with patients who took csDMARDs. Additionally, longer duration of TNFi therapy appeared to reduce the risk of CVD events.

Findings on whether or not there is an association between TNFi therapy and heart failure has varied. In the most recent data, the findings showed similar rates of heart failure in new TNFi users and new users of csDMARDs. However, the investigators acknowledged that the difference may have existed before the black box warning was introduced in 2002. Additionally, a dose-dependent association was observed between glucocorticoid-use and heart failure.

The findings suggest that the overall effect of TNFi is more beneficial than harmful, according to the study authors.

Patients with RA have an increased risk of cancer compared with the general population. Treatment with TNFi shows the association with a minimal increase in the risk of squamous cell carcinoma of the skin. In terms of other cancers, the rates appeared to be no different from rates seen in patients treated with csDMARDs, according to the authors.

“The impact of biologic therapies on outcomes for patients has been substantial in terms of their disease control,” the authors wrote. “In addition, it appears that TNFi at least can improve some of the burden of comorbidity associated with the disease, particularly CVD.”

According to the authors, any increased risk of lymphoma from TNFi—–if present––is likely to be small. Furthermore, the small number of studies investigating cancer recurrence suggests that TNFi may be safe in this population as well.

Although TNFi treatment comes with an increased risk of SIs in the first 6 months, it later diminishes in patients with RA who continued with the treatment.

“There remains a paucity of data on the impact of TNFi on other common comorbidities, such as depression, GI disease, and osteoporosis. Furthermore, newer biologic agents with different mechanisms of action to TNFi, such as RTX, ABT, and TCZ, have not been studied in sufficient detail to draw firm conclusions about their effects,” the authors concluded.