Biologic Therapy in Rheumatoid Arthritis Yields Mixed Results for Comorbid Conditions

Substantial outcomes and significant disease control can be linked to biologic therapy in patients with rheumatoid arthritis (RA), but questions remain concerning comorbid conditions, according to a review published in Arthritis Research & Therapy.¹

Deborah Symmons, MD, FFPH, FRCP, of the Arthritis Research UK Centre for Epidemiology at the University of Manchester and the Manchester Academic Health Science Center, and colleagues conducted a review of observational data to assess the impact of biologic therapies on outcomes for various common comorbidities (infection, cardiovascular disease [CVD], malignancy, gastrointestinal (GI) disease, osteoporosis, and depression²) seen in patients with RA.

“Biologic therapies (biologic disease-modifying antirheumatic drugs, [bDMARDs]) have revolutionized disease control in patients with RA,” wrote Dr Symmons and colleagues. “Theoretically, they have the potential to influence comorbid disease associated with RA through better control of systemic inflammation.” Because RA is a systemic inflammatory disorder, the impact of bDMARDs is not limited to patient’s joints. “Conversely, comorbidity may occur as an adverse effect of the drugs,” the researchers noted. 

Infection

Research has linked RA with an increased risk of serious infection^3-5; bDMARDs target both key cytokines and the cells involved in maintaining inflammation and fighting infection. While early randomized controlled trials of tumor necrosis factor-alpha inhibitors (TNFi) did not indicate a “significantly increased” risk of serious infections, a 2006 meta-analysis of 9 randomized controlled trials focused on adalimumab (ADA) and infliximab (INF) identified a doubled risk of infection compared to the trials’ control arms.⁶ A more recent systemic review and meta-analysis — including 106 randomized controlled trials of 9 biologic therapies — identified an odds ratio (OR) of 1.31 (95% CI], 1.09-1.58) in standard-dose bDMARDs vs conventional synthetic  DMARDS (csDMARDs), reflecting an additional 6 significant infections per 1000 person-years.⁷

Additional risks for infection include tuberculosis, legionellosis, nontuberculosis mycobacteria, listeriosis, salmonellosis, and nocardiosis, as well as herpes zoster, particularly within the first 6 months of TNFi therapy.

Cardiovascular Disease

Patients with RA also exhibit increased rates of CVD,^8-10 which is linked to the “increased prevalence of traditional CV risk factors such as smoking, abnormal lipid profiles, and high body fat [to] muscle mass ratio,” according to the investigators. A 2011 systematic review and meta-analysis suggested an overall 54% reduction in CV event risk in TNFi users vs patients taking csDMARDs.¹¹ Data are conflicted on the association between TNFi use and heart failure, with no demonstrated benefit and 1 reported “worse outcome” in this patient population.^12,13 Observational data focused on the relationship between non-TNFi bDMARDs and CVD in patients with RA are limited.

Cancer

A 2015 meta-analysis found that patients with RA have an increased cancer risk compared with the general population¹⁴; those researchers identified a small but statistically significant increase of 9% overall risk of malignancy. Specifically, patients with RA have been found to have increased risks of lymphoma, nonmelanoma skin cancer, and lung cancer but a decreased risk of colorectal cancers, prostate and cervical cancers, and gastric cancer.^14-17 Specific information related to the recurrence of cancer in patients with prior malignancy is limited, since patients with a history of cancer are typically excluded from TNFi randomized controlled trials. A small number of studies have investigated the risk of malignancy in bDMARD therapy, with one finding lower malignancy rates in TNFi users but equivalent rates in patients treated with rituximab and abatacept vs csDMARD users.¹⁸

GI Disease, Depression, and Osteoporosis

Due to side effects associated with older RA medications, GI disease is an important comorbidity to consider, specifically peptic ulcer disease and GI perforation associated with nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use.^19-20

Data are limited concerning the link between bDMARD use and depression, although depression rates are noted to be higher in patients with RA and associated with pain, disability, and fatigue.²¹ However, few studies have examined the impact of RA treatment on depression. A meta-analysis of data from randomized controlled trials identified no difference in fatigue levels between TNFi therapy and csDMARDs.²²

Although RA is a recognized risk factor for osteoporosis, limited data exist on the link between bDMARDs and bone health; longer disease duration and glucocorticord use have been found to enhance that risk.^23-25

Summary and Clinical Applicability

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

“There remains a paucity of data on the impact of TNFi on other common comorbidities such as depression, GI disease, and osteoporosis,” they continued. “Further, newer biologic agents with different mechanisms of action to TNFi, such as rituximab, abatacept, and tocilizumab, have not been studied in sufficient detail to draw firm conclusions about their effects.”

Disclosures

Dr Hyrich reports receiving honoraria from Pfizer and AbbVie. 

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