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.
High Yield Data Summary
- Biologic therapies have substantial effects on disease control in RA. TNF-α inhibitors can improve some of the comorbidity burden, particularly CVD.
“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.
Research has linked RA with an increased risk of serious infection3-5; 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.
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.
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.”
Dr Hyrich reports receiving honoraria from Pfizer and AbbVie.
- Humphreys J, Hyrich K, Symmons D. What is the impact of biologic therapies on common co-morbidities in patients with rheumatoid arthritis? Arthrit Res Ther. 2016;18:282.
- Baillet A, Gossec L, Carmona L, et al. Points to consider for reporting, screening for and preventing selected comorbidities in chronic inflammatory rheumatic diseases in daily practice: an EULAR initiative. Ann Rheum Dis. 2016;75:965-973.
- Widdifield J, Bernatsky S, Paterson JM, et al. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthrit Care Res. 2013;65:353-361.
- Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002;46:2287-2293.
- Franklin J, Lunt M, Bunn D, Symmons D, Silman A. Risk and predictors of infection leading to hospitalization in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis. 2007;66:308-312.
- Bongartz T, Sutton AG, Sweeting MJ, Buchan I, Matteson EL, Montori V. 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.
- 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.
- Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71:1524-1529.
- Del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737-2745.
- Greenberg JD, Furer V, Farkouh ME. Cardiovascular safety of biologic therapies for the treatment of RA. Nat Rev Rheumatol. 2012;8:13-21.
- Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthrit Care Res. 2011;63:522-529.
- Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2005;109:1594-1602.
- Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133-3140.
- Simon TA, Thompson A, Ghandi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17:212.
- Kalberg H. Rheumatoid arthritis and lung cancer: you probably heard it before. J Rheumatol. 2008;35:1695-1696.
- Mercer LK, Davies R, Galloway JB, et al. Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid arthritis compared with the UK general population. Rheumatology. 2013;52:91-98.
- Chang SH, Park JK, Lee YJ, et al. Comparison of cancer incidence among patients with rheumatic disease: a retrospective cohort study. Arthritis Res Ther. 2014;16:428.
- Solomon DH, Kremer JM, Fisher M, et al. Comparative cancer risk associated with methotrexate, other non-biologic, and biologic disease-modifying anti-rheumatic drugs. Semin Arthritis Rheum. 2014;42:489-497.
- Lanas A, Garcia-Rodriguez LA, Polo-Tomas M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009;104:1633-1641.
- Curtis JR, Xie F, Chen L, et al. The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum. 2011;63:346-351.
- Kojima M, Kojima T, Suzuki S, et al. Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis Rheum. 2009;61:1018-1024.
- Van Hoogmoed D, Fransen J, Repping-Wuts H, Spee L, Bleijenberg G, van Riel PL. The effect of anti-TNF-alpha vs DMARDs on fatigue in rheumatoid arthritis patients. Scand J Rheumatol. 2013;42:15-19.
- Vis M, Haavardsholm EA, Boyesen P, et al. High incidence of vertebral and non-vertebral fractures in the OSTRA cohort study: a 5-year follow-up study in postmenopausal women with rheumatoid arthritis. Osteoporos Int. 2011;22:2413-2419.
- Natsui K, Tanaka K, Suda M, et al. High-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass. Osteoporos Int. 2006;17:105-108.
- Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11:234-250.