Two decades have passed since the first biologic disease-modifying anti-rheumatic drug (bDMARD) was approved. Studies on the long-term use of biologics in different disease states, such as for cardiovascular disease (CVD) and malignancy, as well as for knee/hip replacement, reveal some encouraging news.
Explore this issueDecember 2017
In clinical trials, bDMARDs have been shown to increase the risk of infection and malignancy, but they are also known for better liver and kidney tolerance among patients with rheumatoid arthritis (RA) than synthetic DMARDs (sDMARDs). bDMARDs also have significant clinical benefits over sDMARDs when controlling moderate to severe autoimmune diseases caused by uncontrolled chronic inflammation, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis and polymyalgia rheumatica, but heretofore evidence is lacking that they reduce comorbidities in RA. The most common comorbidities among RA patients are CVD and joint damage.
A systematic literature review, which informed the 2016 update of the EULAR recommendations for RA management, studied the safety and efficacy of synthetic and biologic DMARDs in RA patients and showed that bDMARDs have favorable effects on CV events and total knee/hip replacement.1
It’s worthwhile to review the long-term benefits and risks of biologics among RA patients and other chronic systemic inflammatory patient populations.
Per one study conducted in Sweden, total joint replacement surgeries are increasing in general, while the number of TKR & THR surgeries is decreasing in patients with a primary RA diagnosis. Introduction of biologics in RA patients may be an important contributing factor.
Benefits in Total Knee & Hip Replacements
Considering quality of life, one of the largest burdens for RA patients is total knee or hip replacement (TKR or THR) due to chronic joint damage. TKR and THR have increased in the general patient population with the aging of baby boomers. Prior to the introduction of biologics for RA patients, 25% of these patients would require TKR or THR within 10 years.2 Per one study conducted in Sweden, total joint replacement surgeries are increasing in general, while the number of TKR and THR surgeries is decreasing in patients with a primary RA diagnosis.3 Introduction of biologics in RA patients may be an important contributing factor.
In 2014 in the U.S., researchers used data from the Nationwide Inpatient Sample, Health Care Cost and Utilization Project in a study that focused on the first three tumor necrosis factor (TNF) inhibitors: etanercept, infliximab and adalimumab (FDA approved in 1998, 1999 and 2002, respectively).4 In this study, patients were categorized into three subgroups: 1) RA as primary diagnosis, 2) RA as secondary diagnosis and 3) no RA. With a few exceptions, only the group of patients with RA as primary diagnosis were shown to have experienced an overall 32% and 24% reduction in TKR and THR surgeries, respectively, since 1993, and consistent decreasing rates after 2002.4
At a recent 2017 EULAR press conference, researchers said that a Danish study demonstrated the incidence of RA-related TKR started to decrease after bDMARDs were introduced into their national treatment guidelines.5 This retrospective study showed the number of TKR surgeries in RA patients had been increasing at a rate of +0.19 per 1,000 person years before 2002, but dipped to -0.20 per 1,000 person years after 2003, when bDMARDs were introduced in Denmark. The incidence of THR in RA patients had been equivalent to -0.38 per 1,000 person years both before and after the introduction of bDMARDs.5
Although the same Danish researchers, using data from England and Wales in 2016, could not show a statistically significant reduction in THR, they demonstrated that introduction of bDMARDs was associated with a relative reduction of 34% in five-year rates of TKR since 2003.6
These studies demonstrated a reduction of TKR and THR in RA patients receiving biologic treatments despite the high cost of bDMARDs. The cost of biologics for RA patients can reach $30,000 annually, but the average cost for TKR is $44,816 for only the hospital procedure.7 Adding the costs of RA medical care, employer/caregiver and quality-of-life-related expenses, the annual cost of all patients living with RA can reach $40 billion U.S. annually.8
By using biologics in primary RA diagnosed patients, we can stabilize disease status and minimize indirect and overall medical costs due to surgeries and ER visits.
Positive Outcomes in CVDs
CV events are higher among patients with RA and other systemic inflammatory disease states regardless of progressive status.9,10 The most common clinical cardiovascular event in RA patients is atherosclerosis. It is also important to evaluate CVDs’ clinical outcomes among potential treatment options in RA and other systemic inflammatory diseases. The most common therapeutic classes are NSAIDs, DMARDs, biologics and systemic corticosteroids.
Long-term, modest-dose corticosteroids and NSAIDs are contraindicated in RA patients with CVD comorbidities. The American Heart Association suggested clinicians avoid using NSAIDs in patients with history of CVD and limit the use of NSAIDs in all patient populations due to its mechanism of inhibiting both COX-1 and COX-2.11,12 Long-term systemic corticosteroids also contribute to adverse cardiovascular events, including dyslipidemia and hypertension.13
Based on the 2016 EULAR recommendations for CVD management in RA patients, CVD risk decreases in RA patients with long-term use of bDMARDs, including TNF inhibitors, tocilizumab and rituximab.14 Chronic systemic inflammatory diseases clearly play a role in promoting the development of atherosclerosis due to actions on endothelial cells and leukocytes.15 A proposed mechanism by which anti-TNF therapies reduce CVD risk is through a reduction in the inflammatory cascade and signaling, eventually reducing atherosclerosis and other cardiovascular events. The proposed mechanism of reducing CVD risk by tocilizumab and rituximab is their beneficial effect on carotid intima-media thickness, a surrogate marker for CVD.14
In addition to anti-inflammatory effects, infliximab and adalimumab have also been shown to improve lipid profiles; where infliximab increased both HDL-C and LDL-C panel, adalimumab increased HDL-C with no changes of LDL-C.15
One study showed that adalimumab reduced aortic stiffness independently of its RA response.16
Another study showed that lipoprotein(a) (LP[a]) is a risk factor for atherosclerotic CVD and that the plasma level of LP(a) in RA patients is increased significantly in comparison to the general population. LP(a) cannot be normalized by statin treatment, but can be better controlled by TNF inhibitors. This result indicates a need for TNF inhibitors in RA patients to provide better CVD protection.17
A systematic review and meta-analysis published in 2011 showed that use of TNF inhibitors was associated with a reduced risk for all cardiovascular events in observational cohort studies; however, there was heterogeneity among the studies and possible publication bias.18 Additionally, the meta-analysis of three randomized, controlled trials showed only a trend, which was not statistically significant, toward decreased risk.18 This meta-analysis included 16 studies that had been conducted prior to 2009, but only 11 studies were included in the meta-analysis.
A study published in 2015 showed that even though anti-TNFs and methotrexate demonstrated reduction in the risk of all CV events, anti-TNFs were superior in reducing risk of myocardial infarctions, strokes and major adverse cardiac events where methotrexate failed to show statistical significance.9
A more recent study published in 2016 compared hypertension outcomes between DMARDs and anti-TNFs in a retrospective cohort study using insurance claims data. It demonstrated that TNF inhibitors had no statistical significance over DMARDs in controlling hypertension.19 The researchers concluded that anti-TNFs were not associated with a reduced risk of incident hypertension compared with cDMARDs.19
Finally, a retrospective review/examination/audit of the Olmstead County population–based medical records study demonstrated that there has been statistical improvement in CV mortality in each of the past three decades, with the most recent decade having the most apparent improvement.20
Even though the FDA has levied a warning for TNF inhibitors in RA patients with congestive heart failure (CHF), recent studies showed no CHF recurrence or new CHF onset while patients were using TNF inhibitors.21,22 Only in New York Heart Association class III or IV patient populations does the 2015 ACR RA guideline recommend using sDMARDs, non-TNF biologic or tofacitinib over TNF inhibitors.23
Moreover, TNF inhibitors still showed positive CVD outcomes in RA patients after balancing risks and benefits. RA patients treated with TNF inhibitors had a lower risk of CVD compared with biologic-naive RA patients. Also, risk of CVD is similar between non-RA patients and RA patients treated with TNF inhibitors.24
Risks of Malignancy
The new EULAR safety recommendations compared the risk for malignancies among patients receiving bDMARDs with the general population, as well as with those patients on sDMARDs, and concluded that there is no increased risk for solid cancers.1 Patients on bDMARDs had a higher risk for lymphoma and nonmelanoma skin cancer than the general population, but not significantly greater in than patients receiving sDMARDs.1
The literature shows a positive correlation between severity of RA and the risk of both non-Hodgkin’s lymphomas (NHL) and Hodgkin’s lymphoma (HL), and it is believed that immunological elements can trigger transformation of normal lymphocyte polyclonal population into lymphoproliferative disease.25,26 Severe RA has a higher risk of lymphoma than the general population. In general, the risk ratio for lymphoma in RA patients is 2.0, and the hazard ratio for lymphoma in RA patients receiving bDMARDs falls into the range of 2.3–5.9, which is not significantly different from RA patients receiving sDMARDs per EULAR safety recommendations.1,27 Per these summarized data, there is no clear evidence that RA lymphoma risks are increased by bDMARDs.
Per new EULAR safety recommendations, the risk of melanoma may be slightly increased in patients receiving bDMARDs compared with sDMARDs with an adjusted HR of 1.5.1 However, a recent malignancy risk study conducted in Australian RA patients showed that melanoma risk was increased in both TNFi-treated and biologic-naive RA patients compared with the general population, with a standardized incidence ratio (SIR) of 2.72 and 2.03, respectively.28
An evaluation of the long-term risks and benefits of using bDMARDs suggests that bDMARDs have more statistically significant clinical benefits in the areas of total joint replacement and CVD risk in RA patients. Malignancy should not be a barrier for RA patients to receive bDMARDs, as long as patients are under close monitoring by both rheumatologists and oncologists. Based on current studies, bDMARDs showed significant value clinically, but work still needs to be done to show significant long-term economic value. Future studies should be designed to demonstrate comprehensive and clear clinical roles of bDMARDs in heterogenous diseases, such as CVD.
Nan Yang, PharmD, is a one-year postgraduate employed by Evergreen Pharmacy in West Allis, Wis.
Kurt Oelke, MD, is the clinical studies director at the Rheumatic Disease Center in Glendale, Wis.
- Ramiro S, Sepriano A, Chatzidionysiou K, et al. Safety of synthetic and biological DMARDs: A systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2017 Jun;76(6):935–938.
- Wolfe F, Zwillich SH. The long-term outcomes of rheumatoid arthritis: A 23-year prospective, longitudinal study of total joint replacement and its predictors in 1,600 patients with rheumatoid arthritis. Arthritis Rheum. 1998 Jun;41(6):1072–1082.
- Hekmat K, Jacobsson L, Nilsson JÅ, et al. Decrease in the incidence of total hip arthroplasties in patients with rheumatoid arthritis—results from a well defined population in south Sweden. Arthritis Res Ther. 2011 Apr 21;13(2):R67.
- David G, Tandon N, Waters HC, et al. Rheumatoid arthritis and joint replacement: Impact of biologics. Am J Pharm Benefits. 2014;6(6):256–264.
- Cordtz R, Hawley S, Prieto-Alhambra D, et al. Incidence of knee and hip replacements in rheumatoid arthritis patients following introduction of biological DMARDs: An interrupted time series analysis using nationwide health care registers [abstract 2017 OP0251]. EULAR 2017, Madrid.
- Hawley S, Cordtz R, Dreyer L, et al. The impact of biologic therapy introduction on hip and knee replacement among rheumatoid arthritis patients: An interrupted time series analysis using the clinical practice research datalink [abstract]. Arthritis Rheumatol. 2016;68(suppl 10)..
- Rheumatoid arthritis treatment costs. Rheumatoid Arthritis Support Network. Last updated 2016 Aug 3.
- Birnbaum H, Pike C, Kaufman R, et al. Societal costs of rheumatoid arthritis patients in the US. Cur Med Res Opin. 2010 Jan;26(1):77–90.
- Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: A systematic review and meta-analysis. Ann Rheum Dis. 2015 Mar;74(3):480–489.
- Zanoli L, Granata A, Lentini P, et al. The effect of tumor necrosis factor antagonists on functional aortic stiffening. Clin Rheumatol. 2017 Aug;36(8):1927–1928.
- National Center for Chronic Disease and Prevention. Heart disease and stroke prevention: Addressing the nation’s leading killers [fact sheet].
- Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal anti-inflammatory drugs: An update for clinicians: A scientific statement from the American Heart Association. Circulation. 2007 Mar 27;115(12):1634–1642.
- Ng MK, Celermajer DS. Glucocorticoid treatment and cardiovascular disease. Heart. 2004;90(8):829–830.
- Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017 Jan;76(1):17–28.
- Mckellar GE, Mccarey DW, Sattar N, Mcinnes IB. Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol. 2009 Jun;6(6):410–417.
- Vassilopoulos D, Gravos A, Vlachopoulos C, et al. Adalimumab decreases aortic stiffness independently of its effect in disease activity in patients with rheumatoid arthritis. Clin Rheumatol. 2015 Feb;34(2):359–364.
- Sverre H, Ingvild O, Tor-Arne H, et al. Increased levels of lipoprotein(a) in RA patients with cardiovascular disease [abstract 1474]. Arthritis Rheumatol. 2016;68(suppl 10).
- Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011 Apr;63(4):522–529.
- Desai RJ, Solomon DH, Schneeweiss S, et al. Tumor necrosis factor-α inhibitor use and the risk of incident hypertension in patients with rheumatoid arthritis. Epidemiology. 2016 May;27(3):414–422.
- Myasoedova E, Gabriel SE, Mattson E, et al. Decreased cardiovascular mortality in patients with incident RA in recent years: Dawn of a new era in cardiovascular disease in RA? J Rheumatol. 2017 Jun;44(6):732–739.
- AbbVie Inc. Product information: HUMIRA subcutaneous injection, adalimumab subcutaneous injection.
- Solomon DH, Rassen JA, Kuriya B, et al. Heart failure risk among patients with rheumatoid arthritis starting a TNF antagonist. Ann Rheum Dis. 2013 Nov;72(11):1813–1818.
- Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1–26.
- Ljung L, Askling J, Rantapää-dahlqvist S, et al. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: A national cohort study. Arthritis Res Ther. 2014 Jun 18;16(3):R127.
- Yadlapati S, Efthimiou P. Autoimmune/inflammatory arthritis associated lymphomas: Who is at risk? BioMed Res Int. 2016;2016:8631061. doi:10.1155/2016/8631061.
- Tvarůzková Z, Pavlová S, Doubek M, et al. [Lymphoproliferative disease in patients with autoimmune and inflammatory diseases: significance of antigenic stimulation and inflammatory processes]. Cas Lek Cesk. 2011;150(3):161–168.
- Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004 Jun;50(6):1740–1751.
- Buchbinder R, Van doornum S, Staples M, et al. Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necrosis factor therapy: Analysis of the Australian Rheumatology Association Database (ARAD) prospective cohort study. BMC Musculoskelet Disord. 2015 Oct 20;16:309.