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TNFi use may not affect joint replacement rates for RA patients

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Other factors likely explain decreased rate of joint replacement

The arrival and widespread use of tumor necrosis factor inhibitors (TNFi) in the late 1990s has “created a perception of causality” that led many to believe that TNFi use was associated with decreased rates of joint replacement. However, the decline in total hip arthroplasties (THAs), total knee arthroplasties (TKAs), and other joint replacements is likely because of a confluence of factors, Susan M. Goodman, MD, and Anne R. Bass, MD, wrote in an editorial accompanying the report by Hawley et al. (Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/kez022).

Dr. Susan M. Goodman, Hospital for Special Surgery, New York

Dr. Susan M. Goodman

“The early and aggressive management of RA, plus expansion of the treatment armamentarium available for refractory patients (including, of course, TNFi), likely had a greater impact on disease outcomes and joint replacement rates over the last 20 years than the introduction of any particular class of drug,” the authors wrote. “While this paper adds some clarity to the debate regarding the impact of TNFi on arthroplasty rates, further work is needed.”

Although Hawley et al. attempted to mitigate confounding in their study by using a propensity score when comparing TNFi and conventional synthetic disease-modifying antirheumatic drug (csDMARD) users, there was a preference for physicians prescribing biologics at a rate of 87% versus 13%, and the biologic preference was associated with disease severity, which is “a strong driver of the need for surgery.” In addition, in patients 60 years or older for whom TNFi reduced indications for joint replacement, “[t]he differential effect of TNFi use on THA utilization in the elderly is especially curious because a previous study by the same authors demonstrated that TKA, but not THA, rates were impacted by introduction of NICE guidance in 2002.”

Dr. Anne Bass is the rheumatology fellowship program director at the Hospital for Special Surgery, New York

Dr. Anne R. Bass

“This paradox may not be explained until the reasons for less TNFi use among the elderly are better understood and its confounding effect can be addressed in study design,” Dr. Goodman and Dr. Bass said.

The authors also noted clinicians should exercise caution in extrapolating the results of Hawley et al. because the effects of biologic treatment in patients with a long disease duration, such as in this study, may not be generalizable to most RA patients.

Dr. Goodman and Dr. Bass are rheumatologists and professors of clinical medicine at Cornell University and the Hospital for Special Surgery, both in New York. Dr. Goodman disclosed financial relationships with Novartis and UCB outside the scope of this work.



Patients with rheumatoid arthritis using tumor necrosis factor inhibitors do not appear to have a lower rate of joint replacement when compared with patients taking conventional synthetic disease-modifying antirheumatic drugs, according to an analysis of data in the British Society for Rheumatology Biologics Register for RA.

Samuel Hawley of the University of Oxford (England)

Samuel Hawley

Although there was not a general protective effect, patients with rheumatoid arthritis (RA) who were 60 years or older had a 40% reduction in total hip replacement (THR) when using tumor necrosis factor inhibitors (TNFi), according to first author Samuel Hawley from the Nuffield Department of Orthopaedics in the Rheumatology and Musculoskeletal Sciences at the University of Oxford (England) and his colleagues.

“While a reduction in THR amongst older TNFi users offers some support for biologics playing a role in reducing need for joint replacement, it must also be noted that the lack of an overall protective effect is suggestive that other factors apart from TNFi are likely to be involved in the ... downward population trends in joint replacement rates in RA,” Mr. Hawley and his colleagues wrote in their report published in the journal Rheumatology.

The researchers analyzed prospectively collected data on 11,202 RA patients from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) from 2001-2016 who were using TNFi (n = 9,558) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; n = 1,644). Patients had a median disease duration of 11.0 years in the TNFi group and 10.8 years in the csDMARD group. TNFi and csDMARD users were matched based on their propensity to receive treatment, and researchers used a Cox regression analysis to compare the rates of total knee replacement (TKR), THR, and other joint replacement. The researchers utilized each csDMARD user a median of three times (interquartile range, one to six) in the comparisons.

The incidence rate for THR was 5.22/1,000 person-years for TNFi users and 6.30/1,000 person-years for csDMARD users, while the incidence rate for TKR was 8.89/1,000 person-years for TNFi users and 8.09/1,000 person-years for csDMARD users. Mr. Hawley and his colleagues found no association between TNFi use and THR when compared with csDMARD users (adjusted pooled hazard ratio, 0.86; 95% confidence interval, 0.60-1.22; P = .39) based on 589 THRs during follow-up. There was also no association between the incidence of TKR and TNFi use when compared with csDMARD users (adjusted pooled HR, 1.11; 95% CI, 0.84-1.47; P = .46) based on 846 TKRs during follow-up. When the researchers examined 336 other joint replacements performed during follow-up, there was also no significant difference in incidence between TNFi and csDMARD users (HR, 1.15; 95% CI, 0.75-1.77).

For patients 60 years or older, TNFi use was associated with a 40% reduction in THR incidence (HR, 0.60; 95% CI, 0.41-0.87; P = .008), but not in TKR incidence. However, younger patients using TNFi did not have a reduced incidence of THR, and there were no associations between TNFi use and incidence of TKR or other joint replacements.

“It could be that the relatively long disease duration at our baseline meant there was greater potential for prevention of joint destruction at the hip over knee, although details of differential natural history of RA disease at these two joints are not well established,” the researchers wrote. “It is also very difficult to disentangle the impact of TNFi on improved function and overall quality of life and how this may have mediated effects on longer-term progression of joint damage, potentially differentially at the knee and hip.”

The researchers said the study was limited by the potential for residual confounding by indication, and the long disease duration of patients means that the results would not be generalizable to patients with early RA. In addition, underreporting of joint replacement could create bias because the registry information is a combination of physician-reported and self-reported incidences, they added.

This study was funded by an award from the National Institute for Health Research (NIHR) and support from the Oxford NIHR Biomedical Research Unit. Four authors disclosed financial relationships with industry, including many companies marketing biologics for RA. Other authors reported no relevant conflicts of interest.

SOURCE: Hawley S et al. Rheumatology. 2019 Jan 10. doi: 10.1093/rheumatology/key424.

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