BALTIMORE—Rheumatoid arthritis (RA) is one of the most commonly encountered diseases in rheumatology. Thus, it’s helpful to stay abreast of its most recent guidelines and research developments. At the 18th Annual Advances in the Diagnosis & Treatment of the Rheumatic Diseases, held May 13–14 at the Johns Hopkins School of Medicine, Baltimore, Clifton O. Bingham, MD, professor of medicine and director of the Arthritis Center at Johns Hopkins School of Medicine, provided an outstanding talk, addressing:
- The application of RA guidelines to clinical decision making;
- Recent drug safety findings; and
- The monitoring of patient symptoms and improved shared decision-making practices.
Guidelines
Dr. Bingham
Dr. Bingham noted EULAR’s 2019 recommendations for the management of RA with synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs) and the ACR’s 2021 guideline for the treatment of RA have many overlapping recommendations, but they also contain some key differences.1,2
The EULAR guideline recommends methotrexate be part of the first-line treatment strategy for patients with RA. EULAR also recommends the short-term use of glucocorticoids when initiating or considering conventional synthetic DMARD therapy—albeit with tapering as rapidly as possible. In contrast, the ACR guideline conditionally recommends the use of DMARDs without glucocorticoids.
Additionally, the EULAR guideline advises that biologic DMARDs and targeted synthetic DMARDs always be combined with conventional synthetic DMARDs. Tapering biologic DMARDs or targeted synthetic DMARDs can be considered when a patient has achieved RA remission, which can potentially be followed by tapering conventional synthetic DMARDs.
On the other hand, the ACR guideline conditionally recommends the gradual discontinuation of methotrexate over tapering biologic DMARDs or targeted synthetic DMARD therapy. This approach is partly driven by the views of patients involved in the development of the guideline. Patients noted the difficulty of tolerating methotrexate due to side effects and limitations on alcohol intake, which make it less appealing.
Treatments
For starting therapy, Dr. Bingham noted the ACR guideline recommends hydroxychloroquine or sulfasalazine as a first-line treatment for patients with low disease activity. However, through a series of clinical vignettes, he helped illustrate that disease activity for a patient can differ based on the measure being employed, such as the Clinical Disease Activity Index (CDAI), Disease Activity Score-28 for Rheumatoid Arthritis with ESR (DAS28 ESR) or others. Specifically, because the CDAI does not include inflammatory markers, such as ESR and C-reactive protein (CRP), patients with elevated markers may be misidentified as having low disease activity, particularly if they have fewer swollen or tender joints at the time of the exam.
The ACR also recommends that patients who have not met targeted control of their disease on oral methotrexate be switched to subcutaneous methotrexate rather than another DMARD. A prior ACR guideline recommended escalating to triple therapy (i.e., methotrexate, sulfasalazine and hydroxychloroquine) for patients not at target on oral methotrexate.3 However, the 2021 guideline conditionally recommends adding a biologic DMARD or targeted synthetic DMARD over triple therapy for patients on the maximum methotrexate dose who are still not at target.
Drug Safety
Dr. Bingham also addressed drug safety issues, specifically related to Janus kinase (JAK) inhibitors. The ORAL Surveillance study is a clinical trial that enrolled patients aged 50 and older with moderate to severe RA and one or more cardiac risk factor for whom methotrexate proved inadequate. The study excluded patients with current or prior malignancy. The patients were divided into one of three clinical arms: 5 mg of tofacitinib given twice daily plus methotrexate; 10 mg of tofacitinib given twice daily plus methotrexate; however, after the drug safety monitoring review, this dose was lowered to 5 mg given twice daily; or a tumor necrosis factor-α (TNF) inhibitor plus methotrexate.4
The study demonstrated that tofacitinib combined with methotrexate was not non-inferior to TNF inhibitors plus methotrexate. Specifically, the number needed to harm for major adverse cardiac events over one year would be 567 for 5 mg of tofacitinib taken twice daily and 319 for 10 mg of tofacitinib taken twice daily.4
Dr. Bingham noted that independent risk factors for major adverse cardiac events included current smoking, aspirin use, being 65 years or older, and being male. Moreover, he stated that the highest rates of major adverse cardiac events were seen in patients with coronary artery disease and in patients with a high risk of major adverse cardiac events based on traditional risk factors.5 Thus, Dr. Bingham advocated for the use of an atherosclerotic cardiovascular disease (ASCVD) risk calculator, such as that available through the website of the American College of Cardiology, to assess which patients may or may not be good candidates for treatment with JAK inhibitors.
Regarding malignancy, lung cancer was the most frequently seen cancer in the ORAL Surveillance study, with independent risk factors of being age 65 years or older and current or past smoking. Interestingly, data indicate that non-melanoma skin cancer risk may be increased with methotrexate use. Thus, Dr. Bingham noted that patients on any form of DMARD therapy may be well served by an annual skin exam with a dermatologist. Finally, venous thromboembolism and pulmonary embolism were found to be an increased risk only in patients on the higher dose of tofacitinib.6
The final portion of the presentation dealt with advice on medication tapering and treating to target while keeping patient views in mind. With regard to tapering medication in patients who have been at target for at least six months, the ACR guideline conditionally recommends continuing DMARD therapy over tapering. However, if a compelling reason to taper exists, such as patient preference or comorbidities that may benefit from reducing medication burden, then dose reduction is conditionally recommended over gradual discontinuation, and gradual discontinuation is conditionally recommended over abruptly stopping DMARD therapy.2
Dr. Bingham advocated for the use of an atherosclerotic cardiovascular disease risk calculator to assess which patients may or may not be good candidates for treatment with JAK inhibitors.
Patient Care
With respect to treating to target, the goal should be remission of disease or low disease activity. Achieving these goals involves shared decision making between patients and physicians. This approach means patients should be able to understand the options available to them, the pros and cons of those options, and the ways in which their own goals and treatment preferences guide their care.
From a patient perspective, important considerations may include symptoms, such as pain and fatigue; physical function; valued life activities and roles; independence; avoidance of side effects; and financial costs. Because the clinical goals of the rheumatologist may not always include these objectives, it’s important that an open dialogue exist between patients and doctors to enhance trust and understanding, which are imperative to the therapeutic relationship.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
References
- Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020 Jun;79(6):685–699.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021 Jul;73(7):1108–1123.
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016 Jan;68(1):1–26.
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022 Jan;386(4):316–326.
- Charles-Schoeman C, Buch M, Dougados M, et al. Risk factors for major adverse cardiovascular events in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs. TNF inhibitors [abstract: 0958]. Arthritis Rheumatol. 2021 Oct; 73(suppl 10).
- Curtis J, Yamaoka K, Chen Y, et al. Malignancies in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors [abstract: 1940]. Arthritis Rheumatol. 2021 Oct; 73(suppl 10).
