Rheumatology

Rheumatoid Arthritis

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Seronegative Rheumatoid Arthritis: Differential Diagnosis and Treatment Strategies

clinical topic updates by Leonard H. Calabrese, DO

Overview

The diagnosis of seronegative rheumatoid arthritis (RA) is challenging, as there are many potential diseases that can mimic RA. Ruling out these alternative diagnoses is critical prior to the initiation of treatment.

Expert Commentary

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

In our approach to seronegative RA, we must rule out other conditions that are common in patients with inflammatory joint changes.”

Leonard H. Calabrese, DO

There is a lot of talk about RA being a forgone conclusion as a diagnosis in patients with inflammatory arthritis. We recognize that RA has well-established classification criteria that are guided by molecular tests that examine anti-citrullinated protein antibodies and rheumatoid factor. But every rheumatologist knows that we all do the same thing when patients present with joint pain: They are assessed as having either inflammatory disease or noninflammatory disease. Great concern—if not trepidation—surrounds the diagnosis of those who are suspected of having inflammatory disease but are seronegative because we recognize that RA is distinct among many similar clinical entities. Studies that look at the genetics of seronegative RA show that there are really no strong genetic associates like there are with anti-citrullinated protein antibody–positive disease. This suggests that seronegative disease may also be heterogeneous. Thus, in our approach to seronegative RA, we must rule out other conditions that are common in patients with inflammatory joint changes. In older people, disorders such as polymyalgia rheumatica can mimic RA quite convincingly. In younger people, we have to consider viral polyarthritis or some type of infectious-related arthritis, particularly when the symptoms have been present for less than 6 weeks. If the symptoms have been coming and going, we should consider palindromic rheumatism, which is seronegative in 50% of patients and for which the outcome is still relatively undefined. Further, we have to consider peripheral spondyloarthritis and arthritis associated with inflammatory bowel disease, psoriatic arthritis, and post-infectious reactive arthritis. There are also some rare and unusual conditions of which we must remain mindful, including sarcoid arthropathy and polyarticular crystalline arthritis. In addition, some noninflammatory conditions that sometimes give us difficulty but are always on the radar screen for rheumatologists include hypermobility syndromes and fibromyalgia. Although they are typically easy to separate from RA, they might occasionally cause difficulty because there may be slight elevations of acute-phase reactants. Finally, there are immune-related reactions that are associated with joint pain with some of the checkpoint inhibitors used in oncology, and these are usually seronegative. Overall, we should exert caution when making the diagnosis of seronegative disease, with aggressive targeted therapy being reserved for the cases where we are quite confident of the diagnosis. The treatment for these patients is similar to the treatment for those with seropositive disease, although rituximab and abatacept do not work as well in seronegative patients.

References

Barra L, Pope JE, Orav JE, et al; CATCH Investigators. Prognosis of seronegative patients in a large prospective cohort of patients with early inflammatory arthritis. J Rheumatol. 2014;41(12):2361-2369.

de Moel EC, Derksen VFAM, Trouw LA, et al. In rheumatoid arthritis, changes in autoantibody levels reflect intensity of immunosuppression, not subsequent treatment response. Arthritis Res Ther. 2019;21(1):28.

Doss J, Mo H, Carroll RJ, Crofford LJ, Denny JC. Phenome-wide association study of rheumatoid arthritis subgroups identifies association between seronegative disease and fibromyalgia. Arthritis Rheumatol. 2017;69(2):291-300.

Milewicz DM, Reid AJ, Cecchi AC. Vascular Ehlers-Danlos syndrome: exploring the role of inflammation in arterial disease. Circ Cardiovasc Genet. 2014;7(1):5-7.

Nordberg LB, Lillegraven S, Aga AB, et al. Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial. RMD Open. 2018;4(2):e000752.

Paalanen K, Rannio K, Rannio T, Asikainen J, Hannonen P, Sokka T. Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study. Clin Exp Rheumatol. 2019;37(1):37-43.

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

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