Seronegative RA and Fibromyalgia May Be Linked

Seronegative rheumatoid arthritis (RA) is strongly associated with fibromyalgia, according to a newly published study.

However, one expert suggests the difference seen between seronegative vs seropositive RA and fibromyalgia might reflect the greater scrutiny of patients with seronegative RA in typical clinical practice.

Jayanth Doss, MD, from the Division of Rheumatology and Immunology, Duke University, Durham, North Carolina, and colleagues report their findings in an article published September 2 in Arthritis & Rheumatology.

The researchers used phenome-wide association study (PheWAS) analysis of electronic health records (EHRs) to examine disease associations for patients with RA who were either seropositive for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (ACPA) or seronegative for either or both of those markers.

The investigators found that patients with seronegative RA were twice as likely to have PheWAS codes for “myalgia and myositis” (odds ratio [OR], 2.1; P = 3.7 × 10⁻¹⁰; the strongest association found in the study) compared with patients with seropositive RA. Patients with seronegative RA were also more likely to have back pain.

Dr Doss told Medscape Medical News, “While we have known associations of seropositive RA with vasculitis and interstitial lung disease, we don’t have a lot of literature regarding seronegative RA. This study identifies a disease association (ie, fibromyalgia) with seronegative RA. Hopefully, this can spur future studies into the seronegative subset of RA patients, which is a large subgroup (between 20%-40% of RA patients, depending on the study).”

Manual record review of 100 randomly selected records for patients with codes for “myalgia” and “myositis” showed that these codes were used to indicate fibromyalgia in 80% of cases. The researchers next used a specific EHR algorithm for fibromyalgia and confirmed that seronegative RA was strongly associated with fibromyalgia (OR, 1.8; P = 4.0 × 10⁻⁶).

The authors suggest that the PheWAS approach will help “discover novel phenotype associations within different subgroups of a disease.” Yet relying on EHR data also has a down side: the risk for selection bias.

Frederick Wolfe, MD, from the National Databank for Rheumatic Diseases, Wichita, Kansas, who was not involved in the study, told Medscape Medical News that the researchers’ conclusion “is probably wrong.”

“The result is likely to be due to differential misclassification. That is, the doctors who wrote down the symptoms were more thorough with seronegative RA. I have seen it a thousand times. [The researchers] don’t really know who has fibromyalgia and who does not,” Dr Wolfe said.

The PheWAS analysis also showed that seropositive RA was strongly associated with chronic airway obstruction (OR, 2.2; P = 1.4 × 10⁻⁴) and tobacco use (OR, 2.2; P = 7.0 × 10⁻⁴).

The authors conclude, “This PheWAS in RA patients identifies a strong association between seronegativity and fibromyalgia. It also affirms relationships between seropositivity with chronic airway obstruction and seropositivity with tobacco use.”

The findings have clinical implications in both RA subgroups. Dr Doss said, “The study supports the assertion that the seronegative subgroup is different from the seropositive subgroup. Physicians should be aware of the higher incidence of fibromyalgia in seronegative populations. It also reminded me of the importance of continuing to encourage smoking cessation in RA patients, with the hope they will not progress to [chronic obstructive pulmonary disease].”

A key reason for this analysis was to help flesh out the sparse information on seronegative RA. The authors explain, “Seropositive RA patients have more severe disease and more rapid radiographic progression. However, most studies do not look at seronegative RA as an area of emphasis and very little literature exists in describing this subgroup.” The 2199 patients with RA whose records were studied included 1382 who were seropositive (63%) and 817 who were seronegative (37%).

Coauthor Leslie J. Crofford, MD, director of the Division of Rheumatology & Immunology, Vanderbilt University, Nashville, Tennessee, told Medscape Medical News that the patients with seronegative RA met stringent criteria for the diagnosis of RA and were not instances of RA being misdiagnosed in patients with fibromyalgia. Dr Crofford said, “Although it is difficult to be certain, our interpretation is that in the absence of positive serologies, clinicians will often make the diagnosis of [fibromyalgia] musculoskeletal pain. In our study, the diagnosis of [fibromyalgia] was often made close to the time of the RA diagnosis, so it is certainly possible that there was diagnostic confusion before and even after the diagnosis of seronegative RA.”

“I was actually quite surprised by the strength of the association of fibromyalgia in seronegative vs seropositive RA patients,” Dr Crofford added. “We know all RA patients have an increased prevalence of fibromyalgia compared with a general population, and don’t know of a biologic reason that [fibromyalgia] would be more prevalent in those without antibodies. It is for that reason that we hypothesize diagnostic fluidity.”

In view of the apparent clinical uncertainty, Dr Crofford advised clinicians to remain alert for synovitis in seronegative patients with multifocal musculoskeletal pain.

The use of PheWAS to compare patients with seropositive and seronegative RA is likely to be a harbinger of future studies. Dr Doss explained, “Over the last few years, we have seen a dramatic growth of use of patient data from clinical EHRs to create cohorts of patients for comparison. These cohorts are often used [to] compare disease cases to healthy controls using linked genetic data for genome-wide association studies or for a number of disease case/control groups designated for a PheWAS. By using disease subgroups as the two groups for comparison, we used PheWAS to identify phenotypic differences within a disease population. If DNA biobank samples are available, then investigators could look for genetic differences between the groups, potentially identifying genes driving those differences in presentation, prognosis, and treatment, which could lead to better understanding disease mechanisms of rheumatoid arthritis or other diseases.”