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Predicting which people with inflammatory rheumatic musculoskeletal diseases (I-RMDs) may experience flares after COVID-19 vaccination just got a bit easier, thanks to a new analysis of more than 7,000 European RMD patients.

Factors associated with increased flare rates post-vaccination included active disease at the time, female sex, and -- most strongly -- stopped or reduced doses of anti-rheumatic medications, according to Pedro M. Machado, PhD, of University College London, and colleagues.

Those weren't particularly unexpected. But the analysis of 7,336 patients included in the European Alliance of Associations for Rheumatology Coronavirus Vaccine (COVAX) registry, , also yielded some surprises when the researchers looked for factors predicting lowered flare risk.

These included older age, use of certain classes of disease-modifying anti-rheumatic drugs (DMARDs), and receiving less-often used COVID-19 vaccine products.

Some of these associations became nonsignificant, however, when Machado and colleagues restricted the analysis to flares severe enough to warrant increased DMARD doses or new medications. With those as the endpoint, only moderate-to-high disease activity and DMARD withdrawal or dose reduction remained significantly predictive of flare risk. As well, only use of methotrexate or rituximab (Rituxan) were significantly associated with less risk of severe flares.

Most reassuringly, flares were uncommon across all subgroups -- fewer than 4% of registry patients suffered them, and for half of these the flares weren't severe enough to require medication adjustments.

"These findings will assist patients, clinicians, and other healthcare professionals in making informed decisions regarding the management of I-RMDs in the context of SARS-CoV-2 vaccination and contribute to the development of the most appropriate vaccination strategies for patients with I-RMDs," Machado's group concluded.

Better understanding of flare risk is essential for guiding patients and clinicians as they consider new rounds of COVID-19 vaccination, given that regular booster doses are likely to remain necessary, as with influenza vaccines, for the foreseeable future. Previous studies have shown some degree of increased flare risk after vaccination, Machado and colleagues observed, but quantitative estimates have varied, especially between patient- and physician-reported flares. Notably, some guidelines have called for stopping or reducing DMARD dosing around the time of vaccination, in hopes of boosting antiviral immune response.

The COVAX registry recorded outcomes after COVID-19 vaccination as reported by physicians for patients with RMDs, inflammatory or otherwise, from September 2021 to October 2022. Patients who received a combination of vaccine products, and those who had more than two doses of a single product, were excluded (the latter because baseline disease activity data were collected only at the first dose).

Patients with any of 29 specific conditions were included in the analysis. Those afflicting at least 250 patients were rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis, lupus, Sjögren's syndrome, and polymyalgia rheumatica. RA accounted for more than one-third of the total, and axSpA for one-sixth.

Mean age was about 58, although this varied somewhat among diagnostic categories (older for vasculitides, younger for "other" RMDs not considered joint or connective tissue diseases). Two-thirds of the overall group were women, which also varied among condition types -- women predominated even more for connective tissue diseases but less so for vasculitis and "other" non-joint diagnoses.

Well over half of patients received the Pfizer/BioNTech mRNA vaccine (Comirnaty) -- 74% of those receiving two doses and 43% of those getting only one dose. AstraZeneca's now-withdrawn product, which used a viral vector expressing SARS-CoV-2 antigens, accounted for 13% of two-dose immunizations and 9% of one-dose administrations. Moderna's mRNA vaccine (Spikevax) was used in 9% and 31% of two- and one-dose regimens, respectively. Other products accounted for the rest; they were not listed specifically in the Annals report but vaccines sold by Novavax, Sanofi Pasteur, Valneva, and HIPRA, as well as the Russian and Chinese vaccines, have been available at various times.

Curiously, it was this "other" group of products that seemed to come with the least flare risk. Compared with the Pfizer/BioNTech vaccine, "other" vaccines had just one-tenth the rate of all flares (OR 0.10, 95% CI 0.01-0.74). There was no substantial difference in flare rates between the Pfizer/BioNTech and Moderna or AstraZeneca vaccines.

Machado and colleagues couldn't explain this finding, other than to suggest it could have been a statistical fluke, given the small number of patients (80) receiving them, or perhaps influenced by what the group called "reporting bias." Also, when the analysis only counted severe flares, there were too few to support a meaningful comparison.

The researchers were also interested in whether flare risk was linked with the types of DMARDs patients had been taking. This proved more fruitful: risk was significantly lower among patients using methotrexate (OR 0.57, 95% CI 0.37-0.90), tumor necrosis factor (TNF) inhibitors (OR 0.55, 95% CI 0.36-0.85), and rituximab (OR 0.27, 95% CI 0.11-0.66), all in comparison with no anti-rheumatic therapy. When focusing only on severe flares, the reduced risk was still apparent for methotrexate and rituximab, but not TNF inhibitors.

Associations with baseline disease activity, meanwhile, defied intuition. Relative to patients in remission at the time of vaccination, those with low disease activity showed significantly increased flare risk (OR 1.45, 95% CI 1.08-1.94), but it appeared no greater, and was nonsignificant, for those with moderate/high activity (OR 1.37, 95% CI 0.97-1.95).

On the other hand, risk for severe flares did show increased risk with higher disease activity: the odds ratio was 3.08 (95% CI 1.91-4.97) among the moderate/high activity group versus 1.47 (95% CI 0.94-2.29) for patients with low activity, again relative to patients in remission.

The strongest predictor for flare risk was stopping or reducing DMARD doses (OR 4.76, 95% CI 3.44-6.58, for all flares; OR 2.24, 95% CI 1.33-3.78, for severe flares).

Limitations to the study were numerous. It was confined to Europe, where the range of available vaccines and demographic factors differs considerably from other regions. COVAX registry reporting was voluntary and to some extent subjective, and thus vulnerable to various biases. No particular time span between vaccination and event occurrence was prespecified and it therefore varied among reports. Finally, it's possible that some events classified as disease flares were actually vaccine reactions, particularly for complaints of joint pain.

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