Rheumatic Conditions Are a Common Cause of Unexplained Fever, Inflammation


A review found rheumatic conditions cause 22.2% of global cases of fever and inflammation of unknown origin.

Rheumatic conditions are a common cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO), according to a review published in Seminars in Arthritis and Rheumatism.

Specifically, rheumatic conditions are a cause for 22.2% of global FUO/IUO cases and 25.9% of cases in high-income countries.

The authors conducted a systematic literature review and meta-analysis using 66 studies published between January 2002 and December 2021 to estimate the proportion of FUO/IUO cases caused by rheumatic conditions.

Each study included at least 50 patients with FUO/IUO, with a collective 16,723 patients in the review. Because the review only included studies published in English, there was a notable lack of studies included from Central and South America. Regarding patient characteristics, the authors found no association between the proportion of rheumatic conditions and age, sex, or fever pattern.

The review found that rheumatic conditions explained 22.2% (95% CI, 19.6-25.0%) of FUO/IUO cases.

According to multivariable meta-regression analysis, rheumatic disease was associated with fever duration (0.011; 95% CI, 0.003-0.021; P = .01) and the fraction of patients with IUO (1.05; 95% CI, 0.41-1.68; P = .002).

The authors also found varying frequencies of conditions in the review. Adult-onset Still disease was the most common rheumatic condition in this review, explaining 22.8% of global cases (95% CI, 18.4-27.9%).

The large amount of patients with adult-onset Still disease and FUO/IUO warrants a high index of suspicion, according to the authors.

Additionally, 11.4% of cases were caused by giant cell arteritis (95% CI, 8.0-16.3%), and 11.1% were caused by systemic lupus erythematosus (95% CI, 9.0-13.8%).

“While these disorders are three well-known entities, it remains important to emphasize that FUO/IUO may be caused by relatively common conditions presenting with uncommon manifestations rather than by rare disorders, such as giant cell arteritis presenting with nonspecific constitutional symptoms due to isolated large vessel vasculitis or older males presenting with signs and symptoms of systemic lupus erythematosus,” the authors wrote.

The review also showed that rheumatic conditions were significantly proportionately higher in high-income countries (25.9%) compared with middle-income countries (19.5%), as well as in prospective studies (27.0%) compared with retrospective studies (20.6%).

On top of differing disease prevalence based on country, the authors noted these variations may also be linked to access to diagnostic tools and potential diagnostic bias in different areas.

According to the authors, these findings reflect how important it is for physicians to consider rheumatic conditions when treating patients with FUO/IUO.

“However, establishing a final diagnosis of rheumatic disease requires a thorough knowledge of the specific entities associated with FUO/IUO, as diagnosis is often based on clinical judgement,” the authors wrote. “As a result, it seems crucial that the care of patients with FUO/IUO involves physicians who are familiar with the diagnostic workup of rheumatic disorders.”


Betrains A, Moreel L, De Langhe E, Blockmans D, Vanderschueren S. Rheumatic disorders among patients with fever of unknown origin: a systematic review and meta-analysis. Semin Arthritis Rheum. Published online July 7, 2022. doi:10.1016/j.semarthrit.2022.152066

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