Increased Fatigue Observed in Progressive Clinically Suspect Arthralgia

arthritis in the hand
MODEL RELEASED. Man rubbing sore hand.
Researchers examined the course of fatigue in clinically suspect arthralgia during progression to rheumatoid arthritis.

In patients with clinically suspect arthralgia (CSA), fatigue increases gradually toward the development of rheumatoid arthritis (RA), according to study findings published in Joint Bone Spine.

Researchers conducted a longitudinal study in the Netherlands among patients with CSA who were consecutively included in the Leiden University CSA cohort and had at least 1 year of follow-up. The CSA cohort that comprised patients who have arthralgia of the small joints for  less than 1 year that is considered suspicious for progression to RA.

All patients from the CSA cohort were followed for 2 years for the development of RA, which was confirmed by the presence of joint swelling during physical examination by a rheumatologist. Follow-up visits occurred at 4 months, 12 months, 24 months, and more regularly if any increased musculoskeletal symptoms developed between follow-up visits. All patients in the CSA cohort were not treated with any disease-modifying antirheumatic drugs (DMARDs), including corticosteroids, during follow-up.

A total of 600 patients with CSA were followed for the development of RA. Another 710 patients with early RA were investigated at diagnosis. Fatigue, which was evaluated at every visit, was rated on a scale of 0 to 100. Inflammation was measured with use of the Disease Activity Score in 44 joints score and C-reactive protein level (DAS44-CRP. Analyses were stratified by anticitrullinated protein antibody (ACPA) status.

Results of the study showed that in 88 patients with CSA who developed RA, prearthritis fatigue levels increased gradually over time by 7 points per year (95% CI, -2 to 16) toward a mean of 48 (95% CI, 41-55) at the development of RA. Patients with CSA who did not develop RA demonstrated decreasing levels of fatigue by 4 points per year after baseline (95% CI, -6 to -3; P <.001).

At the onset of CSA, inflammation was associated with fatigue (β=18, which translates to 18 points more fatigue per point increase in DAS score; P <.01). This association was stronger than at diagnosis of RA (β=5; P <.001).

Stratified analyses according to ACPA status showed that fatigue in patients who were both ACPA-negative and ACPA-positive increased to the same extent toward the development of RA. Patients who were ACPA-negative, however, were more fatigued than those who were ACPA-positive both before and at the development of RA (mean difference in fatigue, 13; 95% CI, 1-24; P <.05).

Additionally, fatigue was not significantly associated with inflammation in patients with ACPA-negative CSA, whereas inflammation and fatigue were significantly associated in participants with ACPA-positive CSA. The link between inflammation and fatigue in patients with ACPA-positive CSA was stronger than in patients with ACPA-positive RA (β=25 and β=9, respectively).

Limitations of the study include the absence of a validated inflammation score in patients with “pre-RA.” Observed associations between inflammation and fatigue do not prove causation. The follow-up duration of 2 years may be insufficient to identify all patients with CSA who converted to RA.

The study authors conclude that the findings from the current study suggest that DMARD treatment in patients with CSA may decrease the burden of fatigue more effectively compared with the effect of DMARDs in patients with classified RA, particularly those who are ACPA-positive. This remains as a topic for future research.


Khidir SJH, Wouters F, van der Helm-van Mil AHM, Mulligen EV. The course of fatigue during the development of rheumatoid arthritis and its relation with inflammation: a longitudinal study. Joint Bone Spine. Published online June 28, 2022. doi:10.1016/j.jbspin.2022.105432