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One-third of patients with rheumatoid arthritis had unacceptably high levels of pain 5 years after diagnosis, often despite low levels of inflammation, Swedish researchers found.

In an inception cohort of 232 patients with early rheumatoid arthritis, 34.1% still reported unacceptable pain at 5 years -- defined as pain scores above 40 mm on a 100-point visual analog scale, reported Anna Eberhard, MD, of Lund University in Malmö, and colleagues.

And in 22.5% of patients, unacceptable pain at 5 years was reported among those whose levels of inflammation were categorized as low, with C-reactive protein (CRP) levels below 9 mg/L. "This indicates large unmet needs in rheumatoid arthritis pain management and highlights that noninflammatory mechanisms contribute substantially to the pain spectrum," the researchers wrote in the study online in .

Pain in arthritis is thought to result from activation of synovial nociceptors by inflammatory cytokines, and some research has suggested that central sensitization also may play a role.

But little is known about the trajectory of pain and predictors of persistent pain in rheumatoid arthritis, so Eberhard and colleagues analyzed data from a cohort of patients recruited at Malmö University Hospital from 1995 to 2005 who were followed for 5 years. Participants were managed according to standard of care, with about 62% of patients treated with methotrexate, 29% with prednisone, and 18% with a biologic therapy (some received more than one therapy).

More than two-thirds were women, mean age was 60.5, and mean symptom duration was 7 months at the time of enrollment. A total of 61.6% were seropositive for rheumatoid factor and 57.4% were positive for anti-cyclic citrullinated peptide (CCP), with seropositivity typically reflecting worse disease activity. Swollen and tender joint counts were seven and four, respectively, and 52.2% of patients had CRP levels higher than 9 mg/L.

At baseline, the mean pain score was 41.2, declining to 32.3 at 6 months, for a mean change of -9.2 (P<0.001). However, there was no significant change in pain scores thereafter, the researchers said.

The proportion of patients reporting unacceptable pain was 49.1% at baseline, declining to 30.1% at 1 year and remaining at that level throughout. In 20.2% of patients, unacceptable pain with low inflammation was reported at baseline.

In a univariate analysis, unacceptable pain at 1 and 2 years was associated with higher baseline pain levels, worse disability on the Health Assessment Questionnaire, and higher patient global assessment scores.

In a multivariate analysis, baseline predictors of unacceptable pain at 2 years included female sex (OR 2.57, 95% CI 1.27-5.33) and higher pain scores (1.56 per standard deviation [SD], 95% CI 1.14-2.14). At 5 years, unacceptable pain was associated with worse patient global assessment of disease activity at baseline (OR 1.78 per SD, 95% CI 1.26-2.52) and lower swollen joint count (OR 0.61 per SD, 95% CI 0.42-0.89).

The inverse association of unacceptable pain with swollen joint count (an objective measure of disease activity and inflammation) supports the concept that noninflammatory factors contribute to overall pain in rheumatoid arthritis, the authors noted.

Also in a multivariate analysis, younger age was associated with unacceptable pain and low inflammation at 2 years. At both years 2 and 5, unacceptable pain and low inflammation were associated with anti-CCP negativity (OR 0.43 for seropositivity, 95% CI 0.20-0.95, P=0.04) and higher baseline patient global assessment (OR 1.51, 95% CI 1.01-2.25, P=0.04).

The finding that substantial numbers of patients, even those with low levels of inflammation, had persistent unacceptable pain through 5 years of follow-up highlights the need for improved pain management in rheumatoid arthritis, utilizing modalities such as increased physical activity and the use of medications that can modulate pain such as serotonin and noradrenaline reuptake inhibitors, the researchers said.

"These results all indicate that pain in rheumatoid arthritis is multifactorial and might include central pain mechanisms, encompassing an increased risk of secondary fibromyalgia and persistent nociplastic pain, presumably sharing common mechanisms of disease development, such as central sensitization," Eberhard and co-authors wrote.

Study limitations, the team said, included the lack of data on potentially important comorbidities such as osteoarthritis and depression, and the fact that many patients were enrolled in the cohort before the widespread implementation of treat-to-target strategies.

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