Improvements in RA Fatigue Mediated By Changes in Central Pain

Fatigue contributes significantly to the morbidity associated with RA, however there is continued debate as to the mechanisms driving the fatigue process

New research from a large cohort of patients with rheumatoid arthritis (RA) initiated on anti-tumor necrosis factor (TNF) therapy suggests that improvements in fatigue are mediated not by reductions in peripheral inflammation, but by changes in central pain processes.This data was recently published in Arthritis Care & Research.

Fatigue contributes significantly to the morbidity associated with RA, however there is continued debate as to the underlying mechanisms driving fatigue. While there is data suggesting that short-term control of peripheral inflammation ameliorates fatigue in patients with RA2, there has been less research on the long-term effects of treating inflammatory mediators as a way to treat fatigue.

Thus, researchers sought to elucidate if longer term decreases in fatigue seen with anti-TNF therapy were reflective of modifications in central pain mechanisms, as opposed to peripheral inflammatory pain mechanisms.

High Yield Data Summary

  • In patients with RA started on anti-TNF therapy, improvements in fatigue likely reflect changes in centrally driven pain processes rather than peripheral inflammatory disease activity

Researchers from the University of Aberdeen, Scotland analyzed data from patients enrolled in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA). 

This prospective registry included patients in the U.K. with physician-diagnosed RA, or RA diagnosis according to the American College of Rheumatology criteria, who had started anti-TNF therapy with either infliximab, etanercept, adalimumab, or with traditional disease-modifying antirheumatic drugs (DMARDs).

Changes in disease activity, pain, and fatigue were all followed over the course of 6 months.  Pain was assessed with the short form-36 (SF-36) bodily pain scale, and disease activity was measured using the Disease Activity Score in 28 joints (DAS28). 

Individual composite components of DAS28, including swollen joint count (SJC), tender joint count (TJC), erythrocyte sedimentation rate (ESR), and the visual analog scale for patient’s global assessment (PGA) were used to quantify inflammatory disease activity instead of the DAS28 composite score to avoid either underestimation or overestimation of peripheral inflammation.  

A total of 13 122 patients were identified as having been prospectively registered in the BSRBR-RA and initiated on anti-TNF pharmacotherapy between October 2000 and November 2008.  Of these patients, 2 652 (38.8%) were identified as having severe fatigue at baseline, defined by a score ≤5th percentile (≤12.5; range 0–100) on the SF-36 vitality scale, who also had accompanying fatigue data at the 6-month followup mark. 

At baseline, these patients had a median age of 57 years (interquartile range [IQR] 49–64), median disease activity score of 6.81 (IQR 6.14–7.47), disease duration of 12 years (IQR 6–22), with a majority of participants being female (79.6%) and of white ethnicity (97.3%).  

Varimax rotation was used for principal components factor analysis to determine latent variables of symptom change. Variables with eigenvalues ≥1 were subsequently accepted.  Of the 6 latent variables identified, 2 were accepted (eigenvalues of 2.39 and 1.14, respectively).

After rotation, researchers found distinctively clear loading patterns.  Factor 1 was comprised principally of markers of peripheral inflammation, including changes in ESR (ΔESR 0.3), SJC (ΔSJC 0.8), TJC (ΔTJC 0.8), and PGA (ΔPGA 0.6). This contrasted to components identified in factor 2, which included changes in pain (Δpain 0.8), fatigue (Δfatigue 0.9), and PGA (ΔPGA (0.5) with no eligible loadings of peripheral inflammatory variables. Factor 2 was subsequently labeled central inflammation by researchers.

As changes in the markers of peripheral inflammation displayed distinct loading on factor 1, the factor was labeled peripheral inflammation. Conversely, factor 2 was labeled central inflammation by researchers.

“Improvements in fatigue following anti-TNF therapy commencement reflect changes in centrally driven pain, rather than inflammatory disease activity,” the authors concluded.

Summary and Clinical Applicability

In a large prospectively followed cohort of patients with RA starting anti-TNF therapy for the first time, 2 latent variables were identified that suggest that improvements in fatigue over a 6 month period were mediated by centrally driven pain as opposed to peripheral inflammation.  These results suggest that targeting central pain mechanisms may most effectively treat fatigue in these patients.

“[For] clinicians wishing to treat fatigue, improvements will likely be maximized by the application of pharmacologic and nonpharmacologic treatment modalities that effectively target central pain”, the authors stated.

“The variables also appear to suggest that the effect of improvements in central pain on fatigue management is underestimated by current strategies, which seek to modify pain caused by peripheral inflammation.”

Limitations and Disclosures

  • Use of only patients enrolled in BSRBR-RA registry who initiated anti-TNF therapy resulted in a sample with high RA disease activity, thus limiting generalizability
  • The highly specific eligibility criteria specified by researchers for participant inclusion in data analysis (selecting only patients with high fatigue) raises concern over external validity
  • The use of SF-36 as a global assessment of fatigue has been questioned in past research

The researchers report no competing interests. The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis is funded by UK pharmaceutical companies.  Data analyses, interpretation, and publication were made autonomously of any pharmaceutical contribution.

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1.     Druce KL, Jones GT, Macfarlane GJ, Basu N. Examining changes in central and peripheral pain as mediates of fatigue improvement: results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(7):922-6. 

2.     Druce KL, Jones GT, Macfarlane GJ, Basu N. Patients receiving anti-TNF therapies experience clinically important improvements in RA-related fatigue: results from the British Society of Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford) 2015;54:964–71.