Fatigue in rheumatoid arthritis; a persistent problem: a large longitudinal study

Abstract

Objective: Fatigue is prevalent and disabling in rheumatoid arthritis (RA). Surprisingly, the long-term course of fatigue is studied seldom and it is unclear to what extent it is influenced by inflammation. This study aimed to determine the course of fatigue during 8 years follow-up, its association with the severity of inflammation and the effect of improved treatment strategies.

Methods: 626 patients with RA included in the Leiden Early Arthritis Clinic cohort were studied during 8 years. Fatigue severity, measured on a 0-100 mm scale, and other clinical variables were assessed yearly. Patients included in 1993-1995, 1996-1998 and 1999-2007 were treated with delayed treatment with disease-modifying antirheumatic drugs (DMARDs), early treatment with mild DMARDs and early treatment with methotrexate respectively. After multiple imputation, the serial measurements were analysed using linear quantile mixed models.

Results: Median fatigue severity at baseline was 45 mm and remained, despite treatment, rather stable thereafter. Female gender (effect size=4.4 mm), younger age (0.2 mm less fatigue/year), higher swollen and tender joint counts (0.3 mm and 1.0 mm more fatigue/swollen or tender joint) and C reactive protein-levels (0.1 mm more fatigue per mg/L) were independently and significantly (p<0.05) associated with fatigue severity over 8 years. Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96).

Conclusions: This largest longitudinal study on fatigue so far demonstrated that the association between inflammation and fatigue is statistically significant but effect sizes are small, suggesting that non-inflammatory pathways mediate fatigue as well. Improved treatment strategies did not result in less severe fatigue. Therefore, fatigue in RA remains an 'unmet need'.

Keywords: Inflammation; Outcomes research; Patient perspective; Rheumatoid Arthritis.

Figure 1

Fatigue severity across early patients with arthritis with different diagnoses at disease onset (A) and over 3 years of disease (B). (A) Presented are medians and IQRs of fatigue severity at disease onset. The data of rheumatoid arthritis (RA) are presented in bold. An asterisk indicates a significant different fatigue level compared to RA when adjusted for age and gender. The numbers of patients at baseline are 902 for RA, 73 for SCTD, 48 for RS3PE, 96 for reactive arthritis, 19 for paramalignant arthritis, 65 for sarcoidosis, 25 for others, 126 for inflammatory OA, 13 for lyme arthritis, 706 for UA, 271 for PsA/SpA, 90 for (pseudo)gout, four for septic arthritis and four for post-traumatic joint swelling. (B) Presented are medians of fatigue severity over 3 years of disease. Available, unmodelled data without imputation of missing data is depicted. The numbers of available fatigue data per diagnosis at baseline, one, 2 and 3 years follow-up were respectively: 73, 32, 25 and 21 for SCTD; 902, 537, 411 and 432 for RA; 706, 270, 155 and 139 for UA; 271, 151, 110, 101 for PsA/SpA; 90, 13, 4 and 2 for (pseudo)gout. SCTD, systemic connective tissue disease; RS3PE, remitting seronegative symmetrical synovitis with pitting edema; RA, rheumatoid arthritis; OA, osteoarthritis; UA, undifferentiated arthritis; PsA, psoriatic arthritis; SpA, spondylarthropathy with peripheral arthritis.

Figure 2

The severity of fatigue over 8 years of disease in early rheumatoid arthritis patients. Presented are the median values with IQR of fatigue severity in 626 early patients with RA with missing data imputed. The numbers of patients with available data per year were: 510 for baseline, 350 for year 1, 298 for year 2, 280 for year 3, 266 for year 4, 251 for year 5, 208 for year 6, 192 for year 7 and 166 for year 8.

Figure 3

Different treatment strategies in rheumatoid arthritis in relation to radiographic progression (A) number of swollen joints (B) and fatigue severity over time (C). Presented are three long-term outcomes in relation to treatment strategies. Treatment strategies are reflected by different inclusion periods as the initial treatment strategy differed for different inclusion periods. The inclusion period 1993–1995 comprised 100 patients, 1996–1998 166 patients and 1999–2007 360 patients. Radiographic progression: 1993–1995=reference, 1996–1998 β=0.97 p=0.026; 1999–2007 β=0.92 p<0.001. The β indicates the fold rate of joint destruction per year compared to the reference. Swollen joint count: 1993–1995=reference, 1996–1998 effect size=−1.4 p=0.005; 1999–2007 effect size=−3.6 p<0.001, omnibus test for overall significance of model p<0.001. The effect size indicates the difference in number of swollen joints compared to the reference. Fatigue severity: 1993–1995=reference, 1996–1998 p=0.80; 1999–2007 p=0.79; omnibus test for overall significance of model p=0.96. SHS, Sharp-van der Heijde score; SJC, swollen joint count; DMARD, disease-modifying antirheumatic drugs.