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

van Steenbergen HW, Tsonaka R, Huizinga TW, Boonen A, van der Helm-van Mil AH - RMD Open (2015)

Bottom Line: After multiple imputation, the serial measurements were analysed using linear quantile mixed models.Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96).Improved treatment strategies did not result in less severe fatigue.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.

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'.

No MeSH data available.


Related in: MedlinePlus

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.
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RMDOPEN2014000041F3: 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.

Mentions: In general, improved treatment strategies in RA have resulted in improved disease outcomes. To validate this notion in present data set, we explored the association of the described treatment strategies with the severity of radiographic progression. A significant difference in radiographic progression was observed between the three groups: with delayed DMARD-treatment as reference (inclusion 1993–1995), patients early treated with mild DMARDs (inclusion 1996–1998) had 0.97-fold less severe radiographic progression per year (p=0.026) and patients early treated with methotrexate followed by DAS-steered treatment (inclusion 1999–2007) had 0.92-fold less severe radiographic progression per year (p<0.001, figure 3A). We also evaluated whether the median number of swollen joints over time was different for the patients with RA treated with different treatment strategies. Indeed, improved treatment strategies associated with a reduction in SJC during disease course: with the delayed treatment group (1993–1995) as reference, patients early treated with mild DMARDs (1996–1998) had 1.4 less swollen joints (p=0.005) over 8 years and patients early treated with methotrexate (1999–2007) had 3.6 less swollen joints over 8 years (p<0.001) (figure 3B). In line with these observations, we hypothesised that improved treatment strategies also associated with a less severe fatigue course. However, no univariable association was observed. Patients with RA early treated with mild DMARDs or methotrexate did not experience less severe fatigue over time compared to patients treated with initial treatment with NSAIDs and delayed DMARD-therapy (p=0.80 and p=0.79, respectively, figure 3C). This indicates that despite improved treatment strategies and subsequent decreased inflammation-levels during the disease course, the fatigue severity in RA remained unchanged.


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

van Steenbergen HW, Tsonaka R, Huizinga TW, Boonen A, van der Helm-van Mil AH - RMD Open (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612698&req=5

RMDOPEN2014000041F3: 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.
Mentions: In general, improved treatment strategies in RA have resulted in improved disease outcomes. To validate this notion in present data set, we explored the association of the described treatment strategies with the severity of radiographic progression. A significant difference in radiographic progression was observed between the three groups: with delayed DMARD-treatment as reference (inclusion 1993–1995), patients early treated with mild DMARDs (inclusion 1996–1998) had 0.97-fold less severe radiographic progression per year (p=0.026) and patients early treated with methotrexate followed by DAS-steered treatment (inclusion 1999–2007) had 0.92-fold less severe radiographic progression per year (p<0.001, figure 3A). We also evaluated whether the median number of swollen joints over time was different for the patients with RA treated with different treatment strategies. Indeed, improved treatment strategies associated with a reduction in SJC during disease course: with the delayed treatment group (1993–1995) as reference, patients early treated with mild DMARDs (1996–1998) had 1.4 less swollen joints (p=0.005) over 8 years and patients early treated with methotrexate (1999–2007) had 3.6 less swollen joints over 8 years (p<0.001) (figure 3B). In line with these observations, we hypothesised that improved treatment strategies also associated with a less severe fatigue course. However, no univariable association was observed. Patients with RA early treated with mild DMARDs or methotrexate did not experience less severe fatigue over time compared to patients treated with initial treatment with NSAIDs and delayed DMARD-therapy (p=0.80 and p=0.79, respectively, figure 3C). This indicates that despite improved treatment strategies and subsequent decreased inflammation-levels during the disease course, the fatigue severity in RA remained unchanged.

Bottom Line: After multiple imputation, the serial measurements were analysed using linear quantile mixed models.Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96).Improved treatment strategies did not result in less severe fatigue.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.

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'.

No MeSH data available.


Related in: MedlinePlus