Biologics Don’t Always Work for Fatigue


Biologics only slightly reduce fatigue in rheumatoid arthritis (RA) patients, a systematic review suggests.

Biologics only slightly reduce fatigue in rheumatoid arthritis (RA) patients, a systematic review suggests.

“Both anti-TNF [tumor necrosis factor] and non-anti TNF biologic treatments led to small to moderate reduction in fatigue in participants with RA,” write Celia Almeida of the University of the West of England, Bristol, United Kingdom, and colleagues. They published the finding June 6 in the Cochrane Database of Systematic Reviews.

The report along with other recently published studies suggests that treatments used for rheumatoid arthritis in general may not be effective against one of its most important symptoms.

Fatigue afflicts as many as 70% of the people with rheumatoid arthritis in the United Kingdom, the Bristol researchers report. Yet they could not find any guidelines for managing this symptom.

Inflammation might cause fatigue, either directly or through pain and impairment, so the researchers wanted to know if biologics could help. They looked for randomized controlled trials of biologics in adults with rheumatoid arthritis that reported fatigue separately as one of the main outcomes measured.

They included both the anti-TNF (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) and non-TNF (rituximab, abatacept, tocilizumab, anakinra, canakinumab and anti-interferon gamma monoclonal antibody) therapies.

They found 32 studies that met their inclusion criteria. These included a total of 9946 participants in intervention groups and 4682 in control groups. Since the studies varied in the range of fatigue outcome measures, the researchers calculated standardized mean differences.

All these studies showed statistically significant improvement in disease activity and pain in the active treatment groups compared with controls. (Two of the studies compared the biologics to other treatments rather than to placebos.)

Overall, the biologics reduced fatigue by a standardized mean difference of -0.43, a statistically significant reduction (P < 0.0001). Anti-TNF agents reduced SMD by 0.42 while non-anti-TNF agents reduced the SMD by 0.46. They translated this to “9 units reduction on a 0-52 scale… compared to 3 united in participants treated by placebo.”

The authors found significant heterogeneity in the anti-TNF results, and used sensitivity analyses to determine the cause. Excluding dose-ranging studies on trials in participants who had failed previous biologic therapy did not affect heterogeneity, but disease duration emerged as a significant factor. Excluding 5 studies that assessed the anti-TNF agents in early rheumatoid arthritis reduced the heterogeneity to statistical insignificance.

Most of the studies lasted 24 weeks or less, so the researchers couldn’t tell whether the improvements in fatigue lasted any longer than that. Also most of the participants had moderate to high levels of fatigue at baseline, so it’s not clear whether people with lower levels of fatigue would benefit in the same way.

Most of the studies did not provide data on anxiety or depression, and the studies used so many different instruments to measure pain that the researchers could not determine whether these symptoms were related to fatigue.

But researchers elsewhere have explored this very question. At Diakonhjemmet Hospital in Oslo, Norway, Cathrine Austad and colleagues examined factors related to sleep disturbance in patients with rheumatoid arthritis. [[{"type":"media","view_mode":"media_crop","fid":"50477","attributes":{"alt":"©Kamira/","class":"media-image media-image-right","id":"media_crop_617706728115","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"6165","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©Kamira/","typeof":"foaf:Image"}}]]

Analyzing cross-sectional data from 986 patients in the Oslo RA Register, they found a modest correlation between sleep disturbance on one hand and pain, fatigue, physical function and utility on the other.

“Our findings further support the association between fatigue and mental components in models for all four measures of sleep disturbance in RA,” they wrote in Scandinavian Journal of Rheumatology.

Fatigue Correlated with Other Symptoms (continued on next page)

Fatigue appears to correlate with a variety of other symptoms, according to researchers from the Mayo Clinic College of Medicine in Rochester, Minnesota.

In an analysis of records on 190 people with RA, they found an association between scores on the Bristol Rheumatoid Arthritis Fatigue (BRAF) questionnaire and the flare-assessment in RA (FLARE) questionnaire, as well as the Health Assessment Questionnaire, the visual analogue scale for pain (VAS), physician clinical assessment (PCA) and patient global assessment (PGA.) Fatigue was also associated with younger age.

But the Mayo Clinic researchers did not find an association between BRAF and C-reactive protein, interleukin-6 or gender.

They concluded that further studies should examine the relationship of flare to fatigue in RA patients.

Meanwhile, for a study published in Rheumatology, researchers at the University of Aberdeen in the United Kingdom, analyzed data on 2652 participants from the British Society for Rheumatology Biologics Register for RA who reported severe fatigue at baseline and then disease remission 6 months later.

Out of 271 who achieved disease remission (defined as a 28-joint DAS < 2.6), 225 (83%) reported at least partial remission of fatigue. And of those who reported at least partial remission, 101 reported complete remission of fatigue.

Those who did not report complete fatigue remission were more likely to have had hypertension, stroke and depression and reported a greater baseline use of antidepressants and steroids.

The authors concluded that patients might benefit from treatments for pain, disability and “broader perceptions of health status” as well as treatments specifically for rheumatoid arthritis.

Though none of the researchers ventured to suggest specific approaches to treating fatigue in RA patients, their findings together suggest that biologics alone will not provide the answer.



Almeida C, Choy EHS, Hewlett S, Kirwan JR, Cramp F, Chalder T, Pollock J, Christensen R. "Biologic interventions for fatigue in rheumatoid arthritis." Cochrane Database of Systematic Reviews 2016, Issue 6.

C Austad, TK Kvien, IC Olsen & T Uhlig (2016): "Sleep disturbance in patients with rheumatoid arthritis is related to fatigue, disease activity, and other patient-reported outcomes." Scandinavian Journal of Rheumatology

E. Myasoedova, C.S. Crowson, J.M. Davis, et al. "Understanding fatigue in patients with rheumatoid arthritis (RA): the role of RA disease activity in flares." Ann Rheum Dis 2015;74:245-246 

Druce KL, Bhattacharya Y, Jones GT. "Most patients who reach disease remission following anti-TNF therapy continue to report fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis Rheumatology." Rheumatology. Published online: June 21, 2016


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