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Table 2 Overview of studies evaluating the effect of inhibiting IL-1 on fatigue severity

From: Interleukin-1 as a mediator of fatigue in disease: a narrative review

Reference Disease activity Design Number of patients Fatigue questionnaire IL-1 intervention Main outcome
Rheumatoid arthritis
 Alten et al., 2011 ≥6 of 28 tender and swollen joints, elevated hsCRP and/or ESR Randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial 274 FACIT-F at 12 weeks MTX combined with canakinumab: (1.) 150mg s.c. every 4 weeks (n = 69), (2.) 300 mg s.c. every 2 weeks (n = 64), (3.) 600 mg i.v. followed by 300 mg s.c. every 2 weeks (n = 71) or placebo s.c. every 2 weeks (n = 70) Decrease in fatigue canakinumab group 1 (p = 0.006) and 3 (p = 0.028) compared to placebo.
 Omdal et al., 2005 Mean DAS28 6.2 ± 1.1 Pilot, non-blinded, no control group 8 FSS and VAS-fatigue at baseline, week 4, and week 8 100 mg s.c. anakinra daily Decrease in FSS (p = 0.002) and VAS-fatigue (p = 0.0001) during the 8 weeks, accompanied by a decrease of the DAS28 score (p < 0.0001).
Sjögrens syndrome
 Norheim et al., 2012 No elevation CRP/ESR Randomized, double-blind, placebo-controlled, parallel-group trial 26, 1 not included in analysis FSS and VAS-fatigue at baseline, week 0, week 2, week 4, and week 5 100 mg s.c. anakinra (n = 12) or placebo (n = 13) daily during 4 weeks No difference FSS scores after 4 weeks, more frequent reduction of VAS-fatigue of >50% in anakinra group (50 vs 8%, p = 0.03).
 Kone-Paut et al., 2011 Moderate or severe disease activity Part 1. open-label, followed by part 2. which was a double-blind withdrawal phase in responders, ending with open-label part 3 35 5-point likert scale, daily first 15 days of part 1, weekly thereafter (physician and patient), FACIT-F Single canakinumab (150 mg) dose in part 1 (n = 35), followed by canakinumab (n = 15) or placebo (n = 16) every 8 weeks for 24 weeks in part 2. At relapse or at end of part 2, patients were treated with canakinumab for 16 more weeks (n = 31). Fatigue absent or minimal at the end of part 1 in >85% of patients paralleled by decreased disease activity. Increase FACIT-F at the end of part 1 (p < 0.05). Fatigue relapse in patients randomized to placebo in part 2.
 Huemmerle- Deschner, 2011 Disease activity requiring medical intervention Open label, phase II trial 7 (pediatric) 5-point likert scale at post-treatment days 1 and 2, and weeks 1 and 5 (physician) Canakinumab 150 mg or 2 mg/kg, repeated after 7 days in absence of complete response. Fatigue was absent or minimal 1 day after canakinumab in all patients. This was accompanied by a decrease in disease activity.
 Hoffman et al., 2008 NLPRP3 mutation combined with classic FCAS/MWS symptoms Part 1. 6-week randomized controlled trial, part 2A. open-label, 2B. randomized controlled trial 47 DHAF rating fatigue over previous 24 h Part 1 loading dose of 320 mg rilonacept/placebo s.c. (n = 47), followed by weekly s.c. injections of 160 mg rilonacept/placebo.
Part 2 (n = 46) weekly s.c. rilonacept 160 mg during 9 weeks followed by 9 weeks rilonacept/placebo.
Decrease in fatigue in part 1 (p < 0.001), relapse in those patients treated with placebo in part 2 (p < 0.001).
 Cavelti-Weder et al., 2011 Type 2 diabetes Randomized, double-blind, placebo-controlled trial 30 Fatigue scale for motor and cognitive functions XOMA052/placebo (0.01–1 mg/kg) At baseline, 53% of patients experienced mild-severe fatigue. One month after treatment, fatigue was increased in the placebo and lowest dosing group; in the two medium dosing groups, fatigue was slightly decreased; and in the two highest dosing groups, fatigue was remarkably decreased.
Effect size dose-dependent effect d = 0.3. The highest dose of 1.0 mg/kg had a favorable effect on motor fatigue (d = 1.05).
 Hong et al., 2015 [108] Advanced non-small cell lung cancer Open label dose escalation trial 16 EORTC-QLQ, at baseline and after 8 weeks Intravenous MABp1 every 3 weeks trough 4 dosing levels (0.25/0.75/1.25/3.75 mg/kg, and 3.75 mg/kg every 2 weeks (until disease progression)) Non significant improvement in fatigue severity. Median disease free progression was 57 days.
 Hickish et al., 2016 Metastatic colorectal cancer refractory to standard chemotherapy Randomized controlled trial 309 EORTC-QLQ MABp1 plus best supportive care or placebo (2:1) Significant improvement of fatigue, increase in appetite, and decrease in pain severity
  1. An overview of all studies that investigated the relationship between IL-1 and fatigue severity
  2. Abbreviations: CAPS cryopyrin-associated periodic syndrome, CRP C-reactive protein, DAS disease activity score, DHAF daily health assessment form, EORTC-QLQ European organization for research and treatment of cancer quality of life questionnaire, ESR erythrocyte sedimentation rate, FACIT-F functional assessment of chronic illness therapy subscale fatigue, FCAS familial cold autoinflammatory syndrome, FSS fatigue severity scale, hsCRP high-sensitive C-reactive protein, MTX methotrexate, MWS Muckle-Wells syndrome, s.c. subcutaneous, VAS visual analog scale