| Outcomes | No of Participants (studies*) Follow up | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects | |
|---|---|---|---|---|---|
| Risk with Control | Risk difference with Immunomodulatory drugs (rituximab, rintatolimod, IV immunoglobulin G) versus placebo (95% CI) | ||||
|
Quality of Life: SF36 physical composite (max % change from baseline) Scale from: 0 to 100. |
28 (1 study) 10 months |
⊕⊕⊝⊝ due to indirectness, imprecision |
The mean quality of life: sf36 physical composite (max % change from baseline) at 10 months in the control groups was 26 |
The mean quality of life: sf36 physical composite (max % change from baseline) at 10 months in the intervention group (rituximab) was 28 higher (1.56 to 54.44 higher) | |
|
Quality of Life: SF36 mental composite (max % change from baseline) Scale from: 0 to 100. |
28 (1 study) 10 months |
⊕⊝⊝⊝ due to indirectness, imprecision |
The mean quality of life: sf36 mental composite (max % change from baseline) at 10 months in the control groups was 5 |
The mean quality of life: sf36 mental composite (max % change from baseline) at 10 months in the intervention group (rituximab) was 4 higher (29.52 lower to 37.52 higher) | |
|
Fatigue/fatigability: Fatigue severity scale Scale from: 9 to 63. |
151 (1 study) 18 months |
⊕⊕⊕⊕ HIGH |
The mean fatigue/fatigability: fatigue severity scale in the control groups was 56.05 |
The mean fatigue/fatigability: fatigue severity scale in the intervention group (rituximab) was 0.07 lower (3.21 lower to 3.07 higher) | |
|
Fatigue/fatigability: numeric rating scale Scale from: 0 to 10. |
151 (1 study) 16-20 months |
⊕⊕⊕⊕ HIGH |
The mean fatigue/fatigability: numeric rating scale in the control groups was 3.18 |
The mean fatigue/fatigability: numeric rating scale in the intervention group (rituximab) was 0.06 lower (0.5 lower to 0.39 higher) | |
|
Psychological status: Hamilton Depression Scale Scale from: 0 to 52. |
49 (1 study) 6 months |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean psychological status: hamilton depression scale at 6 months in the control groups was 10 |
The mean psychological status: hamilton depression scale at 6 months in the intervention groups (IV immunoglobulin G) was 1 lower (3.35 lower to 1.35 higher) | |
|
Psychological status: Zung Self-Rating Depression Scale Scale from: 0 to 80. |
49 (1 study) 6 months |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean psychological status: zung self-rating depression scale at 6 months in the control groups was 40 |
The mean psychological status: zung self-rating depression scale at 6 months in the intervention group (IV immunoglobulin G) was 1 higher (5.44 lower to 7.44 higher) | |
|
Psychological status: mental health on the Medical Outcome Study Short Form Scale from: 0 to 100. |
28 (1 study) 150 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean psychological status: mental health on the medical outcome study short form at 150 days in the control groups was 62.9 |
The mean psychological status: mental health on the medical outcome study short form at 150 days in the intervention group (IV immunoglobulin G) was 4.6 lower (16.07 lower to 6.87 higher) | |
|
Physical functioning: physical functioning on the Medical Outcome Study Short Form/SF36 Scale from: 0 to 100. |
28 (1 study) 150 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean physical functioning: physical functioning on the medical outcome study short form/sf36 in the control groups was 51.8 |
The mean physical functioning: physical functioning on the medical outcome study short form/sf36 in the intervention groups (IV immunoglobulin G) was 4.2 higher (12.62 lower to 21.02 higher) | |
|
Physical functioning: physical functioning on the Medical Outcome Study Short Form/SF36 Scale from: 0 to 100. |
151 (1 study) 24 months |
⊕⊕⊕⊕ HIGH |
The mean physical functioning: physical functioning on the medical outcome study short form/sf36 in the intervention groups (rituximab) was 1.24 higher (7.38 lower to 9.86 higher) | ||
| Physical functioning: functional level percentage |
151 (1 study) 16-20 months |
⊕⊕⊕⊝ MODERATE2 due to imprecision |
The mean physical functioning: functional level percentage in the control groups was 25.93 |
The mean physical functioning: functional level percentage in the intervention group (rituximab) was 0.68 lower (5.9 lower to 4.54 higher) | |
| Adverse events: Serious Adverse Events with possible/probable relation to intervention |
234 (1 study) 42 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 0.5 (0.05 to 5.44) | 17 per 1000 |
9 fewer per 1000 (from 16 fewer to 76 more) (with rintatolimod) |
| Adverse events: major adverse events |
30 (1 study) 21 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 1 (0.24 to 4.18) | 200 per 1000 |
0 fewer per 1000 (from 152 fewer to 636 more) (with IV immunoglobulin G) |
| Adverse events: constitutional symptoms |
99 (1 study) 3 months |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 0.87 (0.72 to 1.05) | 885 per 1000 |
115 fewer per 1000 (from 248 fewer to 44 more) (with IV immunoglobulin G) |
| Adverse events: any serious adverse events (hospitalisations) with possible/probable relation to intervention |
151 (1 study) 24 months |
⊕⊕⊕⊕ HIGH | Peto OR 7.82 (1.89 to 32.35) | 0 per 1000 |
100 more per 1000 (from 30 more to 180 more) (with rituximab) |
| Adverse events: any adverse events of at least moderate severity (CTCAE grade ≥2) with possible/probable relation to intervention |
151 (1 study) 24 months | ⊕⊕⊕⊝ MODERATE2 due to imprecision | RR 2.08 (1.14 to 3.81) | 162 per 1000 |
175 more per 1000 (from 23 more to 456 more) (with rituximab) |
| Adverse events: suspected unexpected adverse reactions |
151 (1 study) 24 months |
⊕⊕⊝⊝ LOW2 due to imprecision | RR 1.92 (0.18 to 20.75) | 14 per 1000 |
12 more per 1000 (from 11 fewer to 267 more) (with rituximab) |
| Activity levels: mean number of steps per 24 hours |
151 (1 study) 17-21 months |
⊕⊕⊕⊕ HIGH |
The mean activity levels: mean number of steps per 24 hours in the control groups was 3904 |
The mean activity levels: mean number of steps per 24 hours in the intervention group (rituximab) was 127 lower (1004 lower to 750 higher) | |
| Exercise performance measure: Treadmill exercise duration in seconds |
208 (1 study) 42 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean exercise performance measure: treadmill exercise duration in seconds at 42 weeks in the control groups was 616 |
The mean exercise performance measure: treadmill exercise duration in seconds at 42 weeks in the intervention group (rintatolimod) was 56 higher (25.94 lower to 137.94 higher) | |
| Return to school or work: Resumption of pre-morbid employment status (full-time) |
49 (1 study) 6 months |
⊕⊝⊝⊝ due to risk of bias, indirectness | Peto OR 10.79 (1.98 to 58.68) | 0 per 1000 |
260 more per 1000 (from 80 more to 450 more) (with IV immunoglobulin G) |
| Symptom scales: Marked reduction in symptoms and improvement in functional capacity |
49 (1 study) 6 months |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 3.77 (1.18 to 12.04) | 115 per 1000 |
320 more per 1000 (from 21 more to 1000 more) (with IV immunoglobulin G) |
The majority of the evidence included an indirect population (downgraded by one increment): downgraded if the ME/CFS diagnostic criteria used did not include PEM as a compulsory feature [original analysis]; no clear definition of “post-exertional fatigue (prolonged) to confirm this is PEM, so unclear how many participants had PEM [PEM reanalysis – see Appendix G for additional details]
Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs
Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
The majority of the evidence included an indirect population (downgraded by one increment): downgraded if the ME/CFS diagnostic criteria used did not include PEM as a compulsory feature [original analysis]; percentage of participants with PEM unclear [PEM reanalysis – see Appendix G for additional details]. Further downgraded for outcome indirectness (unclear if major adverse events were treatment-related) (Peterson 1990)
Studies included for immunomodulatory drugs: Rituximab – Fluge 2011, Fluge 2019; IVIG – Lloyd 1990, Peterson 1990, Vollmer-Conna 1997; Rintatolimod – Strayer 2012
From: Pharmacological interventions
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