Immunosuppression and immunomodulation in IBM
Uitgangsvraag
What does the drug treatment of patients with inclusion body myositis look like?
Hoe ziet de medicamenteuze behandeling van patiënten met inclusion body Myositis eruit?
Aanbeveling
Behandel IBM niet medicamenteus. Bij een atypisch snelle progressie kan dit alsnog overwogen worden in een tertiair centrum.
Overwegingen
Considerations – from evidence to recommendation.
Pros and cons of the intervention and the quality of the evidence
A literature review has been performed on the effect of drug treatment of patients with inclusion body myositis compared to placebo treatment, no treatment or standard care. Six-minute walking distance and muscle strength were defined as crucial outcomes. Adverse events, (self-reported) physical function, number of falls, physical performance and quality of life were considered important outcome measures.
Nine studies were included in the literature analysis for this guideline module. Seven studies were described in the Cochrane review by Rose (2015) and met the inclusion criteria of this guideline module. In addition, two RCTs were included that were published after the last search date of Rose (2015). The only (statistically assessable) outcomes reported in the included studies were MRC scores for measuring muscle strength for the comparison of intravenous immunoglobulin versus placebo and (serious) adverse events for the comparison of methotrexate versus placebo, bimagrumab versus placebo, and sirolimus versus placebo.
Based on the literature, drug treatment with methotrexate does not seem to result in fewer (serious) adverse events compared to placebo treatment. The evidence for this is low. The literature is also very uncertain about the effect of treatment with bimagrumab on adverse events compared to placebo treatment, but also about the effect of intravenous immunoglobulin on muscle strength compared to placebo treatment. The strength of evidence for both comparisons is very low. This is partly due to the small number of events and possible risk of bias due to a large dropout of patients during the study. Treatment with sirolimus does not seem to result in fewer (serious) adverse events compared with placebo.
In addition to the outcome measures from the Cochrane review by Rose (2019), which have been elaborated in the literature analysis using the GRADE, Rose (2019) reported information on various other outcome measures that are important in the treatment of patients with IBM. Rose (2019) reported results on the six-minute walk test, change in muscle strength, hand grip strength, change in muscle mass and the number of times a patient falls per year.
However, due to the lack of raw data per intervention group, it was not possible to incorporate these outcome measures in the literature analysis and to grade the level of evidence. However, the results in the study by Dalakas (1997) showed that treatment with intravenous immunoglobulin after six months of follow-up resulted in a mean increase of 4.2 points on the MRC scale (range -16 to 39.8), while the placebo group showed a decrease of 2.7 points on the MRC scale (range -10 to 8). However, this difference was not statistically significant.
Amato (2021) reported the mean change in six-minute walk test and showed that from baseline, the mean difference in six-minute walk test varied widely between treatment groups and showed a progressive decrease from week 24 to week 104 in both the group receiving was treated with bimagrumab as the placebo group. In the same study, the number of patients experiencing a fall per year was slightly higher in the group of patients treated with bimagrumab.
Trials at IBM are complicated because an optimal outcome measure has not yet been established. Few studies use swallowing function as an outcome measure. The interpretation of muscle strength measurements is complicated because the distribution of weakness differs between patients. The interpretation of changes in muscle strength is further complicated by the fact that the rate of progression varies markedly between patients. The 6 MWD, advocated by the FDA, measures endurance rather than muscle strength. Furthermore, IBM is a relatively rare disease and in particular the earlier studies are small. Nevertheless, based on the available evidence, a number of agents can be assumed to have no effect: interferon beta-1a, MTX, bimagrumab.
For intravenous immune globulins, three small studies gave different results, so there is still doubt about the efficacy. A problem with treatment with IVIg “on trial” is that it is difficult to determine whether the treatment is effective: in some patients a stabilization after, for example, six months will mean a clinically relevant gain, while in others this will reflect the natural course. IVIg is a relatively safe treatment, but the small risk of thromboembolic complications should play a role in the consideration. It should be noted that no studies have been done comparing corticosteroids to placebo. Corticosteroids are not an attractive option, given the often serious side effects associated with lifelong use. A recent controlled double-blind pilot with sirolimus showed no effect on muscle strength but did show a number of secondary outcome measures.
Patient values and preferences
Inclusion body myositis presents itself by muscle wasting and weakness. Therefore, for patients, the aim of treatment is an increase in muscle strength and/or preserving and preventing deterioration of muscle strength. The most frequently affected muscles are pharyngeal muscles, deep finger flexors and quadriceps muscles. This leads to specific functional impairments, such as difficulties in swallowing, weight loss, impaired hand grip, and difficulties rising from chairs, managing stairs, and walking. For patients, self-efficacy is one of the most important values, and therefore is improvement of these functional abilities an important aim of treatment. Since no cure exists, the treating physician and the patient should discuss together which symptoms are most burdensome and decide together which treatment options can be used to target these symptoms. In this process of shared decision making, both the patient’s values and preferences as well as the seriousness and risks of the existing symptoms should be taken into consideration.
Costs
Drug treatment with IVIg is quite expensive especially when the drugs are taken over a prolonged period of time. A less expensive drug treatment is prednisone. Nonetheless there is little to no evicende in favor for both drugs.
Applicability, feasibility and implementation
There are no relevant remarks to be made about this topic.
Recommendations
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Based on the available evidence, a number of agents can be assumed to have no effect: interferon beta-1a, MTX, bimagrumab. For intravenous immune globulins there is doubt about the efficacy. A problem with treatment with IVIg “on trial” is that it is difficult to determine whether the treatment is effective: in some patients a stabilization after, for example, six months will mean a clinically relevant gain, while in others this will reflect the natural course. IVIg is a relatively safe treatment, but the small risk of thromboembolic complications should play a role in the consideration as should the high costs of lifelong monthly treatment. Therefore, the working groups believes that treatment with IVIg should not be advised as standard treatment.
Onderbouwing
Achtergrond
Inclusion body myositis (IBM) is a disease of striated muscle fibers. There is no involvement of cardiac muscle or smooth muscle fibers. Weakness is progressive over years, and results in difficulties with ambulation due to weakness of the quadriceps muscles and foot drop, difficulties using the hands in daily activities due to weakness of finger flexors, and difficulties swallowing. Treatment should be aimed at these disabilities. The pathogenesis of IBM is largely unknown. Auto immune as well as degenerative processes are involved. Novel treatment may be directed at either of these pathways.
Conclusies
Methotrexate treatment versus placebo treatment
5.(Serious) adverse events
|
Low GRADE |
Drug treatment with methotrexate may not reduce (serious) adverse events when compared with placebo treatment in patients with inclusion body myositis.
Sources: Rose (2015), Badrising (2002). |
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of methotrexate treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Bimagrumab treatment versus placebo treatment
5. (Serious) adverse events
|
Very low GRADE |
The evidence is very uncertain about the effect of treatment with bimagrumab regarding (serious) adverse events when compared with placebo treatment in patients with inclusion body myositis.
Sources: Amato (2021). |
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of bimagrumab treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Intravenous immunoglobulin treatment versus placebo treatment
3. Manual muscle testing (MRC-score)
|
Very low GRADE |
The evidence is very uncertain about the effect of treatment with intravenous immunoglobulin regarding muscle strength when compared with placebo treatment in patients with inclusion body myositis.
Sources: Walter (2000). |
1. six-minute walking distance; 2. quantitative muscle testing; 4. maximum voluntary isometric contraction; 5. (serious) adverse events; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of intravenous immunoglobulin treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Intravenous immunoglobulin plus prednisone treatment versus placebo plus prednisone treatment
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 5. (serious) adverse events; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of intravenous immunoglobulin plus prednisone treatment with placebo plus prednisone treatment in patients with inclusion body myositis.
Sources: - |
Anabolic steroid (oxandrolone) treatment versus placebo treatment
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 5. (serious) adverse events; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of anabolic steroid (oxandrolone) treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Beta-interferon 1a treatment versus placebo treatment
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 5. (serious) adverse events; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of beta-interferon 1a treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Sirolimus treatment versus placebo treatment
5. (Serious) adverse events
|
Low GRADE |
Drug treatment with sirolimus may not reduce (serious) adverse events when compared with placebo treatment in patients with inclusion body myositis.
Sources: Benoviste (2021). |
1. six-minute walking distance; 2. quantitative muscle testing; 3. manual muscle testing (MRC-score); 4. maximum voluntary isometric contraction; 6. sIFA; 7. number of falls; 8. quality of life
|
No GRADE |
Due to a lack of useful statistical information in the included literature, no GRADE conclusions could be made for the comparison of sirolimus treatment with placebo treatment in patients with inclusion body myositis.
Sources: - |
Samenvatting literatuur
Description of studies from Rose (2015)
The randomized controlled trial of Dalakas (1997) compared IVIg with placebo treatment in patients with IBM. In total, nineteen patients were randomized into two treatment groups. Patients in the intervention group (n=9) received two milligrams per kilogram of bodyweight IVIg divided into two daily doses of one gram per kilogram each, given slowly less than 200 milliliter per hour. Patients in the control group received the same treatment regime with a placebo. The maximum length of follow-up was three months. The reported outcome was the MRC score.
The randomized controlled trial of Walter (2000) compared IVIg with placebo treatment in patients with IBM. In total, 22 patients were randomized into two treatment groups. Patients in the intervention group received monthly intravenous infusions of two gram per kilogram of bodyweight IVIg given two to five days per month for six months each. Patients in the control group followed the same treatment regime but received a placebo treatment. The maximum length of follow-up was twelve months. The reported outcome was the MRC score.
The randomized controlled trial of Dalakas (2001) compared intravenous immunoglobulin (IVIg) in combination with prednisone with placebo plus prednisone in patients with IBM. In total, 37 patients were randomized into two treatment groups. The intervention group (n=19) received two gram per kilogram of body weight of IVIg divided into two daily doses of one gram per kilogram of bodyweight each, given slowly less than 200 milliliter per hour. The control group followed the same treatment regime but received placebo instead of IVIg. The maximum length of follow-up was three months. The reported outcomes were MRC scores and QMT scores.
The Muscle Study Group (2001) investigated the efficacy and safety of beta-interferon 1a ( INF1a) in relatively young patients with IBM. In total, 30 patients were randomized into two treatment groups. The intervention group (n=14) received a target dose of 30 g per week of INF1a. Treatment was initiated at a dose of 15 g per week and increased to 30 g per week at four weeks. INF1a was given as a single weekly intramuscular injection. The control group followed the same treatment regime but received a placebo treatment. The maximum length of follow-up was 24 weeks. The reported outcomes were MMT, MVIC and SF-36 scores.
The randomized controlled trial of Badrising (2002) aimed to compare the efficacy and tolerability of methotrexate and placebo in slowing down disease progression in IBM. In total, 44 patients were randomized into two treatment groups. Patients in the intervention group (n=21) received methotrexate in a dosage of five milligram per week, each six weeks increased by five milligram up to twenty milligrams. Patients in the control group (n=23) followed the same treatment regime as the intervention group but received a placebo. The maximum length of follow-up was 48 weeks. The reported outcomes in the study were QMT sum scores, MMT sum scores, and adverse events.
The randomized controlled crossover study of Rutkove (2002) compared the effect of oxandrolone with placebo in patients with IBM. In total, 19 patients were randomized into two treatment groups. Patients in the intervention group (n=9) received oxandrolone in a dose of twenty milligram per day orally (ten milligram twice per day). Patients in the control group (n=10) followed the same treatment regime with a placebo treatment. The maximum length of follow-up was three months. The reported outcomes were MVICT scores and MMT scores.
The Muscle Study Group (2004) also investigated the efficacy and safety of INF1a in relatively young patients with IBM. In contrast to the Muscle Study Group (2001) in which low dose of INF1a was investigated, the Muscle Study Group (2004) study investigated high dose of INF1a. In total, 30 patients were randomized into two treatment groups. The intervention group (n=16) received a target dose of 60 g per week of INF1a for four weeks. INF1a was given as a single weekly intramuscular injection. The control group followed the same treatment regime but received a placebo treatment. The maximum length of follow-up was 24 weeks. The reported outcomes were MMT, MVIC and SF-36 scores.
Randomized controlled trials published after the search date of the Cochrane review of Rose (2015)
The randomized controlled trial of Amato (2021) aimed to assess long-term (two years) effects of bimagrumab in patients with IBM. In total, 211 patients were randomized in one of the four treatment groups. Since this review investigates the effect of drug treatment compared with placebo, no treatment, or standard of care, we combined the three intervention groups with patients who received different dosages of bimagrumab in one intervention group. Patients in the intervention group (n=156) received bimagrumab in a dosage of one milligram per kilogram bodyweight, three milligram per kilogram bodyweight, or ten milligram per kilogram bodyweight. Patients in the control group (n=55) received a matching placebo treatment. The maximum length of follow-up was two years. The reported outcome in the study was the number of adverse events.
The randomized controlled phase 2b trial of Benveniste (2021) compared treatment with sirolimus with placebo treatment in patients with IBM. In total, 44 patients were randomized into two treatment groups. The intervention group (n=22) received oral sirolimus at a dose of two milligram per day. The control group (n=22) followed the same treatment regime with a placebo. The maximum length of follow-up was twelve months. The reported outcomes relevant for the literature analyses were six-minute walking distance and the MVIC.
Results
For the following comparisons, no information was found for any of the outcomes from the included studies:
- Intravenous immunoglobulin plus prednisone treatment versus placebo plus prednisone treatment
- Anabolic steroid (oxandrolone) treatment versus placebo treatment
- Interferon beta-1a treatment versus placebo treatment
The following outcomes were assessed:
1. Six-minute walking distance
Although Amato (2021) reported a progressive decline in mean change in 6MWD in both the intervention group (bimagrumab) and the control group (placebo), no numbers were provided, nor were statistical tests performed. Information on results of the 6MWD were insufficient to assess the level of evidence.
2. Quantitative muscle testing (QMT)
None of the included studies reported useful information regarding quantitative muscle testing in patients with inclusion body myositis. The level of evidence could not be graded.
3. Manual muscle testing (MRC-score)
Intravenous immunoglobulin treatment versus placebo treatment
The change of muscle strength measured with the MRC-score was reported in one study (Walter, 2000), at six months follow-up. The mean (SD) MRC-score in the intravenous immunoglobulin treatment group (n=10) was 145.0 (18.1), compared to 137.3 (34.7) in the placebo treatment group (n=3). This resulted in a mean difference (MD) of 7.70 (95% CI -48.54 to 33.14), in favor of the intravenous immunoglobulin treatment group. This was not considered as a clinically relevant difference.
Level of evidence of the literature
The level of evidence regarding the outcome manual muscle testing (MRC-score) was derived from randomized controlled trials and therefore started high. The level of evidence was downgraded by three levels because of uncertainty regarding blinding of participants and personnel in the study (risk of bias, -1), the wide confidence interval crossing the borders of clinical relevance and the small number of patients (imprecision, -2). The level of evidence was very low.
4. Maximum voluntary isometric contraction (MVIC)
None of the included studies reported useful information regarding Maximum voluntary isometric contraction (MVIC) in patients with inclusion body myositis. The level of evidence could not be graded.
5. (Serious) adverse events
Methotrexate treatment versus placebo treatment
The outcome (serious) adverse events for methotrexate versus placebo was reported in one randomized controlled trial, retrieved from the systematic review of Rose (2015) (Badrising, 2002).
The number of patients with a (serious) adverse event in the study of Badrising (2002) in the methotrexate treatment group was 8/21 (38.1%), compared to 1/23 (4.3%) in the placebo treatment group. This resulted in a relative risk ratio (RR) of 8.76 (95% CI 1.19 to 64.28), in favor of the placebo treatment group. This was considered as a clinically relevant difference. The reported adverse events in the study of Badrising (2002) in the methotrexate group were nausea (n=3, hair loss (n=2), arthralgia (n=2), and progressive muscle weakness (n=1).
Level of evidence of the literature
The level of evidence regarding the outcome measure (serious) adverse events was derived from randomized controlled trials and therefore started high. The level of evidence was downgraded by two levels because of the wide confidence interval crossing the borders of clinical relevance and the small number of events (imprecision, -2). The level of evidence was low.
Bimagrumab treatment versus placebo treatment
The outcome (serious) adverse events for bimagrumab versus placebo was reported in one randomized controlled trial (Amato, 2021). The number of patients with a (serious) adverse event in the bimagrumab treatment group was 29/156 (18.6%), compared to 8/55 (14.5%) in the placebo treatment group. This resulted in a relative risk ratio (RR) of 1.28 (95% CI 0.62 to 2.63), in favor of the placebo treatment group. This was considered as a clinically relevant difference. Amato (2021) did not specify all serious adverse events.
Level of evidence of the literature
The level of evidence regarding the outcome measure (serious) adverse events was derived from randomized controlled trials and therefore started high. The level of evidence was downgraded by three levels because of the large number of patients who were lost to follow-up (risk of bias, -1), the wide confidence interval crossing the borders of clinical relevance, and the small number of events (imprecision, -2). The level of evidence was very low.
Sirolimus treatment versus placebo treatment
Both adverse events and serious adverse events were reported in one randomized controlled trial (Benveniste, 2021). The number of patients with any adverse event in the sirolimus treatment group was 22/22(100%), compared to 22/22 (100%) in the placebo treatment group. For serious adverse events, these numbers were 10/22 (45%) and 6/22 (27%), respectively. This resulted in a relative risk (RR) of 1.67 (95% CI 0.73 to 3.79), in favor of the placebo treatment group. For serious adverse events, this is considered a clinically relevant difference.
Level of evidence of the literature
The level of evidence regarding the outcome measure (serious) adverse events was derived from a randomized controlled trial and therefore started high. The level of evidence was downgraded by two levels because of the wide confidence interval crossing both borders of clinical relevance, and the small number of events (imprecision, -2). The level of evidence was low.
6. sIBM Physical Function Assessment (sIFA)
None of the included studies reported useful information regarding sIBM Physical Function Assessment (sIFA) in patients with inclusion body myositis. The level of evidence could not be graded.
7. Number of falls
None of the included studies reported useful information regarding number of falls in patients with inclusion body myositis. The level of evidence could not be graded.
8. Quality of life
None of the included studies reported useful information regarding quality of life in patients with inclusion body myositis. The level of evidence could not be graded.
Table 1: Summary of findings
|
|
Methotrexate vs. placebo |
Bimagrumab vs. placebo |
Intravenous immunoglobulin vs. placebo |
Intravenous immunoglobulin plus prednisone vs. placebo plus prednisone |
Anabolic steroid (oxandrolone) vs placebo |
Interferon beta-1a vs placebo |
Sirolimus vs placebo |
|
Six-minute walking distance |
- |
Progressive decline in both groups |
- |
- |
- |
- |
- |
|
Quantative muscle testing (QMT) |
- |
- |
- |
- |
- |
- |
- |
|
Manual muscle testing (MRC-score) |
- |
- |
MD 7.70 (95% CI -48.54 to 33.14)
Level of evidence: Very low |
- |
- |
- |
- |
|
Maximum voluntary isometric contraction (MVIC) |
- |
- |
- |
- |
- |
- |
- |
|
(Serious) adverse events |
RR 8.76 (95% CI 1.19 to 64.28)
Level of evidence: Low |
RR 1.28 (95% CI 0.62 to 2.63)
Level of evidence: Very low |
- |
- |
- |
- |
RR 1.67 (95% CI 0.73 to 3.79)
Level of evidence: Low |
|
sIBM physical function assessment (sIFA) |
- |
- |
- |
- |
- |
- |
- |
|
Number of falls |
- |
- |
- |
- |
- |
- |
- |
|
Quality of life
|
- |
- |
- |
- |
- |
- |
- |
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question: What are the (un)beneficial effects of immunosuppression and immunomodulation in patients with inclusion body myositis?
P: Patients with inclusion body myositis.
I: Drug treatment (immunosuppression; immunomodulation).
C: Standard of care, placebo, or no treatment
O: Six-minute walking distance, quantitative muscle testing, manual muscle testing, Medical Research Council (MRC), maximum voluntary isometric contraction, (serious) adverse events, sIBM Physical Function Assessment (sIFA), number of falls, quality of life.
Relevant outcome measures
The guideline development group considered six-minute walking distance as a critical outcome for decision making; and quantitative muscle testing, manual muscle testing (MRC-score), maximum voluntary isometric contraction, (serious) adverse events, sIBM Physical Function Assessment (sIFA), number of falls, and quality of life as important outcomes for decision making.
The working group defined a threshold of 15% for continuous outcomes and a relative risk (RR) <0.80 or >1.25 for dichotomous outcomes as a minimal clinically (patient) important difference.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 1990 until 9 February 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 237 hits. Studies were selected based on the following criteria: systematic reviews and randomized controlled trials from 1990 up to present on immunosuppression and immunomodulation in patients with inclusion body myositis. Thirteen studies were initially selected based on title and abstract screening. After reading the full text, ten studies were excluded (see the table with reasons for exclusion under the tab Methods), and three studies were included.
Results
Three studies were included in the analysis of the literature. One study was a systematic review (Rose, 2015), in which seven individual RCTs matched the PICO and were included in this guideline. Furthermore, two additional RCTs (Amato, 2021; Benveniste, 2021), published after the final date of search of the included systematic review, were included. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.
Referenties
- Amato AA, Hanna MG, Machado PM, Badrising UA, Chinoy H, Benveniste O, Karanam AK, Wu M, Tankó LB, Schubert-Tennigkeit AA, Papanicolaou DA, Lloyd TE, Needham M, Liang C, Reardon KA, de Visser M, Ascherman DP, Barohn RJ, Dimachkie MM, Miller JAL, Kissel JT, Oskarsson B, Joyce NC, Van den Bergh P, Baets J, De Bleecker JL, Karam C, David WS, Mirabella M, Nations SP, Jung HH, Pegoraro E, Maggi L, Rodolico C, Filosto M, Shaibani AI, Sivakumar K, Goyal NA, Mori-Yoshimura M, Yamashita S, Suzuki N, Aoki M, Katsuno M, Morihata H, Murata K, Nodera H, Nishino I, Romano CD, Williams VSL, Vissing J, Zhang Auberson L; RESILIENT Study Extension Group. Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT. Neurology. 2021 Mar 23;96(12):e1595-e1607. doi: 10.1212/WNL.0000000000011626. Epub 2021 Feb 17. PMID: 33597289; PMCID: PMC8032371.
- Badrising UA, Maat-Schieman ML, Ferrari MD, Zwinderman AH, Wessels JA, Breedveld FC, van Doorn PA, van Engelen BG, Hoogendijk JE, Höweler CJ, de Jager AE, Jennekens FG, Koehler PJ, de Visser M, Viddeleer A, Verschuuren JJ, Wintzen AR. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol. 2002 Mar;51(3):369-72. doi: 10.1002/ana.10121. PMID: 11891832.
- Benveniste O, Hogrel JY, Belin L, Annoussamy M, .. Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial. The Lancet Rheumatology, Volume 3, Issue 1, 2021, Pages e40-e48, ISSN 2665-9913,
- Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology. 1997 Mar;48(3):712-6. Doi: 10.1212/wnl.48.3.712. PMID: 9065553.
- Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13;56(3):323-7. doi: 10.1212/wnl.56.3.323. PMID: 11171896.
- Muscle Study Group. Randomized pilot trial of betaINF1a (Avonex) in patients with inclusion body myositis. Neurology 2001;57(9):1566-70. (PUBMED: 11706093)
- The Muscle Study Group. Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body myositis. Neurology 2004;63(4):718-20. (PUBMED: 15326251)
- Rose, M. R., Jones, K., Leong, K., Walter, M. C., Miller, J., Dalakas, M. C., ... & Griggs, R. (2015). Treatment for inclusion body myositis. Cochrane Database of Systematic Reviews, (6).
- Rutkove SB, Parker RA, Nardin RA, Connolly CE, Felice KJ, Raynor EM. A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology. 2002 Apr 9;58(7):1081-7. doi: 10.1212/wnl.58.7.1081. PMID: 11940697.
- Walter MC, Lochmuller H, Toepfer M, Schlotter B, Reilich P, Schroder M, . High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double blind, placebocontrolled study. Journal of Neurology 2000;247(1):22-8. (PUBMED: 10701893)
Evidence tabellen
|
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison / control (C) |
Follow-up |
Outcome measures and effect size |
|
Rose (2015) |
SR and meta-analysis of RCTs
Literature search up to On 7 October 2014, the Trials Search Co-ordinator searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL, 2014, Issue 9 in the Cochrane Library), MEDLINE (January 1966 to September 2014), and EMBASE (January 1947 to September 2014).
Study design:
Setting and Country: Not reported.
Source of funding This project was supported by the National Institute for Health Research via Cochrane Infrastructure funding to the Cochrane Neuromuscular Disease Group.
Conflicts of interest: The authors have no conflict of interest.
|
Inclusion criteria SR:
Exclusion criteria SR:
Four studies included
Important patient characteristics at baseline:
N
Mean (SD) or median (IQR) age
Sex:
Disease duration
Groups comparable at baseline? Yes. |
Describe intervention:
|
Describe control:
|
Endpoint of follow-up:
|
Outcome measure 1: adverse events
A: Badrising (2002) I: 8/21 (38.1%) C: 1/23 (4.3%) RR 8.76 (95% CI 1.19 to 64.28)
|
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3 |
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Amato (2021) |
Type of study: Randomized controlled trial.
Setting and country: 38 clinical sites in Australia, Belgium, Denmark, France, Italy, Japan, the Netherlands, Switzerland, the United Kingdom, and the United States.
Funding: Novartis Pharma AG, Basel, Switzerland.
Conflicts of interest: See original article.
|
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: 156 Control: 55
Important prognostic factors2: age ± SD: I: 68.8282 (8.3517| C: 69.9 (7.95)
Sex: I: 112/156 (71.8%) M| C: 36/55 (65.5%)
Groups comparable at baseline? Yes |
Describe intervention (treatment/procedure/test):
Bimagrumab 10 mg/kg + 3 mg/kg + 1 mg/kg combined
|
Describe control (treatment/procedure/test):
Placebo treatment. |
Length of follow-up: 2 years.
Loss-to-follow-up: Subsequently, 178 participants entered the posttreatment follow-up period following treatment period 1. Of 178 participants, 154 (86.5%) completed the follow-up period and 24 (13.5%) discontinued before completion.
|
Outcome 1: at least one serious adverse event, n/N (%) I: 29/156 (18.6%) C: 8/55 (14.5%)
|
Author’s conclusion: Findings from this study, which is the largest and longest ever conducted in sIBM, may help clarify disease pro- gression and provide important input to consider when designing clinical trials testing the anticipated benefits of new investigational drugs.
|
|
Benoviste (2021) |
Type of study:
Setting and country:
Funding:
Conflicts of interest:
|
Inclusion criteria:
Exclusion criteria:
N total at baseline: Intervention: n=22 Control: n=22
Important prognostic factors2: age ± SD: I: 68 (63.5 to 72.3) C: 66 (58.5 to 70.5)
Sex: I: 12/22 (55%) M C: 11/22 (50%)
Age at disease onset I: 60 (55 to 63.8) C: 58 (48.3 to 65)
Groups comparable at baseline? Yes. |
Describe intervention (treatment/procedure/test):
2 mg sirolimus (once-daily) |
Describe control (treatment/procedure/test):
Placebo. |
Length of follow-up: 12 months.
Loss-to-follow-up: None. |
Outcome 1: any adverse events, n/N (%)u I: 22/22 (100%) C: 22/22 (100%)
Outcome 2: any serious adverse event, n/N (%) I: 10/22 (45%) C: 6/22 (27%) |
Author’s conclusion: This study did not provide evidence of the efficacy of sirolimus for treating IBM based on the primary outcome measure and other muscle strength measures and side effects were substantial for some patients. However, we believe there is enough evidence of benefit in certain secondary outcomes to pursue a multicentric phase 3 trial to further assess its safety and efficacy. |
Quality assessment
|
Study
First author, year |
Appropriate and clearly focused question?1
Yes/no/unclear |
Comprehensive and systematic literature search?2
Yes/no/unclear |
Description of included and excluded studies?3
Yes/no/unclear |
Description of relevant characteristics of included studies?4
Yes/no/unclear |
Appropriate adjustment for potential confounders in observational studies?5
Yes/no/unclear/not applicable |
Assessment of scientific quality of included studies?6
Yes/no/unclear |
Enough similarities between studies to make combining them reasonable?7
Yes/no/unclear |
Potential risk of publication bias taken into account?8
Yes/no/unclear |
Potential conflicts of interest reported?9
Yes/no/unclear |
|
Rose (2019) |
Yes |
Yes |
Yes |
Yes |
Not applicable |
Yes |
Yes |
Yes |
Yes |
|
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented? Were patients blinded? Were healthcare providers blinded? Were data collectors blinded? Were outcome assessors blinded? Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
|
Amato (2021) |
Definitely yes.
Reason: eligible participants were randomly assigned (1:1:1:1) to receive IV infusions of bimagrumab 10, 3, 1 mg/kg, or matching placebo every 4 weeks.
|
Probably yes.
Reason: The interactive response technology assigned a randomisation number to the participant, which was used to link the participant to a treatment arm and specify unique medication numbers for packages of the investigational treatment to be prepared for the participant. |
Probably yes
Reason: To maintain masking, study medication was administered only by study center personnel who were unaware of treatment assignments.
|
Probably no
Reason: high number of patients discontinued the treatment. |
Probably yes
Reason: all predefined outcome measures were reported. |
Probably no
Reason: high heterogeneity of the study population in terms of disease severity, distribution of muscle weakness, and physical performance at baseline. |
Some concerns. |
|
Benveniste (2021) |
Definitely yes.
Reason: patients were randomly assigned to one of the treatment groups. |
No information.
Reason: - |
Definitely yes.
Reason: Double-blind study. |
Probably no
Reason: high number of patients discontinued the treatment. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events. |
Probably yes
Reason: all predefined outcome measures were reported. |
Probably yes.
Reason. - |
Some concerns. |
Table of excluded studies
|
Author and year |
Reason for exclusion |
|
Amato (2014) |
Wrong study design. |
|
Badrising (2002) |
Included in the systematic review Rose (2015). |
|
Dalakas (2001) |
Included in the systematic review Rose (2015). |
|
Dalakas (1997) |
Included in the systematic review Rose (2015). |
|
Hanna (2019) |
Same study data as Amato (2021). |
|
Ioannis (2019) |
Non-comparative study. |
|
Lindberg (2003) |
Wrong comparison. |
|
Rutkove (2002) |
Included in the systematic review Rose (2015). |
|
Saltychev (2016) |
Includes the same studies as the systematic review of Rose (2015). |
|
Walter (2000) |
Included in the systematic review Rose (2015). |
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 07-02-2024
Laatst geautoriseerd : 07-02-2024
Geplande herbeoordeling :
Algemene gegevens
The development of this guideline module was supported by the Knowledge Institute of the Federation of Medical Specialists (www.demedischspecialist.nl/ kennisinstituut) and was financed from the Quality Funds for Medical Specialists (SKMS). The financier has had no influence whatsoever on the content of the guideline module.
Samenstelling werkgroep
A multidisciplinary working group was set up in 2020 for the development of the guideline module, consisting of representatives of all relevant specialisms and patient organisations (see the Composition of the working group) involved in the care of patients with IIM/myositis.
Working group
- Dr. A.J. van der Kooi, neurologist, Amsterdam UMC, location AMC. Nederlandse Vereniging voor Neurologie (chair)
- Dr. U.A. Badrising, neurologist, LUMC. Nederlandse Vereniging voor Neurologie
- Dr. C.G.J. Saris, neurologist, Radboudumc. Nederlandse Vereniging voor Neurologie
- Dr. S. Lassche, neurologist, Zuyderland MC. Nederlandse Vereniging voor Neurologie
- Dr. J. Raaphorst, neurologist, Amsterdam UMC, locatie AMC. Nederlandse Vereniging voor Neurologie
- Dr. J.E. Hoogendijk, neurologist, UMC Utrecht. Nederlandse Vereniging voor Neurologie
- Drs. T.B.G. Olde Dubbelink, neurologist, Rijnstate, Nederlandse Vereniging voor Neurologie
- Dr. I.L. Meek, rheumatologist, Radboudumc. Nederlandse Vereniging voor Reumatologie
- Dr. R.C. Padmos, rheumatologist, Erasmus MC. Nederlandse Vereniging voor Reumatologie
- Prof. dr. E.M.G.J. de Jong, dermatologist, werkzaam in het Radboudumc. Nederlandse Vereniging voor Dermatologie en Venereologie
- Drs. W.R. Veldkamp, dermatologist, Ziekenhuis Gelderse Vallei. Nederlandse Vereniging voor Dermatologie en Venereologie
- Dr. J.M. van den Berg, pediatrician, Amsterdam UMC, locatie AMC. Nederlandse Vereniging voor Kindergeneeskunde
- Dr. M.H.A. Jansen, pediatrician, UMC Utrecht. Nederlandse Vereniging voor Kindergeneeskunde
- Dr. A.C. van Groenestijn, rehabilitation physician, Amsterdam UMC, locatie AMC. Nederlandse Vereniging van Revalidatieartsen
- Dr. B. Küsters, pathologist, Radboudumc. Nederlandse Vereniging voor Pathologie
- Dr. V.A.S.H. Dalm, internist, Erasmus MC. Nederlandse Internisten Vereniging
- Drs. J.R. Miedema, pulmonologist, Erasmus MC. Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
- I. de Groot, patient representatieve. Spierziekten Nederland
Advisory board
- Prof. dr. E. Aronica, pathologist, Amsterdam UMC, locatie AMC. External expert.
- Prof. dr. D. Hamann, Laboratory specialist medical immunology, UMC Utrecht. External expert.
- Drs. R.N.P.M. Rinkel, ENT physician, Amsterdam UMC, locatie VUmc. Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
- dr. A.S. Amin, cardiologist, werkzaam in werkzaam in het Amsterdam UMC, locatie AMC. Nederlandse Vereniging voor Cardiologie
- dr. A. van Royen-Kerkhof, pediatrician, UMC Utrecht. External expert.
- dr. L.W.J. Baijens, ENT physician, Maastricht UMC+. External expert.
- Em. Prof. Dr. M. de Visser, neurologist, Amsterdam UMC. External expert.
Methodological support
- Drs. T. Lamberts, senior advisor, Knowledge institute of the Federation of Medical Specialists
- Drs. M. Griekspoor, advisor, Knowledge institute of the Federation of Medical Specialists
- Dr. M. M. J. van Rooijen, advisor, Knowledge institute of the Federation of Medical Specialists
Belangenverklaringen
The ‘Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling’ has been followed. All working group members have declared in writing whether they have had direct financial interests (attribution with a commercial company, personal financial interests, research funding) or indirect interests (personal relationships, reputation management) in the past three years. During the development or revision of a module, changes in interests are communicated to the chairperson. The declaration of interest is reconfirmed during the comment phase.
An overview of the interests of working group members and the opinion on how to deal with any interests can be found in the table below. The signed declarations of interest can be requested from the secretariat of the Knowledge Institute of the Federation of Medical Specialists.
|
Werkgroeplid |
Functie |
Nevenfuncties |
Gemelde belangen |
Ondernomen actie |
|
van der Kooi |
Neuroloog, Amsterdam UMC |
|
Immediate studie (investigator initiated, IVIg behandeling bij therapie naive patienten). --> Financiering via Behring. Studie januari 2019 afgerond |
Geen restricties (middel bij advisory board is geen onderdeel van rcihtlijn) |
|
Miedema |
Longarts, Erasmus MC |
Geen. |
|
Geen restricties |
|
Meek |
Afdelingshoofd a.i. afdeling reumatische ziekten, Radboudumc |
Commissaris kwaliteit bestuur Nederlandse Vereniging voor Reumatologie (onkostenvergoeding) |
Medisch adviseur myositis werkgroep spierziekten Nederland |
Geen restricties |
|
Veldkamp |
AIOS dermatologie Radboudumc Nijmegen |
|
Geen. |
Geen restricties |
|
Padmos |
Reumatoloog, Erasmus MC |
Docent Breederode Hogeschool (afdeling reumatologie EMC wordt hiervoor betaald) |
Geen. |
Geen restricties |
|
Dalm |
Internist-klinisch immunoloog Erasmus MC |
Geen. |
Geen. |
Geen restricties |
|
Olde Dubbelink |
Neuroloog in opleiding Canisius-Wilhelmina Ziekenhuis, Nijmegen |
Promotie onderzoek naar diagnostiek en outcome van het carpaletunnelsyndroom (onbetaald) |
Geen. |
Geen restricties |
|
van Groenestijn |
Revalidatiearts AmsterdamUMC, locatie AMC |
Geen. |
Lokale onderzoeker voor de I'M FINE studie (multicentre, leiding door afdeling Revalidatie Amsterdam UMC, samen met UMC Utrecht, Sint Maartenskliniek, Klimmendaal en Merem. Evaluatie van geïndividualiseerd beweegprogramma o.b.v. combinatie van aerobe training en coaching bij mensen met neuromusculaire aandoeningen, NMA). Activiteiten: screening NMA-patiënten die willen participeren aan deze studie. Subsidie van het Prinses Beatrix Spierfonds. |
Geen restricties |
|
Lassche |
Neuroloog, Zuyderland Medisch Centrum, Heerlen en Sittard-Geleen |
Geen. |
Geen. |
Geen restricties |
|
de Jong |
Dermatoloog, afdelingshoofd Dermatologie Radboudumc Nijmegen |
Geen. |
All funding is not personal but goes to the independent research fund of the department of dermatology of Radboud university medical centre Nijmegen, the Netherlands |
Geen restricties |
|
Hoogendijk |
Neuroloog Universitair Medisch Centrum Utrecht (0,4) Neuroloog Sionsberg, Dokkum (0,6) |
beide onbetaald |
Geen. |
Geen restricties |
|
Badrising |
Neuroloog Leids Universitair Medisch Centrum |
(U.A.Badrising Neuroloog b.v.: hoofdbestuurder; betreft een vrijwel slapende b.v. als overblijfsel van mijn eerdere praktijk in de maatschap neurologie Dirksland, Het van Weel-Bethesda Ziekenhuis) |
Medisch adviseur myositis werkgroep spierziekten Nederland |
Geen restricties |
|
van den Berg |
Kinderarts-reumatoloog/-immunoloog Emma kinderziekenhuis/ Amsterdam UMC |
Geen. |
Geen. |
Geen restricties |
|
de Groot |
Patiënt vertegenwoordiger/ ervaringsdeskundige: voorzitter diagnosewerkgroep myositis bij Spierziekten Nederland in deze commissie patiënt(vertegenwoordiger) |
|
Geen |
Geen restricties |
|
Küsters |
Patholoog, Radboud UMC |
Geen. |
Geen. |
Geen restricties |
|
Saris |
Neuroloog/ klinisch neurofysioloog, Radboudumc |
Geen. |
Geen. |
Geen restricties |
|
Raaphorst |
Neuroloog, Amsterdam UMC |
Geen. |
|
Restricties m.b.t. opstellen aanbevelingen IvIg behandeling. |
|
Jansen |
Kinderarts-immunoloog-reumatoloog, WKZ UMC Utrecht |
Docent bij Mijs-instituut (betaald) |
Onderzoek biomakers in juveniele dermatomyositis. Geen belang bij uitkomst richtlijn. |
Geen restricties |
Inbreng patiëntenperspectief
Attention was paid to the patient's perspective by offering the Vereniging Spierziekten Nederland to take part in the working group. Vereniging Spierziekten Nederland has made use of this offer, the Dutch Artritis Society has waived it. In addition, an invitational conference was held to which the Vereniging Spierziekten Nederland, the Dutch Artritis Society nd Patiëntenfederatie Nederland were invited and the patient's perspective was discussed. The report of this meeting was discussed in the working group. The input obtained was included in the formulation of the clinical questions, the choice of outcome measures and the considerations. The draft guideline was also submitted for comment to the Vereniging Spierziekten Nederland, the Dutch Artritis Society and Patiëntenfederatie Nederland, and any comments submitted were reviewed and processed.
Qualitative estimate of possible financial consequences in the context of the Wkkgz
In accordance with the Healthcare Quality, Complaints and Disputes Act (Wet Kwaliteit, klachten en geschillen Zorg, Wkkgz), a qualitative estimate has been made for the guideline as to whether the recommendations may lead to substantial financial consequences. In conducting this assessment, guideline modules were tested in various domains (see the flowchart on the Guideline Database).
The qualitative estimate shows that there are probably no substantial financial consequences, see table below.
|
Module |
Estimate |
Explanation |
|
Module diagnostische waarde ziekteverschijnselen |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Optimale strategie aanvullende diagnostiek myositis |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Autoantibody testing in myositis |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Screening op maligniteiten |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Screening op comorbiditeiten |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Immunosuppressie en -modulatie bij IBM |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Treatment with Physical training |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Treatment of dysphagia in myositis |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Treatment of dysphagia in IBM |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Topical therapy |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Treatment of calcinosis |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
|
Module Organization of care |
No substantial financial consequences |
Outcome 1 No financial consequences. The recommendations are not widely applicable (<5,000 patients) and are therefore not expected to have any substantial financial consequences on collective expenditures. |
Werkwijze
Methods
AGREE
This guideline module has been drawn up in accordance with the requirements stated in the Medisch Specialistische Richtlijnen 2.0 report of the Advisory Committee on Guidelines of the Quality Council. This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).
Clinical questions
During the preparatory phase, the working group inventoried the bottlenecks in the care of patients with IIM. Bottlenecks were also put forward by the parties involved via an invitational conference. A report of this is included under related products.
Based on the results of the bottleneck analysis, the working group drew up and finalized draft basic questions.
Outcome measures
After formulating the search question associated with the clinical question, the working group inventoried which outcome measures are relevant to the patient, looking at both desired and undesired effects. A maximum of eight outcome measures were used. The working group rated these outcome measures according to their relative importance in decision-making regarding recommendations, as critical (critical to decision-making), important (but not critical), and unimportant. The working group also defined at least for the crucial outcome measures which differences they considered clinically (patient) relevant.
Methods used in the literature analyses
A detailed description of the literature search and selection strategy and the assessment of the risk-of-bias of the individual studies can be found under 'Search and selection' under Substantiation. The assessment of the strength of the scientific evidence is explained below.
Assessment of the level of scientific evidence
The strength of the scientific evidence was determined according to the GRADE method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org/). The basic principles of the GRADE methodology are: naming and prioritizing the clinically (patient) relevant outcome measures, a systematic review per outcome measure, and an assessment of the strength of evidence per outcome measure based on the eight GRADE domains (downgrading domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias; domains for upgrading: dose-effect relationship, large effect, and residual plausible confounding).
GRADE distinguishes four grades for the quality of scientific evidence: high, fair, low and very low. These degrees refer to the degree of certainty that exists about the literature conclusion, in particular the degree of certainty that the literature conclusion adequately supports the recommendation (Schünemann, 2013; Hultcrantz, 2017).
|
Definitie |
|
|
High |
|
|
Moderate |
|
|
Low |
|
|
Very low |
|
When assessing (grading) the strength of the scientific evidence in guidelines according to the GRADE methodology, limits for clinical decision-making play an important role (Hultcrantz, 2017). These are the limits that, if exceeded, would lead to an adjustment of the recommendation. To set limits for clinical decision-making, all relevant outcome measures and considerations should be considered. The boundaries for clinical decision-making are therefore not directly comparable with the minimal clinically important difference (MCID). Particularly in situations where an intervention has no significant drawbacks and the costs are relatively low, the threshold for clinical decision-making regarding the effectiveness of the intervention may lie at a lower value (closer to zero effect) than the MCID (Hultcrantz, 2017).
Considerations
In addition to (the quality of) the scientific evidence, other aspects are also important in arriving at a recommendation and are taken into account, such as additional arguments from, for example, biomechanics or physiology, values and preferences of patients, costs (resource requirements), acceptability, feasibility and implementation. These aspects are systematically listed and assessed (weighted) under the heading 'Considerations' and may be (partly) based on expert opinion. A structured format based on the evidence-to-decision framework of the international GRADE Working Group was used (Alonso-Coello, 2016a; Alonso-Coello 2016b). This evidence-to-decision framework is an integral part of the GRADE methodology.
Formulation of conclusions
The recommendations answer the clinical question and are based on the available scientific evidence, the most important considerations, and a weighting of the favorable and unfavorable effects of the relevant interventions. The strength of the scientific evidence and the weight assigned to the considerations by the working group together determine the strength of the recommendation. In accordance with the GRADE method, a low evidential value of conclusions in the systematic literature analysis does not preclude a strong recommendation a priori, and weak recommendations are also possible with a high evidential value (Agoritsas, 2017; Neumann, 2016). The strength of the recommendation is always determined by weighing all relevant arguments together. The working group has included with each recommendation how they arrived at the direction and strength of the recommendation.
The GRADE methodology distinguishes between strong and weak (or conditional) recommendations. The strength of a recommendation refers to the degree of certainty that the benefits of the intervention outweigh the harms (or vice versa) across the spectrum of patients targeted by the recommendation. The strength of a recommendation has clear implications for patients, practitioners and policy makers (see table below). A recommendation is not a dictate, even a strong recommendation based on high quality evidence (GRADE grading HIGH) will not always apply, under all possible circumstances and for each individual patient.
|
Implications of strong and weak recommendations for guideline users |
||
|
|
||
|
|
Strong recommendation |
Weak recommendations |
|
For patients |
Most patients would choose the recommended intervention or approach and only a small number would not. |
A significant proportion of patients would choose the recommended intervention or approach, but many patients would not. |
|
For practitioners |
Most patients should receive the recommended intervention or approach. |
There are several suitable interventions or approaches. The patient should be supported in choosing the intervention or approach that best reflects his or her values and preferences. |
|
For policy makers |
The recommended intervention or approach can be seen as standard policy. |
Policy-making requires extensive discussion involving many stakeholders. There is a greater likelihood of local policy differences. |
Organization of care
In the bottleneck analysis and in the development of the guideline module, explicit attention was paid to the organization of care: all aspects that are preconditions for providing care (such as coordination, communication, (financial) resources, manpower and infrastructure). Preconditions that are relevant for answering this specific initial question are mentioned in the considerations. More general, overarching or additional aspects of the organization of care are dealt with in the module Organization of care.
Commentary and authtorisation phase
The draft guideline module was submitted to the involved (scientific) associations and (patient) organizations for comment. The comments were collected and discussed with the working group. In response to the comments, the draft guideline module was modified and finalized by the working group. The final guideline module was submitted to the participating (scientific) associations and (patient) organizations for authorization and authorized or approved by them.
References
Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.
Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwaliteit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html
Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.
Schünemann H, Brożek J, Guyatt G, . GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.
Zoekverantwoording
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