Treatment of calcinosis

Beoordeeld: 07-02-2024

Uitgangsvraag

How should calcinosis in patients with idiopathic inflammatory myopathy (IIM) or juvenile dermatomyositis be treated?

Hoe ziet de behandeling van calcinoses bij patiënten met idiopathische inflammatoire myopathie (IIM) of juveniele dermatomyositis eruit?

Aanbeveling

Aanbeveling 1

Behandel primair de myositis, behandel secundair de calcinosis

Aanbeveling 2

Overweeg bij een medicamenteuze behandeling een van de volgende medicamenten:

Colchicine, 0.5-1.5 mg/dag, met name bij calcinose met een sterk inflammatoir karakter
Diltiazem, 180-480 mg/dag
Bisfosfonaten, met name pamidronaat, alendronaat en etidronaat. Gezien gebrek aan data is er geen aanbeveling te doen voor de bepaalde doseringschema’s
Minocycline, 50-200 mg/dag

NB. Bovengenoemde doseringen zijn doseringen voor volwassenen. Voor doseringen op kinderleeftijd, zie kinderformularium.

Aanbeveling 3

Overweeg een behandeling met TNF-α inhibitoren, JAK-stat inhibitoren en/of Rituximab; houd dan echter rekening met een verhoogd infectierisico en de kosten van deze middelen.

Aanbeveling 4

Overweeg een chirurgische behandeling alleen bij ernstige gecompliceerde en/of symptomatische laesies, maar wees terughoudend gezien het risico op slechte wondgenezing.

Overwegingen

Considerations – from evidence to recommendation

Pros and cons of the intervention and the quality of the evidence

There is a lack of literature on the treatment of calcinosis cutis in patients with IIM. Data is available mostly from retrospective case histories (n = 365, 75.6%), a single RCT, and a limited number of prospective (non-comparative) studies. Furthermore, the effect is reported differently in the publications, ranging from (in)complete or no response to quantitative data from imaging, without clear delineation of the specific criteria. As a result, the effect size and the weight of evidence cannot be determined. The few data that are available also show little consistency (see also table 1). There are a few therapies described in the literature as potentially effective: infliximab or adalimumab, pamidronate, minocycline, sodium thiosulfate, and manual intervention with (surgical or non-surgical) excision. The evidence for these treatments is very low, due to the lack of comparative research and data on the long-term effects of the treatments. This conclusion is supported by two analyzed reviews, which do not give firm recommendations due to lack of evidence. The published recommendations of those reviews (depicted in table 2) are consistent with the cross-analysis, with one difference. Where diltiazem is recommended by Chung & Chung (2019) as the first choice, this recommendation has been revised in Traineau (2020) and is not supported by the combined data. This difference can be explained by the difference in the underlying data: 26 patients, the majority of whom showed no positive effect after using diltiazem, were not included by Chung & Chung (2019) for unknown reason.

Table 2: Treatment recommendations for calcinosis in (dermato)myositis in recent literature reviews, described wih the pooled response rate found in all included publications.

Treatment	Chung (2019)	Traineau (2020)	n	Response
Anti-inflammatory agents
Colchicine	May be discussed in DM patients for symptomatic relief of inflammation	May be discussed in DM and SSc patients	30	9
Minocycline	Promising in SSc patients; needs further study in DM patients	May be discussed in SSc patients	12	10
Cyclophosphamide		May be discussed in DM patients	26	9
Intravenous immunoglobulin	May be discussed in DM patients	May be discussed in DM patients	21	10
Thalidomide			1	1
Intralesional steroids	May be alternative treatment to surgery		3	1
Infliximab	May be discussed in DM patients	May be discussed in DM patients	22	12
Infliximab or adalimumab			28	23
Adalimumab			3	3
Etanercept			4	2
Rituximab	May be discussed in DM patients	May be discussed in DM and SSc patients	64	24
Abatacept	May be discussed in DM patients	May be discussed in DM patients	1	1
Anakinra	Experimental use, needs further study		1	1
Baricitinib			2	0
Tofacitinib	May be discussed in DM patients		2	2
Calcium and phosphate modulation
Diltiazem	Consider as first-line approach in conjunction with surgical excision of discrete, symptomatic lesions	May have a preventive effect, should be discussed in SSc patients and DM with Raynaud phenomenon	56	19
Alendronate	May be discussed in DM patients	May be discussed in DM patients¹	21	7
Clodronate		May be discussed in DM patients¹	1	0
Etidronate	May be discussed in DM patients	May be discussed in DM patients¹	10	3
Pamidronate	May be discussed in DM patients	May be discussed in DM patients¹	10	10
Risedronate		May be discussed in DM patients¹	3	1
Sodium thiosulfate	Topical and intralesional use may be discussed in DM patients, IV use has insufficient evidence with negative results	Topical and intralesional use may be discussed in DM and SSc patients, IV use should not be recommended	26	16
Aluminium hydroxide	Consider alternative therapies		13	8
Warfarin	Should not be recommended	Should not be recommended	28	5
Probenecid	May be discussed in DM patients		4	4
Nifedipine			2	0
Surgical and non-medicinal interventions
Surgical excision	May be discussed in DM patients for large, discrete, and/or symptomatic lesions accessible for surgical removal	May be discussed in DM and SSc patients	67	56
Shockwave lithotripsy	May be alternative treatment to surgery	May be alternative treatment to surgery	9	7
Carbon dioxide laser		May be alternative treatment to surgery	7	6

DM = (dermato)myositis, SSc = systemic sclerosis, IV = intravenous.

¹ Bisphosphonates were treated as a single class in the recommendation of Traineau (2020).

Values and preferences of patients

One could argue that non-invasive treatments can be preferred above invasive treatments for patients with calcinosis.

Costs

The average costs of the most drugs mentioned are low (on average € 1-4 per day) (www.farmacotherapeutischkompas.nl). The prices of several more expensive drugs such as TNF-α inhibitors dropped tenfold over the last several years, but these drugs are not the first treatment option. Intravenously administered immunoglobulins (IVIg drugs) remain expensive and the costs for surgery are higher compared with most drugs, but surgery and IVIg are not the first treatment options.

Acceptability, feasibility and implementation

There are no relevant factors with regard to this topic. All of the mentioned treatments are considered as usual care. No implementation barriers are identified.

Recommendations

Rationale

For patients with persistent and/or recurrent calcinocus cutis with complaints of pain, ulcerations, secondary infections or mechanical impediments with contracture development, treatment can be considered. Due to the lack of adequately controlled studies of high quality, strong recommendations cannot be made. Nonetheless, some treatments can be considered based on the pooled data from table 2. Only treatment options are recommended for which data of 5 of more patients are available.

In the literature analysis, only systematic reviews were included (which were allowed to have included case series and/or case reports). Additional, independent case reports, not included in the systematic reviews used, have demonstrated a favorable impact of JAK inhibitors on calcinosis cutis. Consequently, we made the decision to incorporate JAK inhibition therapy in our recommendations, as supported by studies conducted by Shneyderman (2021), Wendel (2019), and Sabbagh (2019).

Onderbouwing

Achtergrond

Calcinosis causes calcium depositions in the skin, subcutaneous tissue, fascia, tendons and/or muscles. Calcinosis is often associated with dermatomyositis (DM) or systemic sclerosis (SSc). In particular, the variant in the skin and subcutaneous tissues, calcinosis cutis, can develop in 30% of adults with DM and 30-70% of juvenile DM patients, as well as in 18-49% of patients with SSc, although the definitions and therefore the numbers vary in different studies (Traineau, 2020). Calcinosis occurs despite normal serum calcium and phosphate levels (Kul Cinar, 2021) and can cause significant deterioration in quality of life, through ulceration or secondary infections (Kul Cinar, 2021; Traineau, 2020).

Pathogenesis

The mechanism involved in the development of calcinosis cutis is still poorly understood. Calcium release from mitochondria has been proposed as a possible mechanism for calcinosis (Chander & Gordon, 2012; Chung & Chung, 2019). Lesions generally occur in tissues enduring chronic stress, be it by local trauma (e.g. knees, elbows, buttocks) or inflammatory response (Chander & Gordon, 2012). These calcifications show a high hydroxyapatite content, which is distinct from physiological bone composition, as well as the presence of macrophages, IL-6, IL-1β, and TNF-α (Chander & Gordon, 2012; Hoeltzel, 2014). Consistently, the TNF-α-308A polymorphism, which is associated with higher TNF-α production, shows increased risk of developing calcinosis as compared to the TNF-α-308G allele (Chander & Gordon, 2012; Hoeltzel, 2014). Additionally, DM patients, especially those with the juvenile variant, have a higher risk of developing calcinosis cutis, correlating with longer disease duration, sustained activity, immunosuppression, and anti-NXP2 autoantibodies (Chander & Gordon, 2012; Chung & Chung, 2019; Hoeltzel, 2014; Kul Cinar, 2021). For SSc patients, digital ulcers, which are associated with ischemia, have in turn been associated with calcinosis, suggesting a role in its pathogenesis (Chander & Gordon, 2012; Chung & Chung, 2019).

Calcification rarely occurs in non-pathological conditions, though extracellular calcium phosphate products are close to saturation. Calcification is normally prevented by inhibition through matrix gammacarboxyglutamic acid protein (MGP) and fetuin-A (Chander & Gordon, 2012), balanced by calcification promoters, such as osteonectin. Disruption of this balance could thus be involved in the pathogenesis (Chander & Gordon, 2012). MGP is a vitamin K-dependent inhibitor of vascular calcification, induced by increased calcium levels in tissue. It was found to be expressed in areas of muscle damage in JDM and scleroderma patients, while being only occasionally present in controls (Chander & Gordon, 2012). JDM patients suffering from calcinosis showed higher levels of its phosphorylated form than those without calcinosis. Contrastingly, no difference in fetuin-a and osteopontin levels were found between JDM patients and age-matched controls (Chander & Gordon, 2012).

Treatment

There is a distinct lack of consensus regarding the treatment of calcinosis cutis (Chander & Gordon, 2012; Traineau, 2020), though initiatives exist to identify best practices for JDM (Enders, 2017). This is likely explained by the lack of knowledge regarding its pathogenesis, the lack of evidence due to the multitude of used treatment strategies, and the low prevalence of the disease (Chander & Gordon, 2012). Thus, treatment of calcinosis is generally based on a trial-and-error approach, although the order of this approach differs. This heterogeneity is unsurprising, as evidence has been mostly limited to case reports. Broadly, three therapeutic strategies can be distinguished in literature: 1) management of the underlying inflammatory condition, 2) alteration of calcium or phosphate metabolism, or 3) surgical or non-medicinal removal of calcinosis lesions (Chung & Chung, 2019). The former two options are aimed at prevention, given the (limited) information regarding the pathogenesis of calcinosis, while the latter is mostly aimed at symptomatic relief. Several literature reviews have summarized the available evidence, noting again and again the lack of controlled clinical data (Chander & Gordon, 2012; Chung & Chung, 2019; Hoeltzel, 2014; Kul Cinar, 2021; Traineau, 2020). Therefore, no clear recommendation has been made regarding the preferential treatment strategy or order of attempted strategies, in both literature and the previous guideline (Nederlandse Vereniging voor Neurologie, 2005).

Samenvatting literatuur

Description of studies

Five literature reviews were included for full-text analyses: Chander & Gordon (2012) described 36 patients, reported in 12 publications, Chung & Chung (2019) described 294 patients, reported in 64 publications, Hoeltzel (2014) described 67 patients, reported in 30 publications, Kul Cinar (2021) described 152 patients, reported in 35 publications, and Traineau (2020) described 251 patients, reported in 24 publications. Importantly, most of the included publications were reviewed in several of these reviews, with only Chung & Chung (109 patients, 25 publications), Kul Cinar (52 patients, 8 publication), and Traineau (101 patients, 12 publications) reporting data from more than 10 new, previously unreviewed patients. The included reviews referenced a total of 92 papers (2 RCTs, 15 prospective case series/reports, and 75 retrospective case series/reports), describing 28 different treatment strategies. These underlying papers often reported different treatments and different study populations per article: a total of 121 study populations were identified. A significant number of these populations were small, with 79 (65.3%) comprising fewer than 4 individuals, with a median per arm of n = 2 (range 1 to 28).

Results

A considerable variation in treatment response was reported for the various treatment regimens. A successful treatment was defined as stabilization or mild improvement of calcinosis (partial response) or a complete response. An overview of the treatments and their respective results is shown in Table 1. Based on the pooled response rates and excluding treatments with less than five patients, the best results were reported for pamidronate (100%), infliximab or adalimumab (54.6% up to 100%), carbon dioxide laser treatment (85.7%), surgical excision (83.6%), minocycline (83.3%), shockwave lithotripsy (77.8%), sodium thiosulfate (61.5%), and aluminum hydroxide (61.5%). Warfarin (17.9%) had the lowest response rate.

Data on the efficacy of thalidomide, intralesional steroids, clodronate, risedronate, probenecid, nifedipine, etanercept, abatacept, anakinra, and the JAK inhibitors baricitinib and tofacitinib were scarce (n < 5) and could therefore not be assessed properly.

Table 1: Overview of used therapeutic interventions in literature and their pooled success rate in treating calcinosis cutis. Results are not consistently split by disease in all publications, meaning some populations can only be described using the mix of their underlying diseases.

Treatment	n	Disease (n)	PR	CR
Anti-inflammatory agents
Colchicine	30	DM (12), SSc (1), DM/SSc (7), DM/other (9), other (1)	7	2
Minocycline	12	SSc (9), DM/SSc (3)	2	8
Cyclophosphamide	26	DM (26)	0	9
Intravenous immunoglobulin	21	DM (13), Scl (1), DM/other (7)	0	10
Thalidomide	1	DM (1)	0	1
Intralesional steroids	3	DM (2), SSc (1)	0	1
Infliximab	22	DM (21), other (1)	1	11
Infliximab or adalimumab	28	DM (28)	0	23
Adalimumab	3	DM (3)	2	1
Etanercept	4	DM (4)	0	2
Rituximab	64	DM (42), Scl (1), SSc (19), other (2)	11	13
Abatacept	1	DM (1)	0	1
Anakinra	1	DM (1)	0	1
Baricitinib	2	DM (2)	0	0
Tofacitinib	2	DM (2)	0	2
Calcium and phosphate modulation
Diltiazem	56	DM (22), SSc (12), DM/SSc (14), DM/other (7), other (1)	14	5
Diltiazem & pamidronate	1	DM (1)	0	1
Alendronate	21	DM (11), DM/SSc (2), DM/other (5)	4	3
Clodronate	1	DM/other (1)	0	0
Etidronate	10	DM (6), Scl (3), SSc (1)	1	2
Pamidronate	10	DM (10)	2	8
Risedronate	3	DM (2), other (1)	0	1
Sodium thiosulfate	26	DM (12), SSc (6), DM/other (5), other (3)	4	12
Sodium thiosulfate & abatacept	5	DM (3), SSc (2)	0	1
Aluminium hydroxide	13	DM (13)	0	8
Warfarin	28	DM (13), SSc (9), DM/SSc (3), other (3)	1	4
Probenecid	4	DM (4)	0	4
Nifedipine	2	DM (1), other (1)	0	0
Surgical and non-medicinal interventions
Surgical excision	67	DM (11), SSc (22), DM/SSc (28), DM/other (6)	7	49
Shockwave lithotripsy	9	DM (2), SSc (6), DM/SSc (1)	2	5
Carbon dioxide laser	7	SSc (6), Scl (1)	5	1

PR = partial response, CR = complete response, DM = dermatomyositis, Scl = scleroderma, SSc = systemic sclerosis.

Zoeken en selecteren

Search and select

A systematic review of the literature was performed to answer the following question:

Which are the positive and possible negative effects of the treatment of calcinosis in patients with juvenile dermatomyositis?

P: Patients with idiopathic inflammatory myopathy (IIM) or juvenile dermatomyositis (JDM)

I: Treatments for calcinosis: colchicine, diltiazem, bisphosphonates, minocycline or other antibiotics, corticosteroids (intralesional), surgical excision, CO2 laser treatment, shock wave lithotripsy, IVIg, B-cell depletion (rituximab), natriumthiosulfate.

C: Placebo or usual care

O: Pain, number and size of the calcifications, ulcerations

Relevant outcome measures

The guideline development group considered pain, number and size of calcinosis lesions and ulcerations as critical outcome measures for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

For continuous outcome measures the guideline development group defined a 10% difference as a “minimal clinically (patient) important difference”. For dichotomous outcome measures a 25% difference was defined as a “minimal clinically (patient) important difference”.

Search and select (Methods)

The databases Medline (via OVID), Embase (via Embase.com) were searched with relevant search terms until 21 July 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 171 hits. Studies were selected based on the following criteria:

Article full text available in Engels or Dutch
Primary comparative research
Study design Systematic Review, RCT or observational research
Published between 2000 and July 2021
Study population are patients with IIM or juvenile dermatomyositis

In total, 12 studies were initially selected based on title and abstract screening. After reading the full text, 12 studies were excluded (see the table with reasons for exclusion under the heading Evidence Tables), and none of the studies were included.

Results

Based on the GRADE criteria, no studies were included in the analysis. Since it was important to present recommendations for the treatment of calcinosis cutis in DM patients, a combined review of the published literature was constructed as an alternative. Therefore, the four literature reviews focusing on treatment of calcinosis cutis in patients with DM (Chung & Chung, 2019; Hoeltzel, 2014; Kul Cinar, 2021; Traineau, 2020) were initially selected for full -text analysis, and an additional review was selected as it was referenced by two of the aforementioned reviews (Chander & Gordon, 2012) and analyzed treatment options and their respective outcomes. Outcome measures varied between publications, with some reporting partial or complete response (consolidation or improvement/disappearance of calcinosis, respectively); others included quantitative data such as CT or DEXA scan results. This complicates a comparison of the various study results.

Therefore, three outcome levels were defined, which could be extracted from all included publications: 1) complete response: significant regression or complete resolution of calcinosis, 2) partial response: stopping progression or mild regression, and 3) no or negative response. Disease status and its regression were assessed by the treating physician or study physician or determined based on quantitative data. All referenced publications were pooled, and treatment recommendations were compared between reviews.

Referenties

Chander, S., & Gordon, P. (2012). Soft tissue and subcutaneous calcification in connective tissue diseases. Curr Opin Rheumatol, 24(2), 158-164. doi:10.1097/BOR.0b013e32834ff5cd
Chung, M., & Chung, L. (2019). Management of Calcinosis Associated with Dermatomyositis. Current Treatment Options in Rheumatology, 5(4), 242-257. doi:10.1007/s40674-019-00134-w
Bellutti Enders F, Bader-Meunier B, Baildam E, Constantin T, Dolezalova P, Feldman BM, Lahdenne P, Magnusson B, Nistala K, Ozen S, Pilkington C, Ravelli A, Russo R, Uziel Y, van Brussel M, van der Net J, Vastert S, Wedderburn LR, Wulffraat N, McCann LJ, van Royen-Kerkhof A. Consensus-based recommendations for the management of juvenile dermatomyositis. Ann Rheum Dis. 2017 Feb;76(2):329-340. doi: 10.1136/annrheumdis-2016-209247. Epub 2016 Aug 11. PMID: 27515057; PMCID: PMC5284351.
Hoeltzel, M. F., Oberle, E. J., Robinson, A. B., Agarwal, A., & Rider, L. G. (2014). The presentation, assessment, pathogenesis, and treatment of calcinosis in juvenile dermatomyositis. Curr Rheumatol Rep, 16(12), 467. doi:10.1007/s11926-014-0467-y
Kul Cinar, O., Papadopoulou, C., & Pilkington, C. A. (2021). Treatment of Calcinosis in Juvenile Dermatomyositis. Curr Rheumatol Rep, 23(2), 13. doi:10.1007/s11926-020-00974-9
Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med, 6(7), e1000097. doi:10.1371/journal.pmed.1000097
Nederlandse Vereniging voor Neurologie. (2005). Richtlijn Dermatomyositis, polymyositis en sporadische 'inclusion body'-myositis. Retrieved from https://www.neurologie.nl/uploads/136/85/richtlijnen_-_myositis.pdf
Sabbagh S, Almeida de Jesus A, Hwang S, Kuehn HS, Kim H, Jung L, Carrasco R, Rosenzweig S, Goldbach-Mansky R, Rider LG. Treatment of anti-MDA5 autoantibody-positive juvenile dermatomyositis using tofacitinib. Brain. 2019 Nov 1;142(11):e59. doi: 10.1093/brain/awz293. PMID: 31603187; PMCID: PMC6821280.
Shea, B. J., Grimshaw, J. M., Wells, G. A., Boers, M., Andersson, N., Hamel, C., Bouter, L. M. (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol, 7, 10. doi:10.1186/1471-2288-7-10
Shneyderman M, Ahlawat S, Christopher-Stine L, Paik JJ. Calcinosis in refractory dermatomyositis improves with tofacitinib monotherapy: a case series. Rheumatology (Oxford). 2021 Nov 3;60(11):e387-e388. doi: 10.1093/rheumatology/keab421. PMID: 33961025; PMCID: PMC8566241.
Traineau, H., Aggarwal, R., Monfort, J. B., Senet, P., Oddis, C. V., Chizzolini, C., Chasset, F. (2020). Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: A review of the literature. J Am Acad Dermatol, 82(2), 317-325. doi:10.1016/j.jaad.2019.07.006
Wendel S, Venhoff N, Frye BC, May AM, Agarwal P, Rizzi M, Voll RE, Thiel J. Successful treatment of extensive calcifications and acute pulmonary involvement in dermatomyositis with the Janus-Kinase inhibitor tofacitinib - A report of two cases. J Autoimmun. 2019 Jun;100:131-136. doi: 10.1016/j.jaut.2019.03.003. Epub 2019 Mar 9. PMID: 30862449.

Evidence tabellen

Table 1: Quality assessment for included literature reviews, according to the AMSTAR (Shea ., 2007) and PRISMA (Moher, Liberati, Tetzlaff, & Altman, 2009) checklists.

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/n.a.	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
Chander, 2012	No	No	No	No	N/a	No	Unclear	No	Unclear
Chung, 2019	No	No	No	No	N/a	Yes	Unclear	No	Unclear
Hoeltzel, 2014	No	No	No	No	N/a	No	Unclear	No	Unclear
Kul Cinar, 2021	No	No	No	No	N/a	No	Unclear	No	Unclear
Traineau, 2020	Yes	Yes	Yes	Yes	N/a	Yes	Unclear	No	Unclear

1. Research question (PICO) and inclusion criteria should be appropriate and predefined

2. Search period and strategy should be described; at least Medline searched; for pharmacological questions at least Medline + EMBASE searched

3. Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons

4. Characteristics of individual studies relevant to research question (PICO), including potential confounders, should be reported

5. Results should be adequately controlled for potential confounders by multivariate analysis (not applicable for RCTs)

6. Quality of individual studies should be assessed using a quality scoring tool or checklist (Jadad score, Newcastle-Ottawa scale, risk of bias table etc.)

7. Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, intervention and definition of outcome measure to allow pooling? For pooled data: assessment of statistical heterogeneity using appropriate statistical tests (e.g. Chi-square, I2)?

8. An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). Note: If no test values or funnel plot included score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies.

9. Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.

Exclusietabel

Tabel Exclusie na het lezen van het volledige artikel

Auteur en jaartal	Redenen van exclusie
Campanilho-Marques, 2020	Retrospectieve analyse zonder controlegroep
Chung & Chung, 2019	Literatuursamenvatting van retrospectieve data
Ge, 2021	Literatuursamenvatting van retrospectieve data
Hinze, 2018	Survey onder behandelaars, geen klinische data
Hoeltzel, 2014	Literatuursamenvatting van retrospectieve data
Jiang, 2021	Retrospectieve analyse zonder controlegroep
Kul Cinar, 2021	Literatuursamenvatting van retrospectieve data
Marco Puche, 2010	Retrospectieve analyse zonder controlegroep
Robert, 2020	Retrospectieve analyse zonder controlegroep
Traineau, 2020	Literatuursamenvatting van retrospectieve data
Valenzuela & Chung, 2015	Literatuursamenvatting van retrospectieve data van systemische sclerose
Walling, 2010	Literatuursamenvatting van retrospectieve data

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 07-02-2024

Laatst geautoriseerd : 07-02-2024

Geplande herbeoordeling : 01-12-2025

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Neurologie

Geautoriseerd door:

Nederlandse Internisten Vereniging
Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
Nederlandse Vereniging van Revalidatieartsen
Nederlandse Vereniging voor Cardiologie
Nederlandse Vereniging voor Dermatologie en Venereologie
Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
Nederlandse Vereniging voor Kindergeneeskunde
Nederlandse Vereniging voor Neurologie
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Reumatologie
Vereniging Spierziekten Nederland

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	Voorzitter Spierziektencentrum Nederland (betaald) Eenmalige deelname advisory board ArgenX om het starten van trial in myositis (met efgartigimod). AMC zou als onderzoekslocatie deel kunnen nemen.	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.	Fee voor deelname advisory board 2020: nintedanib voor progressieve longfibrose (Boehringer Ingelheim), niet meer actueel. Fee voor enkele voordrachten Intersitiele longziekten, niet gerelateerd aan het onderwerp van de werkgroep myositis (Boehringer Ingelheim, Roche) Patent behandeling sarcoidose met JAK remmer, in bezit van Erasmus MC, niet gerelateerd aan het onderwerp myositis	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	Lid van Wereld Psoriasus Dag Commissie binnen de NVDV (vacatiegelden) Secretaris van de domeingroep Inflammatoire dermatosen binnen de NVDV (vacatiegelden)	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.	Has received research grants for the independent research fund of the department of dermatology of the Radboud university medical centre Nijmegen, the Netherlands from AbbVie, Novartis, Janssen Pharmaceutica and Leo Pharma. Has acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis including AbbVie, Janssen Pharmaceutica, Novartis, Lily, Celgene, Leo Pharma, UCB and Almirall 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)	Plaatsvervangend voorzitter Commissie Buitenlands Gediplomeerden Volksgezondheid (CBGV), ministerie van VWS, en lid CBGV, commissie artsen 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)	Als patiënt (vertegenwoordiger) betrokken bij diverse, onbetaalde projecten op gebied van myositis, reumatische ziekten in het algemeen (EULAR en OMERACT ReumaZorg Nederland, Reuma Nederland) en spierziekten (Spierziekten Nederland, Myositis Netwerk Nederland). Voor Prinses Beatrix Spierfonds lid van Gebruikers Commissie: vacatiegeld	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.	Subsidie Sanquin Plasma Products voor het uitvoeren van een fase-2 RCT naar het effect van Ivlg-add on Immediate studie (investigator initiated, IVIg behandeling bij therapie naive patienten). --> Financiering via Behring. Studie januari 2019 afgerond.	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).

GRADE	Definitie
High	there is high confidence that the true effect of treatment is close to the estimated effect of treatment; it is very unlikely that the literature conclusion will change clinically relevant when results of new large-scale research are added to the literature analysis.
Moderate	there is reasonable assurance that the true effect of treatment is close to the estimated effect of treatment; it is possible that the conclusion changes clinically relevant when results of new large-scale studies are added to the literature analysis.
Low	there is low certainty that the true effect of treatment is close to the estimated effect of treatment; there is a real chance that the conclusion will change clinically relevant when results of new large-scale research are added to the literature analysis.
Very low	Very low there is very low certainty that the true effect of treatment is close to the estimated effect of treatment; the literature conclusion is very uncertain.

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.

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