Treatment guidelines for idiopathic inflammatory myopathies in adults: a comparative review

Abstract

Myositis, or idiopathic inflammatory myopathy, encompasses a group of autoimmune diseases with broad-spectrum clinical presentations, with a common presentation of muscle weakness and inflammation. The management of myositis presents significant challenges due to the rarity and variability of the disease and lack of large-scale, randomized controlled trials. Due to limited evidence available from smaller studies as well as variation in treatment practices across geographical regions and disease subtypes, available published treatment recommendations vary significantly. There is a need, therefore, to develop multidisciplinary consensus-driven guidelines that appropriately reflect the diverse and complex nature of the disease. This comparative review presents an in-depth analysis of existing myositis treatment guidelines from diverse organizations, highlighting similarities and key differences in diagnoses, treatment and management recommendations. We propose that there is a need for developing globally unified, consensus-driven standardized set of guidelines for effective myositis management.

Graphical Abstract

Rheumatology key messages.

• Challenges exist in the management of myositis, including a lack of standardized, internationally applicable treatment guidelines.

• Myositis treatment recommendations from organizations in the fields of rheumatology, dermatology and neurology are heterogenous.

• There is a need for updated evidence-based consensus treatment guidelines for different myositis subtypes.

Introduction

Idiopathic inflammatory myopathies (IIMs), or myositis, are a heterogeneous group of rare autoimmune disorders primarily affecting skeletal muscles [1]. Although the treatment landscape for myositis is expanding, challenges in disease management including poor understanding of disease pathogenesis and heterogeneity in disease diagnosis and classification exist [2, 3]. Mirroring the diagnostic heterogeneity, there is a congruent lack of standardized treatment guidelines and current treatment recommendations are supported by limited evidence. The treatment landscape includes broad off-label and limited on-label options that provide symptomatic relief/resolution without targeting disease-specific mechanisms [2, 4]. Nevertheless, efforts to evaluate new therapeutic approaches for myositis are intensifying, making it an opportune time to develop updated guidelines.

In this comparative review, we present an overview of myositis disease states and discuss currently available treatment guidelines/recommendations for myositis management in adults, their heterogeneity, and the need to develop interdisciplinary, rigorous and evidence-based guidelines.

Disease overview

Myositis is a group of systemic diseases characterized primarily by skeletal muscle involvement and progressive weakness. Extramuscular manifestations associated with myositis involve the skin, joints, lungs, gastrointestinal tract and heart [1, 2]. Variations in muscle and extramuscular involvement make clinical presentation complex and variable across subtypes [1]. Patients with myositis often experience a high disease burden, poor quality of life (QoL) and increased risk of mortality [1, 5–7]. Although available biomarkers provide some insights into disease presence and progression, there is a lack of myositis-specific biomarkers for treatment response and prognosis [1]. Multiple myositis-associated and myositis-specific autoantibodies (MSAs) have been identified that are useful in diagnosis, prognosis and may inform future treatment strategies, however MSAs may not be detectable in all myositis subtypes/patients [1, 8, 9].

Disease subtypes

Based on clinical, serological and pathological findings, the main subtypes of myositis are DM, immune-mediated necrotizing myopathy (IMNM), overlap myositis (OM), anti-synthetase syndrome (ASyS), IBM and PM (Fig. 1) [1, 10].

Figure 1.

Myositis subtypes: clinical and demographic characteristics. ^aCutaneous features include heliotrope, shawl sign, Gottron’s papules, etc. Autoantibody target molecules: CCAR1: cell division cycle and apoptosis regulator 1; cN1A: cytosolic 5′-nucleotidase 1A; EJ: glycyl-tRNA synthetase; YRS/HA: tyrosyl-tRNA synthetase; HMGCR: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; Jo1: anti-histidyl-transfer RNA synthetase; KS: asparaginyl-tRNA synthetase; Ku: Ku70/Ku80 DNA-binding protein; MDA5: melanoma differentiation-associated protein 5; Mi2: helicase protein; NXP2: nuclear matrix protein 2; OJ: isoleucyl-tRNA synthetase; PL7: threonyl-tRNA synthetase; PL12: alanyl-tRNA synthetase; PM/Scl: PM-scleroderma; Ro52: Ro52 polypeptide; SAE: small ubiquitin-like modifier activating enzyme; Sp4: specificity protein 4; SRP: signal recognition particle; TIF1γ: transcriptional intermediary factor 1 gamma; U1RNP: U1 ribonucleoprotein; ZO: phenylalanyl-tRNA synthetase; ADM: amyopathic dermatomyositis; ILD: interstitial lung disease

DM is the most common form of myositis, with characteristic muscle inflammation/weakness and cutaneous involvement [10, 11]. JDM has characteristic symptoms of adult DM with more frequent extramuscular manifestations [12]. Subtypes of DM/JDM include amyopathic DM (ADM), characterized by skin involvement with no muscle involvement, and hypomyopathic DM (HDM), characterized by muscle inflammation in the absence of clinical muscle weakness [13–15].

IMNM is characterized by severe proximal muscle weakness and myofibre necrosis with minimal infiltrate in muscle biopsy and less frequent extramuscular involvement [11, 16]. The two most common MSAs in IMNM are anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies. There are also reports of seronegative/autoantibody-negative IMNM [11, 16].

OM is characterized by acute/subacute weakness of arms and legs that may coexist with another autoimmune disorders [10]. ASyS, characterized by the presence of anti-transfer RNA synthetase autoantibodies, was traditionally categorized under OM [10, 17] or as a subtype of DM due to DM-overlapping cutaneous manifestations [18]. Although considered a separate myositis subtype by most of the experts, lack of a validated classification criteria for ASyS led to the Classification Criteria of Anti-Synthetase Syndrome (CLASS) project aimed at developing a validated criteria set for ASyS [19].

IBM is the most commonly acquired myositis subtype in patients >50 years, with distinct asymmetric onset of slow-progressing chronic symptoms [10, 20]. IBM is usually irregular or sporadic (sIBM) but may be inherited (hIBM) [20].

PM is the rarest form of myositis, characterized by chronic muscle weakness without skin involvement [1, 10]. It is often misdiagnosed due to its non-distinct clinical features [3]. As such, the classification of PM as a discrete subtype remains debatable and diagnosis is usually made by exclusion of other subtypes of myositis [1, 10].

Epidemiology

Myositis is classified as a ‘rare disease’, defined in the Federal Food, Drug and Cosmetic Act as any disease that affects <200 000 persons in the USA [21]. The incidence and prevalence of myositis varies with age, gender and geographical region [22]. While DM can affect both children and adults, other forms of myositis are predominantly observed in adults. DM, PM, OM and ASyS mainly occur in adults aged 45–60 years and IMNM and IBM typically occur in adults aged 50–60s years [22–25]. Men are more frequently affected by IBM while all other subtypes are more common in women [1, 22]. The incidence and prevalence of myositis is estimated to be in the range of 0.2–2 cases per 100 000 person-years and 2–25 cases per 100 000 persons, respectively [22]. However, the true burden of myositis may be obscured by evolving classification criteria and heterogeneity within different myositis subgroups [22, 26], lack of diagnosis/improper diagnosis due to clinical similarities with other rheumatic diseases [27, 28] and biases in patient identification based on diagnostic codes in studies using administrative healthcare claims databases [22, 29]. While mortality estimates/survival rates vary, the prognosis for myositis has improved with lower mortality rates over time for patients with DM or PM [30]. Generally, patients with myositis experience higher mortality compared with the general population. Comorbidities such as malignancies, cardiovascular diseases, interstitial lung disease and infections are predominant causes of death [30, 31].

Aetiology and risk factors

The aetiology of myositis remains unclear and the rarity and heterogeneity of the disease pose challenges in better understanding of the risk factors. Several intrinsic and extrinsic factors are implicated in disease pathogenesis including genetic and environmental risk factors, as well as immune and non-immune-mediated processes [32]. The human leucocyte antigen (HLA) ancestral haplotype HLA 8.1 has been identified as a key genetic risk factor in some myositis subtypes including DM, PM and IBM [32, 33]. Certain non-HLA loci have also been associated with disease including PTPN22 in PM, PLCL1 and BLK in DM, CCR5 in IBM, and STAT4, TRAF6 and UBE2L3 in different IIM subtypes [32–34]. Environmental risk factors may include infectious and chemical agents, dietary supplements, collagen and silicone implants and exposure to ultraviolet radiation and pollutants [32, 35–37].

Drug-induced risk factors include the use of statins and immune checkpoint inhibitors [32, 37].

Certain immune-mediated processes including cytokine activation (e.g. IFNs anti-TNF agents and chemokines) and autoantibody signalling (e.g. MSAs), as well as non-immune processes (e.g. cell-stress pathways, free radical damage, altered energy metabolism, protein homeostasis and mitochondrial damage) contribute to inflammation and muscle damage in myositis [32]. Certain malignancies (ovarian, breast, lung, gastrointestinal, pancreatic, cervical and colorectal cancers and Hodgkin’s lymphomas) are also associated with myositis pathogenesis [38–40].

Diagnosis

Since myositis is a rare disease with symptoms that overlap with other conditions (e.g. metabolic, genetic and mitochondrial myopathies), and due to the diversity within the myositis spectrum, accurate diagnosis and classification can be challenging [27]. The diagnosis of myositis requires a multifactorial approach involving comprehensive physical examination, evaluation of creatine kinase and aldolase levels, muscle strength examination, electromyography, skin and/or muscle biopsies and serological examinations including testing for the presence of MSAs associated with characteristic clinical features [24, 41]. MSAs are almost always mutually exclusive and fairly specific to myositis with rare occurrence in other conditions, adding value as a biomarker for diagnosis, classification and predicting disease progression [8, 24, 42]. However, autoantibodies have been identified in only ∼50% of patients with myositis [8]. Improved genetic and molecular techniques for autoantibody identification and correlation with clinical manifestation will likely enhance the accuracy of diagnosis.

Classification of myositis

Several classification criteria (Fig. 2) have been used to identify the subtypes of myositis [10, 43, 44]. Bohan and Peter put forth the first diagnostic and classification criteria for DM, JDM, PM and OM [45]. This was followed by modifications to the Bohan and Peter criteria and several other criteria, including classification proposed by Tanimoto et al. [46], Targoff et al. [47], Dalakas and Hohlfeld [12], the European Neuromuscular Center (ENMC) criteria by Hoogendijk et al. [48] and Troyanov et al. [49]. Despite the evolution of classification criteria over time, there are limitations such as overlap in exclusion criteria with other myopathies, non-inclusion of all subtypes of myositis and non-inclusion of autoantibodies as a criterion [26]. In 2017, EULAR/ACR developed the first validated classification criteria for adult and juvenile myositis to overcome some of these limitations. DM, ADM, PM, juvenile myositis and IBM were identified in these criteria [13]. None of the earlier diagnostic or classification criteria included ASyS except for a new classification scheme that was developed by Mariampillai et al. based on phenotypic, biological and immunologic criteria, which provided classification algorithms for DM, IBM, IMNM and ASyS [50]. The criteria by Mariampillai et al. [50] highlighted the importance of MSAs in classification.

Figure 2.

Classification criteria of myositis over time. ADM: amyopathic dermatomyositis; ASyS: antisynthetase syndrome; ENMC: European Neuromuscular Centre; IMNM: immune-mediated necrotizing myopathy

It is noteworthy that even the most widely used EULAR/ACR classification system has several limitations including insufficient evidence from patients with rare subtypes like IMNM, ADM and ASyS, inclusion of only one MSA (anti-Jo1), exclusion of muscle imaging results from the diagnostic algorithm and misclassification of patients due to overlapping symptoms with muscular dystrophies in some cases [43, 51, 52]. Current criteria may cause misclassification and need to be updated, e.g. by adding potential criteria for classifying skin-predominant DM in patients not meeting the EULAR/ACR criteria for ADM [53]. Given the diverse presentation of myositis subtypes, an updated and comprehensive classification system is needed based on combined data from clinical manifestations, histopathological findings and autoantibody profiles that provides valuable insights on myositis subtypes.

Current management of myositis

The main goals of myositis management are reduction in inflammation and improvement of skin symptoms (for DM), restoration of muscle strength, preventing damage to other organs, reduction of morbidity and improvement in QoL [25, 54]. Yet, numerous factors limit the management of myositis [55, 56]. Evidence-based treatment recommendations are limited by a lack of randomized controlled trials (RCTs). The involvement of extramuscular organs might narrow the range of treatment options. Patients with different myositis subtypes may show variable/no response to immunosuppressive therapies such as in the case of IBM. Disease subtypes like IMNM and ASyS, identified based on clinical features and MSAs, can be challenging to differentiate through symptomatic evaluation alone.

Consequent to the complexities in the management of myositis, no standardized guidelines are available and there are very few approved therapeutic options. Repository corticotropin injection (RCI) was approved by the Food and Drug Administration (FDA) in 1952 for the treatment of DM and PM [57]. Due to limited data on its effectiveness, RCI is not routinely used in the treatment of myositis [58]. Human IVIG was approved by FDA and the European Medicines Agency for the treatment of adult DM in 2021 [59, 60] but is associated with risk of thromboembolism and infusion-related adverse events [61]. The lack of inclusion of patients with ADM in the phase 3 IVIG trial [61] led to difficulties in using IVIG in these patients [62].

Current treatment strategies are supported by limited evidence and primarily rely on expert opinion and anecdotal evidence from case reports/series [4, 55]. Except for IBM, first-line treatment typically consists of high-dose glucocorticoids (GCs) such as prednisone, which are often combined with immunosuppressive agents (e.g. MTX or AZA). Second- and third-line options include MMF, tacrolimus, ciclosporin, CYC, RCI, rituximab or other biologics [4]. In cases of refractory response or severe cutaneous, muscular or respiratory manifestations, IVIG may be used [56]. For cutaneous manifestations or ADM, antimalarials like HCQ may be combined with immunosuppressive agents and minimal oral GCs [4]. With the advent of emerging therapeutic options with unique mechanisms of action, many agents are increasingly being used off-label (e.g. rituximab, abatacept, tocilizumab, etc.) and numerous ongoing clinical trials are exploring the use of other molecules including Janus kinase inhibitors and IFN-α and -β inhibitors, as well as molecules with other modes of action [63, 64]. Exercise and physical therapy are encouraged to improve muscle strength and prevent the deterioration of QoL [55].

No pharmacological treatment is available for IBM and corticosteroids and immunosuppressants provide only transient benefit [65, 66]. ENMC members to developed a protocol clinical guidelines on diagnosis and pharmacological and non-pharmacological treatment recommendations for IBM [67].

Available guidelines for myositis treatment

Challenges in the treatment of myositis arise from a dearth of targeted, approved treatment options and the use of treatments approved for other inflammatory conditions but inadequately studied in this disease. Treatment approaches are not standardized across disease or disease subtypes. Nevertheless, treatment recommendations are available from key regional/global organizations in the field of rheumatology, dermatology and neurology, and are valuable tools for healthcare providers and patients managing the disease. This section focuses on currently available guidelines, focusing on points of alignment and differences in treatment recommendations, especially for adult myositis. Published treatment guidelines identified through PubMed searches were reviewed and compared for myositis treatment recommendations. Of note, most guidelines are based on limited evidence and may not be followed globally.

In 1996, The American Academy of Dermatology published guidelines for the treatment of DM [68]. Key recommendations encompass pharmacological treatments including topical corticosteroids, systemic corticosteroids (prednisone), antimalarials (HCQ) and corticosteroid-sparing agents including MTX, AZA, CYC and ciclosporin. Non-pharmacological therapy includes physical therapy, photoprotection and adequate nutrition.

More recent treatment guidelines (Table 1) for adult myositis are available from the German Society of Neurology/German Society of Dermatology [69], the ENMC [70], the Brazilian Society of Rheumatology [71], the Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association [72] and the British Society for Rheumatology (BSR) [73]. Detailed treatment recommendations from each guideline are presented in Table 2, including pharmacological and non-pharmacological recommendations for skeletal muscle and skin manifestations, as applicable. For this review, we have focused specifically on guidelines available for adults with myositis. Of note, none of the guidelines provide recommendations for patients with IBM.

Table 1.

Guidelines for myositis treatment from different organizations

Guideline/organization	Disease indication	Population	Year of publication
German Society of Neurology/German Society of Dermatology [69]	DM, PM and IMNM	Adult and juvenile	2016
European Neuromuscular Center (ENMC) [70]	IMNM	Adult	2018
Brazilian Society of Rheumatology [71]	Myositis overall	Adult	2019
Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association [72]	DM and PM	Adult and juvenile	2019
British Society for Rheumatology (BSR) [73]	Myositis overall (excluding IBM)	Adult and juvenile	2022

IMNM: immune-mediated necrotizing myopathy.

Table 2.

Treatment recommendations (guidelines) for the management of myositis

Guideline/recommending organization	Disease subtype	Treatment recommendation	Quality of evidence
German Society of Neurology/German Society of Dermatology [69]	DM, PM and IMNM		NA
		(i) Skeletal muscle inflammation
		Treatment recommendations are divided into acute/initiation, maintenance and long-term therapy; moderate and severe case recommendations are provided
		Initial therapy: GCs (1–2 mg/kg/day of oral prednisone or other equivalent GCs for at least 2–4 weeks) for moderate disease; high-dose GCs [i.v. methyl prednisolone (500 mg/day for 3–5 days)] with addition of immunosuppressive agents [AZA (2–3 mg/kg/day), MTX (7.5 mg/week and gradually increased to 10–25 mg/week), ciclosporin (2.5–5 mg/kg/day), CYC (1–2 mg/kg/day), MMF (2 g/day), IVIG (2 g/kg divided over 2–5 days every month for a period of 6 months)] for severe disease
		Maintenance therapy: reduction of the corticosteroid dose to below the Cushing threshold (lowest dose) within 6 months
		Long-term therapy: combination of corticosteroids and an immunosuppressive agent for at least 1–3 years
		I.v. rituximab (2× 1000 mg at 14-day intervals) can be given in refractory/recalcitrant cases, although the benefits remain ambiguous
		IVIG use (1–2 g/kg every 1–2 months) is recommended for treatment resistant cases
		(ii) Skin manifestation
		Skin lesions should not be initially treated with immunosuppressive agents in cases of ADM or when patients exhibit only typical cutaneous DM symptoms with corresponding histopathological findings (and no SLE) and no muscle involvement
		GCs (1–2 mg/kg/day for at least 2–4 weeks) are recommended for the topical treatment of skin lesions
		Antimalarial agents [e.g. HCQ (200 mg/1–2 times/day)] are recommended for treating skin symptoms systemically, even when prior immunosuppressive treatments have proven ineffective. Efficacy may be improved by combining HCQ or chloroquine with mepacrine
		Therapies shown to be effective in the treatment of cutaneous symptoms include corticosteroids, MTX, IVIG and MMF (dosage same as that used for skeletal muscle manifestation) and stem cell transplantation
		For cutaneous calcinosis, systemic GCs pulse therapy is recommended
		(iii) Non-pharmacological therapy and/or QoL
		Regular physical therapy
		Sun protection for patients with DM
		Nutritional supplement—creatine monohydrate (limited evidence)
European Neuromuscular Center (ENMC) [70]	IMNM		NA
		(i) Skeletal muscle inflammation
		Treatment recommendations are based on biomarker antibodies: anti-SRP antibody for anti-SRP myopathy and anti-HMGCR antibody for anti-HMGCR myopathy; treatment algorithm focuses on recommendations based on disease severity
		Initial therapy/first-line treatment: oral high-dose GCs (1 mg/kg/day) or i.v. GCs (0.5–1 g/day for 3–5 days) with addition of oral or s.c. MTX (0.3 mg/kg/week) at the same time or within 1 month of initiating therapy. For anti-SRP and anti-HMGCR myopathy, rituximab (750 mg/m2) and IVIG (2 g/kg/month, 3–6 times), respectively, can complement or replace MTX in severe cases. AZA (3 mg/kg) or MMF (2–3 g/day) can be used in case of MTX intolerance or concern of hepatic dysfunction, respectively
		Maintenance therapy: tapering off oral corticosteroids to the lowest possible tolerated dose; tapering off or stopping IVIG; MTX/rituximab can be continued for at least 2 years for well-controlled disease
		Refractory disease: induction therapy, rituximab, plasma exchange, CYC or ciclosporin may be considered
		(ii) Skin manifestation
		NA
		(iii) Non-pharmacological therapy and/or QoL
		Individualized physiotherapy
Brazilian Society of Rheumatology [71]	Myositis overall		Degree of recommendationa
		(i) Skeletal muscle inflammation
		Initial therapy:
		Oral GCs (prednisone 0.5–1.0 g/kg/day for at least 4 weeks) are recommended with gradual dose reduction	C
		I.v. methylprednisolone pulse therapy (1 g/day for 3 consecutive days) followed by a high oral dose of GC should be considered in severe cases	C
		Remission
		Drug doses can be gradually reduced after disease remission starting with GC followed by immunosuppressive/immunomodulatory drugs (MTX, AZA, ciclosporin)	B
		Refractory disease:
		IVIG (2 g/kg divided over 2–5 days) alone or in combination with immunosuppressive agents	B, C
		Rituximab	B, C
		Abatacept (500–1000 mg depending on body weight) for 6 months [74]	B
		Tacrolimus (0.075 mg/kg/day); ciclosporin (3.5 mg/kg/day); tocilizumab (8 mg/kg every 4 weeks) [75]; i.v. CYC pulse therapy	C
		Anti-TNF agents are not recommended	C
		(ii) Skin manifestation
		In severe cases with ulcerated skin lesions, i.v. methylprednisolone pulse therapy (1 g/day for 3 consecutive days) followed by a high dose of oral GC is recommended	C
		Leflunomide appears effective and safe in refractory DM	C
		MMF (1.0–1.5 g twice a day) can be considered in refractory skin disease	C
		(iii) Non-pharmacological therapy and/or QoL
		Strength building and aerobic exercises should complement pharmacological treatments at all stages of the disease to enhance muscle performance and aerobic capacity	B
Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association [72]	DM and PM		Recommendation gradeb
		(i) Skeletal muscle inflammation
		First-line therapy:	B
		GCs recommended with immunosuppressants as first-line of treatment	B
		Prednisolone 0.75–1.0 mg/kg/day is recommended as initial treatment for remission induction of PM and DM	C1
		Patients with DM/PM can be treated with immunosuppressants like MTX (7.5–15 mg/week), AZA (50–100 mg/day), tacrolimus (5–10 ng/ml twice daily), ciclosporin A (100–150 ng/ml twice daily), MMF (1–3 g/day twice daily) in combination with GCs	B
		The addition of immunosuppressants can help in early tapering of GC doses	C1
		Treatment-resistant patients
		IVIG (1–2 g/kg/day) can be initiated in steroid-resistant patients with DM	B
		IVIG (1 g/kg/day) can be initiated in steroid-resistant patients with PM	C1
		Refractory disease:
		Increase the dose of prednisolone or addition of immunosuppressants, IVIG, biological agents (tocilizumab, abatacept, rituximab) or plasmapheresis	B
		Recommendations for the addition of:
		Immunosuppressants	B
		IVIG	B
		Tocilizumab	C1
		Abatacept	C1
		Rituximab	No grade
		TNF inhibitors	C2
		Plasmapheresis	C2
		(ii) Skin manifestation
		Administering systemic corticosteroids or immunosuppressants to patients with DM with skin-only manifestations is not advised. Instead, standard care involves observation or topical therapy with GCs	No grade
		Drugs recommended for severe skin symptoms—dapsone, HCQ, IVIG, MTX, MMF, ciclosporin, tacrolimus	C1
		(iii) Non-pharmacological therapy and/or QoL
		Rehabilitation during the chronic stage is likely effective for muscle strength recovery	B
British Society for Rheumatology (BSR) [73]	Myositis overall (excluding IBM)		Strength of recommendation, GRADE, SoAc
		(i) Skeletal muscle inflammation
		Induction or first-line therapy:
		High-dose GCs [oral prednisolone (0.5–1 mg/kg/day)] recommended for adults at the time of treatment induction	1, B, 100%
		I.v. methylprednisolone should be considered, especially when gastrointestinal absorption is a concern	2, B, 96%
		Oral prednisolone should be tapered according to clinical response	1, B, 100%
		DMARDs (MTX, AZA, tacrolimus, ciclosporin and MMF) should be used to reduce muscle inflammation, achieve clinical remission and reduce steroid burden	1, C, 100%
		MTX, AZA, tacrolimus, ciclosporin and MMF to be considered for treating active myositis and maintaining long-term disease remission	2, C, 96%
		Refractory disease:
		IVIG/CYC to be considered for severe and/or refractory myositis	1, B, 100%
		Rituximab to be considered for refractory myositis in patients showing positive myositis autoantibodies and patients with lower burden of disease damage	2, A, 100%
		Abatacept to be considered for refractory myositis	2, B, 100%
		(ii) Skin manifestation
		Rituximab to be considered when skin disease remains unresponsive to GCs/conventional DMARD-based immunosuppression	2, B, 100%
		IVIG to be considered when skin disease remains unresponsive to GCs/conventional DMARD-based immunosuppression	1, B, 100%
		Avoid sun exposure and regularly using high-factor, broad-spectrum sunscreen to reduce the likelihood of a disease flare	2, C, 100%
		(iii) Non-pharmacological therapy and/or QoL
		Inclusion of a supervised exercise program led by specialized physiotherapists and/or occupational therapists should be included to enhance the QoL and functionality in myositis management	1, B, 100%
		Routine assessment of psychological well-being and health-related QoL	1, B, 100%
		Routine assessment of psychiatric comorbidities	1, C, 92%
		Addressing factors having a detrimental effect on health-related QoL such as skin involvement, pruritus and adverse effects of steroids	1, C, 96%
		Promoting customized exercise and/or rehabilitation strategies to enhance psychological well-being	1, B, 96%

^aDegree of recommendation for evidence: A = consistent level 1 studies; B = consistent level 2 or 3 studies or extrapolations from level 1 studies; C = level 4 studies or extrapolations of level 2 or 3 studies; D = level 5 evidence or studies of any level with inconsistency; or inconclusiveness. The categories/levels were defined as: 1a = systematic review and RCT meta-analysis; 1b = at least one RCT with narrow confidence interval; 2a = systematic review and meta-analysis of cohort studies; 2b = at least one cohort study or low quality RCT; 3a = systematic review and meta-analysis of case–control studies; 3b = at least one case–control study; 4 = at least one case series or cohort study and low-quality case–control studies; 5 = expert opinion without critical evaluation explicit or based on physiology, bench research or ‘fundamental principles’.

^bRecommendation grades (as established by Medical Information Network Distribution Service, Japan, in 2007) were classified as: A = strongly recommended for use in clinical practice because of strong scientific evidence; B = recommended for use in clinical practice because of some scientific evidence; C1 = can be considered for use in clinical practice; C2 = should not be considered for use in clinical practice because of no scientific evidence; D = recommend against use in clinical practice because of some scientific evidence. The levels of evidence were given as: I = systematic review or RCT meta-analysis; II = RCT; III = nonrandomized comparative study; IVa = cohort study; IVb = case–control and cross-sectional studies; V = case report and case series; VI = expert opinion.

^cThe Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology was used for categorizing each reference quality as A = high; B = moderate; C = low/very low. Strength of recommendation: 1 = strong; 2 = conditional. The strength of agreement (SoA) for the finalized recommendations was established using a simple binary voting approach for each voter and is depicted as a percentage. Only recommendations with an SoA exceeding 80% were incorporated into the guideline. ADM: amyopathic DM; GC: glucocorticoid; HMGCR: 3-hydroxy-3-methylglutaryl coenzyme A reductase; IBM: inclusion body myositis; IMNM: immune-mediated necrotizing myopathy; NA: not applicable; QoL: quality of life; RCT: randomized controlled trial; SRP: signal recognition particle.

German Society of Neurology/German Society of Dermatology

The German Society of Neurology in collaboration with members of the German Society of Dermatology developed interdisciplinary S2k guidelines (consensus-based) on myositis syndromes [69]. The guidelines provide detailed treatment recommendations for cutaneous symptoms in DM as well as other myositis subtypes including DM, PM and IMNM. Treatment recommendations are separated temporally and include initial therapy, maintenance therapy, long-term therapy as well as non-pharmaceutical therapy. Overall, GCs (1–2 mg/kg body weight) are favoured as initial therapy for at least 2–4 weeks in combination with additional immunosuppressive therapy (e.g. AZA). IVIG is recommended in case of insufficient therapeutic response, whereas the benefit of rituximab remains uncertain. Initial/acute therapy is usually followed by low-dose maintenance therapy with GCs after at least 6 months. After clinical stabilization, long-term therapy with a combination of low-dose GCs and an immunosuppressant is needed for 1–3 years or longer. For skin lesions, UV protection, topical corticosteroids and calcineurin inhibitors (e.g. tacrolimus 0.1%) are recommended. Systemic treatment for cutaneous symptoms includes antimalarial agents, corticosteroids, MTX, IVIG, MMF and stem cell transplantation.

ENMC

The 224th ENMC international workshop (14–16 October 2016, Zandvoort, The Netherlands) report, published in 2018, provided possible treatment recommendations for IMNM [70] based on the opinion of 18 experts. This is the only guideline to provide treatment recommendations based on autoantibody data and highlights the utility and relevance of measuring MSAs including anti-SRP and anti-HMGCR. A consensus was reached on subdividing IMNM into three distinct subtypes: anti-SRP myopathy, anti-HMGCR myopathy and antibody-negative IMNM. For both anti-SRP and anti-HMGCR myopathy, initial treatment consists of high-dose oral GCs (1 mg/kg/day) or i.v. GCs (0.5 g–1g/day) for 3–5 days along with the addition of another agent (e.g. MTX) at the same time or within 1 month (based on severity and treatment response) of starting GCs. Rituximab (for anti-SRP myopathy) and IVIG (for anti-HMGCR myopathy) could be added instead of, or along with, MTX within 6 months of treatment initiation. Initial treatment of seronegative IMNM and anti-HMGCR myopathy is similar. Maintenance therapy consists of tapering GCs to the minimum dose and continuing MTX and other agents (rituximab/IVIG) for at least 2 years. Individualized physiotherapy is recommended for every patient. This guideline is limited by the lack of clinical trials and a uniform definition of IMNM in literature.

Brazilian Society of Rheumatology

The Myopathy Committee of the Brazilian Society of Rheumatology has developed guidelines for the treatment of systemic autoimmune myopathies [71]. The Brazilian guideline provides treatment recommendations for adult DM and PM based on review of literature through June 2018. This guideline provides 10 recommendations and has segregated treatment into initiation, remission and refractory therapy and provides the degree of recommendation based on the category of evidence for the study. The treatment algorithm recommends starting with GCs as initial therapy followed by combining low-dose GCs with immunosuppressive/immunomodulatory agents (or IVIG when immunosuppressants are contraindicated). For refractory cases, IVIG, rituximab, abatacept or tocilizumab may be used. Early rehabilitation programs consisting of exercise and education to patients and caregivers are recommended.

Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association

In 2018, Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association established a multidisciplinary treatment consensus for the management of DM and PM [72]. A decision tree was made based on consensus amongst rheumatologists, neurologists and dermatologists that address 23 clinical questions to make recommendations (graded based on the level of evidence). Photoprotection and topical treatment for skin symptoms only and systemic treatment for severe cases are recommended. For patients with muscle involvement, high-dose GCs (1 mg/kg bodyweight) or intermediate-dose GCs (0.5 mg/kg bodyweight) in combination with an immunosuppressant are recommended. GCs can be tapered off if the patients respond well; otherwise, addition or change of immunosuppressants and/or IVIG are recommended.

The British Society for Rheumatology

The BSR provides evidence-based recommendations for the diagnosis, classification and treatment of myositis overall, excluding IBM [73]. The BSR guideline is the most rigorous guideline to date for paediatric, adolescent and adult patients with IIM. The recommendations, based on 213 publications, were developed by an expert working group comprising members across a multidisciplinary team and graded based on quality of body of evidence [Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology], strength of recommendation and strength of agreement. For skeletal muscle inflammation, high-dose GCs are recommended at the time of treatment induction. For refractory myositis, IVIG, CYC, rituximab and abatacept can be considered. IVIG or rituximab should be considered when skin disease remains unresponsive to GCs/DMARDs-based immunosuppression. In England, IVIG, rituximab and abatacept are commissioned to be prescribed by National Health Service (NHS) England in refractory disease [76–78]. In Scotland, IVIG is considered appropriate for use by NHS Scotland in patients with resistant/aggressive disease [79]. Exercise and psychological well-being are recommended as an integral part of effective disease management. The guideline emphasizes the importance of taking ethnicity into consideration when evaluating patients and recommending treatment options since clinical manifestations, associated autoantibodies and underlying risk factors may differ based on ethnicity. However, this guideline is also constrained by the limited high-quality evidence from controlled clinical trials.

Key similarities and differences among the treatment guidelines

Similarities across guidelines

As detailed previously, systemic GCs are recommended by all guidelines for primary treatment. Immunosuppressants in combination with GCs are recommended early in the disease (1–6 months) by most guidelines. Maintenance therapy recommendations consist of tapering off GCs to the minimum dose and continuing immunosuppressants for 1–3 years. IVIG and biologics like rituximab and abatacept are considered for refractory/severe cases. Sunscreen is recommended for the prevention of DM-related skin lesions. Topical GCs are recommended by most guidelines for the treatment of skin lesions. Physical therapy and rehabilitation are important components of the disease management plan.

Major differences across guidelines

Muscle

Although all guidelines recommend the use of GCs and addition of immunosuppressants for muscle inflammation, variations exist in the dosing and duration of treatment, as summarized in Table 2. Differences also exist in recommendations for muscle manifestations in refractory disease. The European, British and Brazilian guidelines recommend using IVIG in refractory cases [70, 71, 73], while the Japanese and German guidelines recommend using IVIG in refractory as well as treatment-resistant cases [69, 72]. In Scotland, IVIG is recommended for patients with resistant or aggressive disease [73, 79]. Plasmapheresis/plasma exchange is recommended by the Japanese and European guidelines for refractory muscle disease. Interestingly, the Brazilian guidelines recommend not using TNF inhibitors for refractory disease [71] as no significant treatment effect was observed with their use [80, 81].

Skin

Skin disease is generally managed by sun-protective measures, topical agents and systemic medications, based on severity. German and Japanese guidelines recommend treating ‘skin-only manifestations’ with systemic GCs or immunosuppressants only for severe cases and topical GCs for non-severe skin lesions [69, 72]. Some therapies are specifically recommended in certain guidelines, e.g. for severe skin symptoms, dapsone is recommended in the Japanese guidelines. Despite the lack of quality evidence for the use of topical agents for IIM-specific skin manifestations in the British guidelines, topical tacrolimus and glucocorticoids may be considered with dermatologist’s input [73].

Stepwise treatment plan

Proposed treatment algorithms, including a stepwise treatment plan, are provided by the Japanese, Brazilian and European guidelines; however, these vary across the recommendations [70–72]. The Japanese algorithm is based on presence or absence of skin symptoms, whereas the Brazilian and European algorithms are based on the phase of treatment and the presence of specific biomarkers, respectively [70–72]. While all guidelines provide recommendations for first-line therapy and refractory disease, Brazilian guidelines segregate the recommendations into initiation, remission and refractory therapy [71], and German guidelines segregate recommendations into initiation, maintenance and long-term therapy [69].

Treatment guidelines and recommendations for myositis-associated complications and juvenile myositis

There are some additional guidelines for myositis-associated complications and juvenile myositis, which are beyond the scope of this review and not discussed in detail here. Recommendations for the management of myositis-associated complications including interstitial lung disease, malignancy, dysphagia and cardiovascular disease are provided by BSR [73], ACR [82], the Japanese Respiratory Society and the Japan College of Rheumatology [83], the Spanish Rheumatology Society and Spanish Society of Internal Medicine [84] and the Korean guidelines [85]. Treatment recommendations for JDM are published by the Childhood Arthritis and Rheumatology Research Alliance in North America [86–89], Single Hub and Access Point for Paediatric Rheumatology in Europe [90], The JDM working group of the Society for Paediatric Rheumatology in Germany and Austria [91], The Reference Centre for Childhood Inflammatory Rheumatism and Rare Systemic Diseases in France [92], The Paediatric Rheumatology Association of Japan and The Japan College of Rheumatology in Japan [15] and The Paediatric Rheumatology International Trials Organisation [93].

Challenges in developing standardized treatment guidelines

The management of myositis is complex due to the systemic nature of the disease with multi-organ involvement and overlapping CTDs posing a significant challenge while developing consensus-based treatment guidelines. Currently used therapies are generally approved for other inflammatory conditions and therefore aim for symptom control without targeting specific underlying disease mechanisms. Although multiple RCTs are currently ongoing with molecules targeting distinct mechanisms that are thought to drive myositis [2, 63], there are unique challenges in designing clinical trials in myositis. These include presence of various disease subtypes, insufficient patient enrolment, misdiagnosis due to overlapping symptoms with other inflammatory diseases, ambiguous disease classification criteria, under-representation of minority groups and limited data on patient-reported outcomes [3, 94]. Nevertheless, the explosion of clinical trials in myositis is promising and may inform future treatment guidelines.

The heterogeneity in recommendations from currently available treatment guidelines developed by diverse, international organizations in the field of rheumatology, dermatology and neurology necessitate the development of multidisciplinary and internationally aligned consensus treatment guidelines. Such a consensus will be crucial to ensure that patients receive the most effective treatment to manage the disease. The availability and access to myositis treatment options varies geographically, underscoring the need for strong international collaboration to develop consensus treatment guidelines that are evidence-based and informed by global clinical experience [95].

Conclusions and future perspectives

Available treatment guidelines for myositis are based on limited evidence and are heterogeneous. There is an unmet need to develop rigorous evidence-based consensus treatment guidelines with clear treatment algorithms for different myositis subtypes. While more research is needed, non-pharmacological treatment options including diet and QoL should be addressed in future guidelines to achieve holistic disease management strategies. Furthermore, future guidelines involving multidisciplinary groups or patients may help to personalize treatment decisions based on patients’ specific condition and response to therapy, likely resulting in improved prognosis and QoL outcomes in patients with myositis.

Data availability

No new data were generated or analysed in support of this research.

Contribution statement

J.J.P. Conceptualization, Writing—Review & Editing; V.P.W.: Writing—Review & Editing; H.C.: Writing—Review & Editing; K.R.M.: Writing—Review & Editing; A.J.: Conceptualization, Writing—Original Draft, Writing—Review & Editing; F.H.: Data curation, Writing—Original Draft; C.E.B.: Writing—Review & Editing; D.A.G.: Conceptualization, Project Administration, Writing—Original Draft, Writing—Review & Editing. All authors approved the final version to be submitted for publication.

Funding

This work was supported by Pfizer Inc.

Disclosure statement: J.J.P. received consulting fees from Pfizer Inc., EMD Serono, Argenx, Alexion, Kezar Life Sciences, Roixvant and Novartis; received clinical trial or research support from Priovant, Alexion, Kezar Life Sciences, EMD Serono and Argenx; received royalty from UpToDate; and serves on the Data Safety Monitoring Board for Cabaletta Bio. V.P.W. received honoraria from Janssen, Eli Lilly, Pfizer Inc., Biogen, BMS, Gilead, Amgen, Nektar, Incyte, EMD Sorona, CSL Behring, Crisalis, Viela Bio, Argenx, Kyowa Kirin, Regeneron, AstraZeneca, Abbvie, Octapharma, GSK, Cugene, UCB, Corcept, Beacon Bioscience, Rome Pharmaceuticals, Horizon, Merck, Kezar, Sanofi, Bayer, Akari, Calyx, Cabaletta Bio, Nuvig Pharmaceuticals and Takeda; and received grant support from Celgene, Janssen, Pfizer Inc., Biogen, Gilead, Corbus Pharmaceuticals, Genentech, AstraZeneca, Viela, Syntimmune, Amgen, Regeneron, Argenx, CSL Behring, Ventus, q32 Bio, BMS, Horizon, Rome Pharmaceuticals and Priovant. H.C. received grant support from Pfizer; received speaker honoraria from GSK and UCB; received consulting fees from PTC Therapeutics; and serves as the advisory board member for AstraZeneca and Pfizer and as the Data and Science Monitoring Board chair for Horizon Therapeutics. His work is supported by the National Institution for Health Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. K.R.M. was a Pfizer employee at the time of manuscript conceptualization and drafting and is a shareholder of Pfizer Inc. and Abbvie. F.H. and A.J. have no conflicts of interest to declare. C.E.B. was a Pfizer employee at the time of manuscript conceptualization and drafting and is a shareholder of Pfizer Inc. D.A.G. is a shareholder and employee of Pfizer Inc.