Targeted Therapy for Idiopathic Inflammatory Myopathy.

Introduction

Idiopathic inflammatory myopathies (IIM), commonly referred to as myositis, are a heterogeneous group of autoimmune diseases characterized by chronic muscle inflammation and progressive muscle weakness. The incidence of IIM is estimated to range from 0.2 to 2 cases per 100 000 person‐years, with a prevalence of 2–25 cases per 100 000 person‐years [ 1 ]. The clinical manifestations of IIM are diverse, ranging from muscle weakness to systemic involvement, such as interstitial lung disease (ILD) and skin lesions, which significantly impair patients' quality of life. On the basis of clinical, histological and serological features, IIM can be divided into dermatomyositis (DM), anti‐synthetase syndrome (ASS), immune‐mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), polymyositis (PM) and overlap myositis [ 2 ]. Despite advances in understanding the pathogenesis of IIM, the exact aetiology remains unclear.

Traditional management of IIM has relied on high‐dose glucocorticoids and immunosuppressants. While these therapies can relieve symptoms in many patients, a substantial subset continues to present with refractory or relapsing disease, with some even experiencing long‐term sequelae and significant functional impairments, which pose a major challenge in clinical management. These findings have laid the foundation for targeted therapies for IIM, offering the potential for more precise and effective treatment by targeting specific cells, molecules or signalling pathways.

Currently, targeted therapies for IIM include B‐cell‐targeted therapies, T‐cell‐targeted therapies, cytokine inhibitors, JAK inhibitors, proteasome inhibitors and emerging approaches such as CAR‐T‐cell therapy, BiTE and low‐dose IL‐2 therapy. The targeted therapies discussed in this article have been systematically categorized and summarized in Table 1 , which provides a clear comparison of their respective mechanisms of action, clinical efficacy, safety profiles and levels of evidence, with corresponding references appropriately cited. These strategies have demonstrated promising results in clinical trials and real‐world studies. They aim to modulate specific immune pathways associated with IIM, with the hope of benefiting patients with refractory disease. This article contains a summary diagram summarizing the mechanisms and targets of targeted therapy for IIM (Figure 1 ). However, variable responses among different IIM subtypes, long‐term safety issues and the high cost of some therapies remain unresolved challenges.

This review aims to provide a comprehensive overview of the latest advancements in targeted therapies for IIM, focusing on their mechanisms of action, clinical efficacy, safety profiles and future research directions. By summarizing the existing evidence and identifying research gaps, we hope to contribute to the ongoing quest for more effective and personalized treatment options for this challenging disease group.

B/Plasma Cell–Targeting Therapies

Rituximab (RTX) is a chimeric murine/human anti‐CD20 monoclonal antibody that depletes B cells through complement‐dependent cytotoxicity, antibody‐dependent cellular cytotoxicity and the induction of programmed cell death [ 3 ]. RTX reduces muscle‐infiltrating CD19+ B cells and CD68+ macrophages, thereby attenuating Type I IFN signatures and demonstrating therapeutic potential in refractory IIM.

In a randomized, double‐blind phase IIb trial, RTX and cyclophosphamide showed comparable efficacy in treating connective tissue diseases with ILD, including IIM, with fewer adverse events observed in the RTX group [ 4 ]. A prospective cohort study of patients with refractory active IIM revealed significant clinical improvement in PM but variable responses in DM. While some DM patients experience marked improvements in skin and muscle symptoms, others show no substantial changes in refractory skin lesions or muscle strength [ 5 , 16 ]. In patients with severe refractory ASS, combination therapy with RTX and mycophenolate mofetil improved muscle enzyme levels, myocarditis and pulmonary function with a favourable safety profile [ 6 ]. Furthermore, RTX was effective in both anti‐synthetase antibody‐positive and antibody‐negative IIM, with a notable glucocorticoid‐sparing effect in anti‐synthetase‐positive patients [ 7 ]. Another study confirmed that RTX could reverse lung function decline in ASS‐associated ILD patients, with stable pulmonary function maintained during 2 years of maintenance therapy [ 8 ]. RTX has also shown efficacy in anti‐MDA5 antibody‐positive DM and juvenile DM (JDM) patients. After 12 months of RTX treatment, all patients discontinued glucocorticoids, with improvements observed in pulmonary, skin, and muscle symptoms [ 9 ].

With respect to treatment timing, RTX was found to be more effective in treatment‐naive IIM patients than in those with refractory disease, with early initiation associated with better outcomes [ 10 ]. In pregnant patients with IIM, RTX should be administered during early pregnancy to avoid the risk of neonatal B‐cell depletion and cytopenias [ 11 ]. In terms of dosage, studies have indicated that 1 g × 2 doses and 500 mg × 2 doses provide comparable efficacy, with both demonstrating glucocorticoid‐sparing effects, although the long‐term efficacy of low‐dose RTX requires further investigation [ 12 ]. A meta‐analysis of response rates to RTX reported a pooled complete response rate of 45% ( n = 121), a partial response rate of 39% ( n = 44) and an overall response rate of 65% ( n = 480). The estimated incidence of adverse events was 18% ( n = 135) [ 13 ].

Common adverse events associated with RTX include fever, rash, cytopenia, hypotension, back pain, arthralgia and myalgia [ 14 ]. Additionally, given the greater association between DM and malignancies, RTX treatment may delay cancer diagnosis, necessitating vigilance for potential risks [ 15 ].

Overall, RTX demonstrates significant efficacy and safety in the treatment of IIM and associated ILD, making it an ideal option for refractory IIM patients. RTX has been approved by NHS England for IIM and is recommended by the British Society for Rheumatology (BSR) and the American College of Rheumatology (ACR) for refractory IIM.

Obinutuzumab is a glycoengineered, humanized anti‐CD20 monoclonal antibody currently approved by the Food and Drug Administration(FDA) for the treatment of follicular lymphoma and chronic lymphocytic leukaemia. Compared with RTX, it exhibits enhanced complement‐dependent cytotoxicity and antibody‐dependent cellular cytotoxicity, along with reduced immunogenicity. This agent has recently been applied in the management of IIM. A case series described five patients with refractory IIM—two with ASS, one with DM, one with overlap myositis, and one with systemic lupus erythematosus (SLE)/DM overlap—four of whom had hypersensitivity to RTX and one who had previously failed RTX therapy. Following obinutuzumab treatment, respiratory symptoms improved, and pulmonary imaging and pulmonary function tests remained stable. In another case of refractory anti–Jo‐1 ASS, improvements in myalgia, muscle strength, and creatine kinase levels were observed after one cycle of obinutuzumab. The aforementioned case reports demonstrated no significant adverse reactions, indicating the favourable safety profile of obinutuzumab. This agent shows considerable promise in treating patients with a suboptimal response to RTX [ 17 , 19 , 20 ].

Ocrelizumab, another humanized anti‐CD20 antibody, is FDA‐approved for multiple sclerosis. It was used in a refractory ASS patient without significant clinical benefit, but subsequent treatment with anti‐CD19 chimeric antigen receptor (CAR)‐T‐cell therapy led to improvement. Thus, the role of ocrelizumab in IIM remains to be further elucidated [ 25 ].

Daratumumab, a monoclonal antibody that targets CD38, exerts its effects by targeting not only B cells but also plasma cells. Emerging evidence suggests its potential efficacy in patients with severe clinical courses of anti‐MDA5 DM and anti‐SRP IMNM. Furthermore, daratumumab may represent a promising therapeutic option for IBM patients with anti‐cytosolic 5′‐nucleotidase 1A (cN1A) antibodies, warranting investigation in future studies [ 95 , 96 , 97 , 98 , 99 ].

B‐cell‐activating factor (BAFF) plays a critical role in B‐cell survival and maturation. Elevated serum BAFF levels are associated with various autoimmune diseases, including DM, PM, and IBM [ 21 , 22 ]. Belimumab, a BAFF inhibitor, improves myositis symptoms by reducing serum BAFF levels. A retrospective study revealed that belimumab alleviates muscle pain and fatigue in refractory DM and JDM patients, with significant improvements in subcutaneous ulcers and calcinosis and no severe adverse events reported [ 23 ]. However, in a multicenter randomized controlled trial, no significant clinical differences were observed between the belimumab and placebo groups, indicating the need for further validation of the efficacy of belimumab in patients with IIM [ 24 ].

In summary, the safety profiles of B‐cell‐targeting agents require careful evaluation. RTX may induce infusion‐related reactions, increase the risk of infections and lead to adverse events, including cytopenias. Although preliminary data suggest a favourable safety profile for obinutuzumab, its potent B‐cell‐depleting activity could theoretically increase infection risk. By targeting plasma cells, daratumumab profoundly suppresses humoral immunity. Therefore, a comprehensive risk–benefit assessment, including screening for latent infections and verification of immunization status, is essential before initiating treatment.

CAR‐T‐Cell Therapy

CAR‐T‐cell therapy involves collecting T cells from individuals and genetically engineering them to express CARs that recognize target cells. After expansion, these CAR‐T cells are reinfused into patients, where they specifically target and proliferate to exert cytotoxic effects. Originally developed for the treatment of B‐cell malignancies, CAR‐T‐cell therapy has recently been explored for the treatment of autoimmune diseases because of the critical role of B cells in disease pathogenesis. In patients with inflammatory myopathies, although RTX‐mediated B‐cell depletion has shown significant efficacy, some cases remain refractory, possibly because of incomplete depletion of plasma cells and tissue‐resident B cells. Therefore, CAR‐T‐cell therapy has been used as a potential treatment option for IIM.

In IIM, CD19 CAR‐T‐cell therapy has been successfully applied in several patients with refractory ASS, resulting in marked improvement in both muscle and extramuscular manifestations, with sustained drug‐free remission during follow‐up, with the longest follow‐up period reaching 18 months [ 25 , 26 , 27 ]. Another study proposed combining CAR‐T‐cell therapy with T‐cell suppression (Mycophenolate mofetil，MMF) to induce sustained drug‐free remission in patients with ASS [ 28 ]. Both CD19 and BCMA CAR‐T‐cell therapies have shown promising efficacy in treating refractory IMNM [ 29 , 30 ]. Recently, the first case of JDM treated with CD19 CAR‐T‐cell therapy was reported, showing gradual improvement in both muscle and skin involvement. Sustained drug‐free remission in IIM following CAR‐T‐cell therapy is hypothesized to result from complete B‐cell depletion and subsequent reconstitution of a B‐cell system lacking pathogenic B cells [ 31 ]. Given the high cost and complex manufacturing process of autologous CAR‐T‐cell therapy, allogeneic CAR‐T‐cell therapy has been explored in patients with IMNM, resulting in significant clinical improvement and B‐cell depletion without graft‐versus‐host disease [ 30 ]. However, a recent case report described a patient with refractory AAS who achieved disease remission following treatment with CD19‐directed CAR‐T‐cell therapy; however, disease relapse occurred 9 months later. Reinfusion of the same CAR‐T‐cell mixture failed to induce expansion. This case highlights the ongoing challenges associated with CAR‐T‐cell reinfusion [ 32 ].

Additionally, CAR‐T‐cell therapy has demonstrated favourable safety and tolerability profiles in IIM patients. Common adverse events include leukopenia, mild cytokine release syndrome (CRS), immune effector cell‐associated neurotoxicity syndrome (ICANS) and infections, with no life‐threatening adverse reactions observed to date. CRS and ICANS require management according to clinical guidelines. Regular monitoring of immunoglobulin levels with replacement therapy when indicated is essential during treatment. Furthermore, the long‐term immunological consequences and characteristics of potential late‐onset toxicities remain incompletely understood. To mitigate these risks, a comprehensive pretherapeutic assessment of organ function and infectious status, along with vigilant long‐term monitoring for signs of infection and haematological abnormalities, is imperative [ 33 ].

BiTE

The T‐cell engager teclistamab acts on T cells via CD3, and targets plasmablasts and plasma cells through BCMA. Teclistamab has demonstrated considerable efficacy in patients with multiple myeloma. In a case series, teclistamab was administered to four patients with autoimmune diseases who were resistant to multiple immunosuppressive agents, including RTX. This cohort included one patient with MDA5‐positive DM. Following treatment, the MDA5‐positive DM patient exhibited significant reduction in cutaneous inflammation and ulceration. During therapy, a transient peak in CRP and inflammatory cytokines was observed between Days 2 and 5, without the occurrence of severe adverse events. These findings suggest that BCMA‐targeted T‐cell engagers, represent a feasible therapeutic approach for patients with autoimmune disorders. Further exploration of such agents in the treatment of IIM may be warranted in the future [ 34 ].

T‐Cell–Targeting Therapies

Abatacept, a recombinant fusion protein of CTLA‐4, inhibits T‐cell activation by blocking the interaction between CD80/CD86 and CD28. It has been approved by the FDA for the treatment of rheumatoid arthritis in both adults and children [ 35 ]. Studies have shown that abatacept can increase the frequency of regulatory FOXP3+ T cells and promote the production of amphiregulin, which may facilitate myofiber regeneration [ 36 ]. In a murine C‐protein‐induced myositis (CIM) model, treatment with CTLA4‐Ig or anti‐CD80/86 antibodies effectively suppressed myositis, suggesting its potential therapeutic feasibility for myositis [ 37 ].

Clinical studies further support the application of abatacept in IIM. A study involving 20 patients with refractory DM ( n = 9) or PM ( n = 11) demonstrated that approximately half of the patients experienced a reduction in disease activity after 6 months of abatacept treatment [ 38 ]. Recently, a Phase Ⅲ randomized controlled trial evaluated abatacept in combination with standard therapy for active IIM. The results revealed that the abatacept and placebo groups had comparable safety profiles and similar proportions of patients meeting the International Myositis Assessment and Clinical Studies (IMACS) improvement criteria at 24 weeks. Subgroup analysis revealed a greater proportion of patients who achieved improvement criteria in the non‐DM subgroup treated with abatacept, suggesting that abatacept may provide more sustained benefits for non‐DM subtypes [ 39 ]. Additionally, a retrospective study involving eight patients with ASS‐associated ILD revealed that abatacept alleviated symptoms in all patients without any observed treatment‐related adverse events [ 40 ]. Abatacept has also been explored in JDM. A clinical study of 10 JDM patients with moderate disease activity revealed that 9 patients met the disease improvement criteria at week 24. All core set measures (CSMs), except for muscle enzymes, improved from baseline, and a significant glucocorticoid‐sparing effect was observed. However, 11 Grade 2 or 3 treatment‐related adverse events were reported during the study [ 35 ]. Notably, calcinosis, which is common in JDM and significantly impacts patients' quality of life, may also be ameliorated with abatacept treatment [ 41 ].

In conclusion, current studies indicate the potential efficacy and safety of abatacept in the treatment of IIM. Further research is needed to explore its application in specific disease subtypes and optimize treatment strategies, aiming to improve disease remission rates while minimizing adverse events.

B‐ and T‐Cell–Targeting Therapies

Alemtuzumab, a humanized monoclonal antibody against CD52, depletes B and T cells by binding to CD52 on lymphocytes. In a refractory case of anti‐Jo‐1‐positive PM with ILD, a single cycle of the drug improved muscle symptoms and enabled glucocorticoid tapering but did not prevent respiratory decline, with the patient dying 1 year post‐treatment. This finding indicates that its role in IIM has not yet been proven and that therapy must be personalized according to organ involvement [ 42 ].

TNF Inhibitors

Tumour necrosis factor‐ α (TNF‐ α ) is a pleiotropic cytokine secreted by immune cells that is characterized by its potent proinflammatory activity and is involved in the pathogenesis of IIM. However, the application of TNF‐ α inhibitors in the treatment of IIM remains controversial.

In a case series, five patients with refractory DM were reported to experience disease exacerbation following the administration of etanercept [ 43 ]. In contrast, two randomized, double‐blind, placebo‐controlled trials demonstrated that etanercept facilitated glucocorticoid tapering, significantly slowed disease progression, and was well tolerated [ 44 ]. Another randomized, double‐blind, placebo‐controlled trial enrolled 12 patients with DM or PM presenting with muscle weakness. Compared with the placebo, the addition of infliximab to stable doses of immunosuppressants and glucocorticoids resulted in improved muscle strength [ 46 ]. Furthermore, a cohort study involving 60 JDM patients revealed that treatment with infliximab or adalimumab for at least 3 months improved both muscle and skin manifestations. Among these patients, those who switched from infliximab to adalimumab experienced further reductions in overall disease activity [ 47 ]. Infliximab has also been shown to be effective against calcinosis in refractory JDM patients [ 48 , 49 ]. Case reports suggest that adalimumab may be beneficial for DM patients with ILD who respond poorly to conventional therapies [ 100 , 101 ]. Similarly, early administration of infliximab in DM patients with acute interstitial pneumonia demonstrated favourable outcomes, indicating the potential therapeutic value of TNF‐ α inhibitors in the treatment of IIM‐associated ILD.

However, findings regarding the efficacy of TNF‐ α inhibitors are inconsistent. In a study involving 13 patients with refractory IIM, nine patients completed four infusions of infliximab, while the others discontinued treatment due to adverse events or the detection of malignancies. Follow‐up of the treated patients revealed persistent infiltration of T lymphocytes and macrophages, cytokine expression and increased Type I interferon activity in muscle biopsies after treatment, indicating a lack of therapeutic efficacy [ 50 ]. Another study revealed no significant improvement in patients with refractory JDM treated with etanercept, with some patients experiencing worsening of disease manifestations, such as aggravated rashes [ 102 ]. There have also been reports of TNF‐ α inhibitors inducing inflammatory myopathies in patients with other autoimmune diseases, such as rheumatoid arthritis [ 45 ].

The use of TNF‐ α inhibitors in IIM is complicated by a paradoxical risk of inducing or exacerbating autoimmune phenomena, including the onset of myositis. Additionally, they confer an elevated risk of serious infections, particularly opportunistic infections and reactivation of latent tuberculosis, necessitating rigorous screening and antimicrobial prophylaxis. The potential for increased malignancy risk, although not conclusively established in IIM populations, warrants caution. The benefit–risk balance must be carefully evaluated, with particular consideration given to the patient's specific clinical phenotype, prior history of malignancy, and comprehensive infectious disease screening. In summary, the efficacy of TNF‐ α inhibitors in IIM requires further validation through large‐scale randomized controlled trials.

IFN‐I Receptor Antagonist

Type I IFN (IFN‐I) is a critical pathway in the pathogenesis of IIM, contributing to disease progression by inducing endothelial cell and muscle fibre damage. Studies have demonstrated that IFN‐I‐induced sarcoplasmic MxA expression is significantly associated with the muscle disease activity of JDM patients [ 103 ]. Furthermore, the IFN‐I pathway has been implicated in the upregulation of MHC‐I in DM, which sustains autoimmune inflammatory responses. Additionally, IFN‐I exposure has been shown to cause muscle atrophy, accompanied by the upregulation of atrophy‐related genes, such as Atrogin‐1 and Murf‐1, suggesting that muscle atrophy in DM patients may be linked to the activation of the IFN‐I pathway.

Anifrolumab, a type I IFN antagonist, blocks IFN‐I activity by binding to subunit 1 of the type I IFN receptor. It has been approved for the treatment of systemic lupus erythematosus (SLE) and has shown preliminary evidence of efficacy in the treatment of IIM. In a case report, a 14‐year‐old girl with refractory disease who failed 6 years of treatment with tofacitinib and glucocorticoids showed significant improvement in skin rash within 72 h of the first infusion of anifrolumab, indicating the potential for rapid disease control [ 51 ]. Another multicenter retrospective study included seven patients with refractory DM, all of whom presented with predominant skin involvement, and three had a history of severe muscle damage. Significant improvement in skin disease activity was observed after anifrolumab treatment, with a mean reduction in the Cutaneous Disease Area and Severity Index (CDASI) score of 13.0 after two doses. The main adverse events were infections, including upper respiratory tract infections in two patients and peritonsillar abscess in one patient [ 52 ]. Concurrently, a case series involving four patients with refractory DM demonstrated the potential of anifrolumab in addressing refractory extramuscular manifestations, facilitating prednisone tapering, and enabling discontinuation of systemic therapy [ 53 ].

Therefore, anifrolumab shows promise in the treatment of refractory cutaneous manifestations of DM, although its efficacy and safety require further validation.

IL‐6 Receptor Antagonist

Interleukin‐6 (IL‐6) is closely associated with muscle inflammation and disease activity in patients with IIM. Tocilizumab is a monoclonal antibody that targets the IL‐6 receptor and was first used in 2011 in two patients with refractory ASS. Following treatment, both patients demonstrated significant improvements in joint, muscle, and pulmonary involvement. After more than 10 years of treatment, both patients remained in complete remission, indicating that IL‐6 inhibition might represent a long‐term therapeutic option for refractory ASS [ 54 ]. A patient with NXP2‐positive DM experienced recurrence of rash and edema after cyclophosphamide and methylprednisolone pulse therapy. After three cycles of tocilizumab, the patient showed marked improvement in rashes and recovery of muscle strength. After six cycles of treatment, there was no recurrence of rash or edema, and the dosage of glucocorticoids was gradually tapered [ 55 ]. An open‐label study involving 11 patients with refractory IMNM revealed that 63.6% of patients achieved significant clinical improvement on the basis of the 2016 ACR‐EULAR myositis response criteria following tocilizumab treatment. Baseline serum IL‐6 levels and the percentage of CD56‐positive muscle fibres were positively correlated with the total improvement score (TIS) after 6 months of treatment, potentially serving as predictive factors for the response to tocilizumab [ 56 ]. Tocilizumab has also been reported to be effective in patients with MDA5‐positive DM or JDM complicated by rapid‐progressive ILD (RP‐ILD) [ 57 , 58 ]. In a clinical study, six patients with anti‐MDA5‐positive DM complicating RP‐ILD who were refractory to conventional therapy received tocilizumab treatment. Significant improvements in respiratory symptoms and imaging findings were observed in five patients, indicating that tocilizumab may be a salvage therapy for patients with RP‐ILD refractory to intensive immunosuppressive regimens [ 59 ].

However, in a multicenter, randomized, double‐blind, placebo‐controlled trial involving 36 patients with refractory adult DM and PM, no significant difference in the TIS was observed between the tocilizumab and placebo groups at 24 weeks. Secondary endpoints, including time to improvement, time to worsening, changes in core set measures, safety outcomes, and glucocorticoid‐sparing effects, also showed no significant differences between the two groups. Since the randomized trial of tocilizumab in the treatment of refractory DM/PM failed to meet its primary endpoint, tocilizumab cannot be recommended as a routine treatment option. However, it may serve as an effective salvage therapy for patients with refractory ASS and MDA5‐positive DM complicated by RP‐ILD [ 60 ].

IL‐1 Receptor Antagonists

Elevated expression of IL‐1 α and IL‐1 β in muscle tissue has been confirmed in patients with DM and PM. IL‐1 contributes to disease pathogenesis by inducing the expression of inflammation‐related genes through receptor‐mediated signalling [ 104 ]. Anakinra, an IL‐1 receptor antagonist, reduces the levels of IL‐1 β in muscle fibres, thereby decreasing its colocalization with amyloid precursor protein. This subsequently reduces the deposition of β ‐amyloid and misfolded proteins, leading to disease amelioration [ 61 ]. In a preclinical study, a CIM model revealed significantly increased mRNA and protein levels of IL‐1 α , IL‐1 β and TNF‐ α in muscle tissue. Antagonism of the IL‐1 receptor effectively suppressed the development of myositis, suggesting the potential therapeutic application of IL‐1 receptor blockade in myositis treatment [ 62 ].

The clinical efficacy of anakinra has been further validated. An open‐label study involving 15 patients with refractory myositis demonstrated that seven patients achieved clinical responses after 12 months of anakinra treatment, with no significant adverse events observed. These findings highlight the favourable safety profile of anakinra [ 63 ]. The study also revealed that patients with higher extramuscular involvement scores were more likely to respond to anakinra. Additionally, case reports have shown that anakinra provides rapid and significant improvements in general and extramuscular manifestations in patients with refractory MDA5‐positive DM [ 64 ]. In another study, anakinra was administered to five patients with ASS, resulting in significant reductions in C‐reactive protein and troponin T levels. All patients achieved the major improvement criteria defined by the IMACS group, with no adverse events observed during follow‐up [ 65 ].

However, studies on IBM have shown limited efficacy. Four patients with biopsy‐confirmed IBM who received anakinra for an average of 7.7 months exhibited no improvement in muscle strength or stability [ 61 ]. Similarly, canakinumab, an IL‐1 β receptor antagonist, has demonstrated no significant efficacy in IBM patients [ 66 ].

In conclusion, anakinra may be effective for myositis, particularly in patients with prominent extramuscular involvement, but it is ineffective for the treatment of IBM. Further studies are needed to optimize its dosage and administration and evaluate its therapeutic efficacy.

Fc Receptor‐Targeting Therapies

Efgartigimod is a human IgG1 antibody fragment that binds to the neonatal Fc receptor (FcRn) and competitively inhibits the interaction between IgG and FcRn, thereby promoting the lysosomal degradation of IgG and reducing its recycling [ 67 ]. Currently, it is primarily used for the treatment of myasthenia gravis, where it significantly lowers the serum IgG levels of pathogenic acetylcholine receptor antibodies [ 68 ]. In a humanized mouse model of IMNM, efgartigimod effectively reduced circulating IgG levels, including pathogenic anti‐HMGCR IgG antibodies, prevented muscle fibre necrosis and promoted muscle fibre regeneration [ 67 ]. A subsequent clinical investigation enrolled seven patients with refractory IMNM who received efgartigimod treatment for 4 weeks. The results demonstrated a marked reduction in the serum IgG and anti‐HMGCR/SRP antibody levels compared with those at baseline, with four patients achieving clinical remission. Throughout the treatment period, only one adverse event, mild headache, was reported [ 69 ]. These findings indicate that efgartigimod has promising therapeutic potential and demonstrates favourable safety in the treatment of IIM.

JAK Inhibitors

JAK inhibitors are a class of small‐molecule targeted drugs designed to block the JAK/STAT signalling pathway by competitively binding to ATP, thereby suppressing proinflammatory cytokine activation, alleviating inflammation, and treating diseases [ 33 ]. The JAK family includes JAK1, JAK2, JAK3 and TYK2, with major drugs including tofacitinib, baricitinib, upadacitinib and ruxolitinib.

Tofacitinib

Tofacitinib reduces the levels of anti‐Jo1 autoantibodies, CXCL10, and CXCL13 in memory B‐cell cultures derived from patients with ASS. These findings position the JAK/STAT pathway as a promising novel therapeutic target for modulating B‐cell activity in IIM [ 70 ]. A retrospective study demonstrated that tofacitinib significantly improved skin symptoms in patients with classic DM and amyopathic DM (ADM) but had limited effects on muscle strength in patients with DM or PM; individual patients may experience adverse reactions such as viral infections, EBV‐positive central nervous system lymphoma, and severe headache [ 71 ]. A prospective open‐label study involving 10 patients with refractory active DM revealed that all participants met the disease improvement criteria defined by the IMACS at week 12 [ 72 ]. A Chinese study revealed that, compared with conventional therapy, tofacitinib combined with glucocorticoids improved the 6‐month survival rate in MDA5‐positive DM patients with ILD. Additionally, serum ferritin levels, forced vital capacity (FVC), single‐breath diffusing capacity for carbon monoxide and high‐resolution CT findings were significantly improved, with most adverse events being mild [ 73 ]. Another study revealed that increasing the dose of tofacitinib from 10 mg/d to 20 mg/d could improve symptoms in patients with MDA5‐positive DM who were unresponsive to 10 mg/d tofacitinib [ 71 ]. However, this approach requires careful evaluation of the risk–benefit balance due to the increased risk of infections. In JDM, interferons and Janus kinases play critical roles in pathogenesis. A retrospective analysis revealed that tofacitinib improved skin manifestations, muscle symptoms, ILD, calcinosis and medication tapering in JDM patients [ 74 , 75 ].

Baricitinib

Type I IFN contributes to DM pathogenesis by upregulating the expression of interferon‐stimulated genes (ISGs) in the blood and activating p‐JAK1 and p‐STAT1 in the skin. Baricitinib, a JAK1/JAK2 inhibitor, exerts therapeutic effects on IIM by suppressing Type I IFN‐induced myocyte and microvascular damage. A case report revealed that baricitinib improved the condition of three DM patients who were unresponsive to conventional therapies. In vitro studies revealed significant downregulation of IFI44 and IFI27 expression, confirming that baricitinib reduces ISG levels [ 76 ]. Another study involving 12 DM patients demonstrated that baricitinib significantly improved facial erythema and reduced the levels of CXCL10, CCL2 and galectin‐9. Baricitinib combined with traditional immunosuppressants was effective in treating relapsing JDM, with improvements in skin and muscle symptoms and no severe adverse events observed [ 77 ]. A single‐centre retrospective study demonstrated that baricitinib significantly improved cutaneous manifestations in children with refractory JDM who had inadequate responses to corticosteroids and immunosuppressants. Beneficial effects were also observed in calcinosis and ILD, with concurrent resolution of macrophage activation syndrome. Treatment was well tolerated, with only one patient discontinued due to herpes zoster infection; no other significant adverse events or mortality were reported [ 77 , 78 ]. A randomized controlled clinical trial demonstrated that baricitinib exhibits superior efficacy over RTX in the treatment of refractory MDA5‐positive DM, which is attributable to its capacity to concurrently suppress the interferon and GM‐CSF signalling pathways. This dual inhibition effectively modulates macrophage‐mediated hyperactive autoimmune responses, highlighting its therapeutic advantage in this challenging patient population [ 79 , 80 ]. Currently, randomized controlled trials are underway to evaluate baricitinib in refractory and relapsing DM patients.

Upadacitinib

Retrospective studies have shown that upadacitinib significantly improves skin symptoms in refractory DM and ASS patients, but its effects on muscle strength could not be assessed because of the lack of active muscle disease at baseline [ 81 ]. Another study demonstrated that upadacitinib effectively alleviated skin lesions in refractory DM patients and may help prevent disease recurrence [ 82 ].

Ruxolitinib

Ruxolitinib, a JAK1/JAK2 inhibitor, has shown potential in the treatment of DM. A case report described a female patient with postpolycythemia vera myelofibrosis and DM who experienced significant improvement in DM symptoms during ruxolitinib treatment, suggesting its potential as a therapeutic option for DM [ 83 ]. Studies have also shown that ruxolitinib reduces IFN activity in JDM patients and improves skin lesions, muscle weakness and serum type I IFN levels in refractory DM patients [ 84 , 85 ]. A meta‐analysis revealed that JAK inhibitors significantly reduced CDASI in IIM patients, with ruxolitinib resulting in the most pronounced CDASI reduction [ 86 ].

In conclusion, JAK inhibitors show potential for improving outcomes in IIM patients who are refractory to conventional therapies. However, JAK inhibitors are associated with an increased risk of serious infections, including herpes zoster reactivation and opportunistic infections, which may warrant prophylactic strategies. Cardiovascular and thromboembolic risks, particularly in patients with underlying risk factors, have been highlighted in other inflammatory conditions. Additionally, laboratory monitoring for cytopenias and lipid profile alterations is recommended. The benefit–risk assessment must account for the patient's age, cardiovascular and thrombotic risk profile and vaccination status against herpes zoster.

Proteasome Inhibitors

Zetomipzomib (KZR‐616) is a selective immunoproteasome inhibitor that targets the LMP7 and LMP2 subunits of the immunoproteasome. It reduces the production of proinflammatory cytokines, inhibits plasma cell activity and decreases the production of autoantibodies, thereby showing broad therapeutic potential in various autoimmune diseases [ 87 ]. An animal experiment revealed that KZR‐616 treatment prevented the loss of grip strength in CIM mice, reduced leukocyte infiltration in muscle tissue, and inhibited the elevation of serum creatine kinase levels. On the basis of these preclinical findings, researchers further conducted clinical trials of KZR‐616. In a randomized, double‐blind, placebo‐controlled trial involving 25 IIM patients, KZR‐616 exhibited favourable safety profiles. However, no significant differences in efficacy were observed between the treatment and placebo groups [ 88 ]. Further studies are warranted to elucidate the therapeutic potential of KZR‐616 in IIM.

Low‐Dose IL‐2 Therapy

Low‐dose IL‐2 therapy exerts its therapeutic effects by promoting the expansion and activation of regulatory T cells (Tregs) while suppressing effector T‐cell (Teff) activity, thereby attenuating muscle tissue inflammation. Additionally, low‐dose IL‐2 reduces chemokine secretion by fibroblasts and inhibits peripheral lymphocyte migration, further mitigating muscle damage and inflammatory cascade formation [ 89 ].

A clinical study involving 71 patients with DM/PM and 30 HCs demonstrated that compared with HCs, PM/DM patients presented significantly lower absolute numbers and proportions of peripheral blood Tregs, elevated Th17/Treg ratios and reduced IL‐2 production. Low‐dose IL‐2 treatment significantly increased Treg numbers [ 90 ]. In an expanded cohort of 147 PM/DM patients, comprising 116 patients receiving conventional therapy and 31 receiving conventional therapy plus low‐dose IL‐2, combination therapy resulted in an approximately fourfold increase in absolute Treg numbers and significant improvement in disease parameters, validating the efficacy of low‐dose IL‐2 treatment [ 89 ].

In a prospective cohort study, 18 patients with active IIM received low‐dose IL‐2 treatment for 12 weeks. Among them, 77.78% (14/18) achieved disease remission according to the IMACS criteria, and 83.33% (15/18) met the 2016 ACR/EULAR myositis response criteria. Additionally, patients demonstrated significant improvement in cutaneous manifestations. No significant adverse events were observed during the treatment period, indicating both the efficacy and safety of low‐dose IL‐2 therapy in patients with IIM [ 91 ]. Additionally, a case report confirmed the efficacy of low‐dose IL‐2 in treating hypomyopathic DM with refractory dermatitis [ 92 ]. Another study revealed that low‐dose IL‐2 therapy helps to restore the Th17/Treg balance in DM patients complicated by EBV/CMV viremia [ 93 ]. To further explore the mechanism underlying the use of IL‐2 in the treatment of IIM, researchers discovered that it can exert a therapeutic effect by modulating the dysregulated gut microbiome of IIM patients [ 94 ]. Therefore, the combination of low‐dose IL‐2 with conventional therapy significantly increases Treg cell numbers and maintains immune homeostasis, potentially alleviating symptoms in DM/PM patients while enhancing their anti‐infection capabilities.

Discussion and Conclusion

IIM represents a highly heterogeneous group of autoimmune diseases with unclear aetiology and complex, diverse clinical and histopathological manifestations. Even with first‐line treatments such as glucocorticoids, a subset of patients exhibits a refractory and relapsing course. The development of targeted therapies has transformed the treatment landscape for IIM, offering hope to patients with refractory disease or severe complications. This review synthesizes the current evidence on targeted therapies for IIM, affirming their potential to induce remission in refractory patients while highlighting significant challenges, including variability in efficacy and safety concerns.

B‐cell‐targeted therapies represent a relatively mature treatment paradigm. RTX has demonstrated significant efficacy in reducing disease activity, particularly in patients with ASS and ILD. Compared with conventional therapies, RTX has comparable or superior efficacy and a favourable safety profile, positioning it as one of the preferred treatments for IIM. Supported by meta‐analysis evidence and formal guidelines, RTX has become a cornerstone therapy for refractory disease. Furthermore, the timing of RTX administration is critical, with early intervention associated with improved prognosis. The emergence of next‐generation anti‐CD20 agents, such as obinutuzumab, provides novel options for patients who are resistant or intolerant to RTX. Additionally, drugs that target plasma cells, such as daratumumab, represent a new direction towards deeper depletion of the B‐cell lineage. In contrast, the value of belimumab‐induced BAFF inhibition in IIM remains uncertain because primary endpoints are not met in RCTs, suggesting that not all B‐cell pathways hold equivalent therapeutic relevance in this disease.

T‐cell‐targeted therapies exhibit subtype‐dependent efficacy. Abatacept has unique value in nondermatomyositis subtypes and JDM‐associated calcinosis, although its benefits in classic DM remain limited.

Targeted therapies against specific cytokine pathways have achieved notable successes but are accompanied by thought‐provoking contradictions. The JAK–STAT pathway has been identified as a critical therapeutic target. JAK inhibitors, particularly tofacitinib and baricitinib, show remarkable efficacy in ameliorating refractory cutaneous manifestations. Notably, baricitinib even showed superior efficacy compared with RTX in an RCT for MDA5‐positive DM‐associated ILD, which was attributed to its dual inhibition of the interferon and GM‐CSF signalling pathways. Similarly, the rapid and significant improvement of cutaneous symptoms with anifrolumab in refractory DM and JDM provides strong evidence that the type I interferon pathway is a key driver of specific clinical phenotypes. Although tocilizumab failed to meet primary endpoints in an RCT for refractory DM/PM, it remains an important salvage therapy for refractory ASS‐ and MDA5‐positive DM patients with rapidly progressive ILD. This variability underscores the importance of patient stratification on the basis of clinical phenotypes and potential biomarkers, such as serum IL‐6 levels and CD56‐positive muscle fibres. The IL‐1 receptor antagonist anakinra shows efficacy in IIM patients, particularly those with prominent extra‐articular organ involvement, but clinical studies indicate no significant benefit in IBM, further reinforcing the concept of phenotype‐driven therapy. The use of TNF‐ α inhibitors in IIM remains highly controversial, with reports of improvement in cutaneous and muscular symptoms as well as calcinosis contrasted with studies showing inefficacy or even disease exacerbation. These findings reveal the complex and dual role of cytokines in IIM. The heterogeneity of treatment responses across and within subtypes poses a central challenge, largely because of the diversity of immunopathogenic mechanisms.

Novel mechanisms are expanding therapeutic options. Efgartigimod, by targeting the Fc receptor, offers a new strategy to reduce pathogenic IgG autoantibodies and shows promising results in IMNM. Low‐dose IL‐2 therapy, which aims to restore immune balance by selectively expanding regulatory T cells, has been shown to improve disease activity and is attractive for its potential to enhance anti‐infective capacity. Similarly, bispecific T‐cell engagers (BiTEs), such as teclistamab, which targets BCMA and CD3, represent a novel therapeutic strategy by recruiting and activating a patient's own T cells to eliminate plasma cells and plasmablasts precisely. However, this potent mode of T‐cell activation is associated with inherent risks, including CRS, necessitating further clinical studies to fully elucidate its efficacy and safety profile.

In recent years, CAR‐T‐cell therapy has emerged as a research hotspot in autoimmune disease treatment. By enabling deep B‐cell depletion and inducing profound immune reset, CAR‐T‐cell therapy has shown remarkable efficacy, achieving sustained drug‐free remission in patients with refractory ASS, IMNM and JDM. However, reports of relapse and reinfusion failure, alongside unique adverse events such as CRS, indicate significant challenges in long‐term efficacy and toxicity management.

Despite the exciting progress in targeted therapies for IIM, several systemic challenges remain. First, the existing evidence exhibits significant heterogeneity. Many conclusions are derived from small open‐label studies or case series, which carry inherent risks and have limited generalizability. Inconsistent evidence for therapies such as TNF inhibitors and belimumab necessitates caution and highlights the urgent need for large‐scale, high‐quality RCTs. Second, while adverse events for each therapy have been discussed, deeper risk–benefit stratification is needed. For example, the clinical application of CAR‐T cells and JAK inhibitors demands infection prophylaxis and long‐term monitoring. Third, the high cost and implementation complexity of advanced therapies such as CAR‐T cells currently limit their widespread use, despite their revolutionary potential to induce sustained, drug‐free remission.

Finally, the inability to perform quantitative synthesis (meta‐analysis) in this review reflects the current literature landscape: significant clinical and methodological heterogeneity among numerous small studies makes data pooling difficult. Future accumulation of more homogeneous data may enable systematic reviews and meta‐analyses to provide higher‐level evidence.

In conclusion, targeted therapies are revolutionizing the management of IIM. B‐cell‐targeted agents, T‐cell modulators, cytokine inhibitors, CAR‐T‐cell therapies and proteasome inhibitors have demonstrated efficacy in reducing disease activity and improving clinical outcomes. However, challenges remain in optimizing treatment, managing adverse events, developing novel targeted drugs and conducting larger clinical trials. By addressing these challenges, targeted therapies have the potential to significantly enhance the quality of life and long‐term prognosis of patients with IIM.

Funding

This study was supported by Sichuan Science and Technology Program (2025ZNSFSC0638 [G.Y.] and 2024YFFK0062 [Q.B.X.]). This study was also supported by the National Natural Science Foundation of China (No. 82572070).

Ethics Statement

The manuscript does not contain original clinical studies or patient data. All the authors listed in the manuscript comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle .

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgements

This study was supported by Sichuan Science and Technology Program (2025ZNSFSC0638 [G.Y.] and 2024YFFK0062 [Q.B.X.]). This study was also supported by the National Natural Science Foundation of China (No. 82572070).

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