Pathogenesis and Treatment of Interstitial Lung Disease Accompanied by Anti-melanoma Differentiation-associated Gene 5-positive Idiopathic Inflammatory Myopathies

Abstract

Interstitial lung disease (ILD) progresses rapidly and presents with diffuse alveolar damage for patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive idiopathic inflammatory myopathies. The activation of monocytes/macrophages, B cells, and interferonopathy appears to be involved in the pathogenesis of the disease and can be a therapeutic target. An early diagnosis and intensive immunosuppressive treatment at an early stage are effective for the treatment of ILD. Evidence on treatment, such as the efficacy of Janus kinase inhibitors, rituximab, plasmapheresis, and triple immunosuppressive therapy with glucocorticoids, calcineurin inhibitors, and intravenous cyclophosphamide, has been growing. Careful monitoring of infections and adverse events during intensive immunosuppressive treatment is necessary. It is desirable to elucidate the pathogenesis of the disease, identify indications for intensive treatment, and provide appropriate therapy.

Introduction

In idiopathic inflammatory myopathies (IIMs), myositis-specific autoantibodies are associated with clinical manifestations and are useful in disease classification (1-3). Patients with anti-melanoma differentiation-associated gene 5 (MDA5)-positive IIM present with skin ulcer and arthralgia and are associated with clinically amyopathic dermatomyositis (CADM) (4-7). As ILD often progresses rapidly with an acute or subacute course (rapidly progressive interstitial lung disease, RP-ILD) and presents with diffuse alveolar damage, it should be promptly diagnosed and treatment needs to be initiated before the disease progresses (4,5). Given the high mortality rate within six months of onset followed by good long-term survival, early treatment is crucial (8). Typical lung imaging findings, such as CADM, hyperferritinemia, and confirmation of anti-MDA5 antibodies, are important for the diagnosis (9,10).

The establishment of an effective treatment for RP-ILD accompanied by anti-MDA5-positive IIM is important (4-6). As the disease is rare and progresses rapidly with a poor prognosis, it is difficult to conduct clinical studies with a high level of evidence, such as randomized control trials. Despite these limitations, evidence for the treatment of this disease, such as the efficacy of Janus kinase (JAK) inhibitors, rituximab, plasmapheresis, and triple immunosuppressive therapy with glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IVCY), has been growing (1,11-13) (Table 1).

Table 1.

Representative Remission Induction Regimens for Anti-MDA5-positive Interstitial Lung Disease.

Regimen	Control regimen	Design	Endpoint	Survival rate, regimen vs. control	Country	Reference
Triple immunosuppressive therapy
GC, CyA, CY	-- (single arm)	Prospective	6M	75%	Japan	(1)
GC, CNI, CY with/without PE	Step-up regimen with GC, CNI, CY (historical control)	Prospective	6M	89% vs. 33%	Japan	(46)
JAK inhibitor
TOF, GC, CyA, CY	GC, CyA, CY	Retrospective	12M	60% vs. 0%	Japan	(73)
TOF, GC and/or IS	GC and/or IS	Prospective	6M	100% vs. 78%	China	(12)
Rituximab
RTX (low dose), GC	GC, IS (other than RTX)	Retrospective	6M	64% vs. 36%	China	(86)
RTX, MMF, GC, PE or PMX-DHP	GC, CNI, CY (historical control)	Prospective	12M	64% vs. 33%	Japan	(84)
RTX, TOF, GC, mPSL pulse	-- (single arm)	Prospective	12M	75%	Singapore	(85)
Plasmapheresis
GC, CNI, CY with/without PE	GC, CNI, CY (historical control)	Prospective	6M	89% vs. 71%	Japan	(46)
PE, GC, CNI, CY	GC, CNI, CY	Retrospective	6M	63% vs. 0%	Japan	(13)
PE, GC, IS	GC, IS	Retrospective	12M	100% vs. 25%	Japan	(76)
IVIG
IVIG, GC, IS	GC, IS	Retrospective	6M	77% vs. 47%	China	(87)

CNI: calcineurin inhibitor, CY: cyclophosphamide, CyA: cyclosporine A, GC: glucocorticoid, IS: immunosuppressant, IVIG: intravenous immunoglobulin, JAK: Janus kinase, M: month, MMF: mycophenolate mofetil, mPSL pulse: methyl-prednisolone pulse, PE: plasma exchange, RTX: rituximab, TOF: tofacitinib

Etiology

Viral infection, environmental factor (e.g., seasons and area of residence), and genetic susceptibility [e.g., human leukocyte antigen (HLA)], have been suggested as causes of the disease (14-18). Seasonal trends show peak incidence in winter and spring (15,19,20). Patients with anti-MDA5-positive IIM exhibit heightened antiviral immunity against herpes simplex virus (HSV)-1 and enterovirus B, potentially triggering the disease by activating the type I interferon (IFN) pathway through MDA5 and Toll-like receptor signaling (21,22). HLA-DRB1*01:01 and *04:05 in the Japanese population and HLA-DRB1*04:01, DRB1*12:02, DQA1*06:01, and DQB1*06:09 in the Han Chinese population are associated with susceptibility to anti-MDA5-positive IIM (16-18). Variants in the WDFY4 genes play a role in cross-presentation, which regulates immune responses to viral and tumor antigens, and have been reported in Asian patients with anti-MDA5 antibodies (23,24).

Pathophysiology of Anti-MDA5-positive Idiopathic Inflammatory Myopathies

The activation of monocytes/macrophages, B cells, and interferonopathy appears to be involved in the pathogenesis of the disease and can be a therapeutic target.

Laboratory findings under this condition include several key indicators. Decreased white blood cell counts, elevated hepatobiliary enzymes, and hyperferritinemia are commonly observed, and these findings are suggestive of macrophage activation (1,4,25). Serum ferritin is a powerful marker of macrophage activation and is elevated in anti-MDA5-positive IIM patients, particularly those with severe RP-ILD. Hyperferritinemia is also considered a poor prognostic factor. Macrophage infiltration and inflammation in the liver can elevate hepatobiliary enzymes such as aspartate aminotransferase and alanine aminotransferase. Leukopenia, particularly lymphopenia, is also a common finding in anti-MDA5-positive IIM patients and is a diagnostic criterion for macrophage activation syndrome (26). Beyond these systemic markers, specific signs of inflammation and cellular activity are evident. Significant infiltration of CD68-positive macrophages has been confirmed in lung tissues, particularly within interstitial pneumonia lesions (25). This indicates that macrophages function as the central mediators of lung inflammation. Macrophage infiltration can be observed in muscle biopsies, although its extent may depend on myositis disease activity (27). Elevated serum levels of various monocyte-derived cytokines and chemokines such as interleukin (IL)-6, IL-18, IL-34, C-X-C motif chemokine ligand (CXCL) 10, chitotriosidase, soluble CD163, and galectin-9 (13,28-34). These cytokines produced by macrophages contribute to the exacerbation of inflammation. This hypercytokinemia is considered part of the “cytokine storm" and plays a critical role in the pathogenesis of anti-MDA5-IIM, especially in RP-ILD. Collectively, these elevated mediators indicate a robust inflammatory response driven by monocytic cells.

Further evidence of immune dysregulation is provided by the activation of the type I IFN pathway. This activation is demonstrated by elevated serum levels of type I IFN (35). Patients with anti-MDA5-positive IIM have reported markedly higher serum levels of type I IFN (particularly IFN-α) relative to healthy controls. Furthermore, activation was demonstrated by an increase in IFN-related gene signatures. Significant upregulation of IFN-stimulated genes, which are induced by type I IFN, has been confirmed in peripheral blood mononuclear cells, skin lesions, and lung tissue (35). This indicates a strong systemic activation of the type I IFN pathway. Elevated levels of B cell-activating factor belonging to the tumor necrosis factor family (BAFF) are also an important finding. Increased blood levels of BAFF, an IFN-inducing B-cell activating factor, have also been reported, further suggesting activation of the type I IFN pathway (35). These findings suggest a robust immune response driven by type I IFNs that potentially contributes to the pathogenesis of the disease.

B cells play a multifaceted and crucial role in the pathogenesis of myositis, particularly in anti-MDA5-positive IIM, extending beyond autoantibody production. Their involvement encompasses intricate interactions with other immune cells and modulation of immune responses through various mechanisms. First, B cells actively engage with T cells, which is a critical interaction for the initiation and maintenance of adaptive immune responses. This occurs through co-stimulatory molecules, such as CD40 on B cells binding to CD40L on T cells, along with the secretion of various cytokines, including IL-6 and TNF-α. These interactions are fundamental for the formation of germinal centers where B cells undergo proliferation, somatic hypermutation, and class-switch recombination, ultimately leading to the generation of high-affinity autoantibodies and long-lived plasma cells. Furthermore, B cell survival and antibody production are significantly sustained by cytokines, such as BAFF and a proliferation-inducing ligand (APRIL). Notably, these factors were upregulated within the inflamed muscle microenvironment of patients with myositis, providing local support for pathogenic B cell activity. Consistent with this, serum BAFF levels have been reported to be significantly higher in anti-MDA5-positive IIM patients than in anti-synthetase-positive IIM patients or healthy controls (36). The elevated BAFF concentration may contribute to the survival and activation of autoreactive B cells. Cellular analyses also provide compelling evidence to support B-cell involvement in anti-MDA5-positive IIM. Peripheral blood CD19-positive B cells not only increase in number but also exhibit an activated phenotype in these patients (37). More advanced techniques, such as the single-cell sequencing analysis of peripheral blood and lung tissue from anti-MDA5-positive IIM patients, have provided granular insights, revealing a significant increase in diverse and aberrantly activated B-cell subtypes, including plasma cells and plasma blasts (38,39). These findings suggest a broad dysregulation of the B-cell compartment in this specific myositis subtype. Therefore, B cells contribute to the pathogenesis of myositis not only by secreting pathogenic autoantibodies, but also by actively secreting pro-inflammatory cytokines and engaging in complex interactions with other immune cells, thereby modulating the overall immune landscape and perpetuating the inflammatory response. Understanding the multifaceted roles of B cells will offer promising avenues for targeted therapeutic interventions in anti-MDA5-positive IIM.

Anti-MDA5 Antibodies and Other Coexistent Antibodies

The anti-MDA5 antibody is an autoantibody that targets MDA5, as detected by immunoprecipitation, line blotting, or enzyme-linked immunosorbent assay (7,9,40). MDA5, an intracellular RNA viral sensor, plays a crucial role in innate immunity and induces type I IFN production (4,6). Depending on the report, the epitopes of anti-MDA5 antibodies vary and include helicase, Caspase Recruitment Domain (CARD), and C-terminal domain (CTD) (41-43). Despite the increased MDA5 expression in the skin of patients treated with anti-MDA5 antibodies, the mechanism by which anti-MDA5 antibodies are produced remains unclear (44). Anti-MDA5 antibodies derived from patient B cells stimulate IFN-γ production in peripheral blood cells (45). Although anti-MDA5 antibody titers decrease during effective treatment and plasmapheresis, which removes autoantibodies and cytokines from the blood, the pathogenicity of anti-MDA5 antibodies remains unclear (13,46).

The coexistence of anti-Ro52 antibody positivity is observed in approximately 50% of patients and is associated with a poor prognosis in RP-ILDs (12,47). Ro52, an intracellular Fc receptor, forms a surface complex with IgG/HLA-DR in vitro (48). Antibodies to this complex, found in 90% of anti-MDA5-patients, are correlated with Krebs von den Lungen (KL-6), suggesting a role in inflammatory myopathy pathogenesis (48).

Clinical Characteristics and Rapidly Progressive Interstitial Lung Disease of Anti-MDA5-positive Idiopathic Inflammatory Myopathies

Anti-MDA5-positive IIM is mainly observed in adults (average age, 55 years) but is also observed in juvenile dermatomyositis (JDM) (3,46,49). Anti-MDA5 antibody positivity rates show two peaks at 10-19 and 30-39 years of age (3). In adult patients with IIM, the frequency of anti-MDA5 antibody positivity is approximately 23% in Japan and 13% in North America, indicating a higher prevalence in Asia (3,50).

Skin manifestations predominate over muscle symptoms (CADM): heliotrope rash (approximately 50%), which is an erythematous rash with edema of the upper eyelids; Gottron's papules; and Gottron's sign (87-97%), such as erythema with desquamation on the extensor surfaces of the fingers, elbows, and knees, inverse-Gottron's sign, and rashes at the inner canthus and auricle (3,46) (Fig. 1A, B). Cutaneous mucosal ulcers (24-57%), sore throat, arthralgia, and fever are often observed (3,46). Muscle weakness was present in half of the patients, while there were findings of myositis on needle electromyography and minor elevations in myogenic enzymes on blood tests.

Figure 1.

Representative clinical images of skin and lung manifestations. A: Gottron’s papules and sign. B: Inverse Gottron’s sign. C: Computed tomography findings of calcification in the thigh (arrow). D: Representative high-resolution computed tomography imaging of an anti-MDA5-interstitial lung disease. The image shows ground-glass opacity and consolidation with a subpleural distribution accompanied by pneumomediastinum. A-C: Original data. D: Modified from Int J Rheum Dis 27: e15201, 2024.

RP-ILD associated with IIM is more prevalent in East Asian populations in comparison to Western populations (39-71% vs. 22-57%, respectively) (3,5,46,50). Moreover, when considering only anti-MDA5-positive cases, ILD occurs more frequently in East Asian populations than in Western populations (＞90% vs. 50-60%). However, even among Western patients with anti-MDA5-positive ILD, approximately half experienced rapid disease progression and a poor prognosis. The prognostic trends showed a similar pattern in both Japan and North America. A Japanese multicenter retrospective cohort study (JAMI) demonstrated a decrease in survival rate to approximately 60% within the first 6 months, followed by stable survival for up to 10 years (8). A retrospective study in North America observed a similar trend (5). Consequently, early acute treatment of RP-ILD is crucial to improve patient survival.

Lung involvement is associated with a characteristic clinical course and imaging findings. The intervals between the onset of cutaneous symptoms and the respiratory symptoms are simultaneous or within one month (acute onset) in 20-30% of patients, within 1-3 months (subacute onset) in 47-56%, and ＞3 months (chronic course) in 15-33% (46,51). High-resolution computed tomography (HRCT) patterns of ILD include organizing pneumonia (39-56%), nonspecific interstitial pneumonia with organizing pneumonia (11%), and unclassifiable (33-50%) (46). Consolidations and ground-glass attenuations (GGAs) in the lower lung lobes (50%) and multiple subpleural GGAs (33%) are common, pneumomediastinum is observed in progressive cases, and reticular opacities in the lower lung lobes and intralobular reticular opacities are not uncommon (Fig. 1D) (2,52).

Clinical Characteristics of Anti-MDA5-positive Juvenile Dermatomyositis

ILD is a major cause of death in JDM, and anti-MDA5 antibodies are a risk factor for RP-ILD (53). The frequency of anti-MDA5 antibody positivity in JDM ranges from 15% to 41% in Japan (46,54,55) and is higher than in the UK (6-12.2%) (56,57). The frequencies of skin rash and arthritis are comparable to those in adults, but fever is more common (63-100%) and calcinosis may be observed (3,53-55,58) (Fig. 1C).

Frequencies of ILD in anti-MDA5-positive JDM patients in Japan ranges from 80% to 100%, with an RP-ILD complication rate of 0-44% (3,53-55,58). A Japanese multicenter study of 31 anti-MDA5-positive JDM patients reported an ILD complication rate of 87%, with only one deceased patient. The duration from disease onset to treatment initiation ranges from 0 to 42 months (58). These findings suggest that some patients with juvenile onset may experience a slow disease course. Conversely, a 5-year nationwide survey of Japanese JDM revealed that RP-ILD accounted for 46% of deaths, with anti-MDA5 antibodies present in one-third of these fatalities (59,60). Notably, in a study of 10 JDM-related RP-ILD cases, 3 of the 7 fatal cases presented with no respiratory symptoms and only mild subpleural shadows or pleural effusion in the early stages (53). As observed in adults, RP-ILD can occur in JDM, and the effective management of these patients is a current issue (60).

Diagnosis and Classification Criteria

The difficulty in diagnosing anti-MDA5-positive IIMs is the lack of muscle symptoms, which often prevents adequate classification using the conventional IIM criteria. The classification criteria for IIM, predominantly those proposed by Bohan and Peter in 1975, have been widely used internationally but suffer from low specificity and issues such as the inability to diagnose amyopathic dermatomyositis (ADM) (61). To address this, Sontheimer proposed CADM, a category that includes both ADM and hypomyopathic DM, which is defined by the absence of clinical muscle symptoms for over two years, despite slight evidence of myositis on blood tests and electromyography (62).

The recently proposed 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for IIMs incorporated ADM (63). Applicability of the 2017 EULAR/ACR classification criteria for ADM was 74% using a U.S. registry (64). Conversely, the remaining 26% of ADM patients were not classified as such because their extensive skin manifestations did not meet the new criteria's dermatological symptoms. It is suggested that including more diverse skin findings or skin biopsy results as criteria could improve the ADM classification sensitivity. Furthermore, the Hong Kong registry (98% Chinese) validated the accuracy of the 2017 EULAR/ACR classification criteria for anti-MDA5-positive IIMs (10). When anti-MDA5-positive IIM patients (68% ADM, 32% DM) were classified, 72% were classified as IIM. Clinical features of the patients not classified as IIM (18% of the total) included ILD (88%) and cutaneous ulcerations or inverse Gottron's sign (24%). When the anti-Jo-1 antibody item in the classification criteria was replaced with the anti-MDA5 antibody, the sensitivity of the classification criteria increased to 98%.

These results suggest that anti-MDA5-positive IIMs cannot be adequately diagnosed using conventional IIM classification criteria because of the lack of muscle symptoms, highlighting the importance of testing anti-MDA5 antibodies for their diagnosis.

Evaluation of Interstitial Lung Disease Activity

Disease activity in ILD is assessed using a combination of blood gases, serological tests, HRCT, and respiratory function tests (46,52). Serum sialylated carbohydrate antigen (KL-6) is useful for monitoring ILD activity (65). Serum ferritin levels and anti-MDA5 antibody titers correlate with disease activity and the prognosis (4,66). Conversely, deceased cases may show a discrepancy in which serum ferritin levels worsen while anti-MDA5 antibody levels decrease (46). Patients with positive anti-MDA5 antibodies but without normalized titers after RP-ILD remission are more prone to earlier relapse (66). After anti-MDA5 antibodies become negative when patients are in remission, some patients show elevated anti-MDA5 antibody titers at relapse (66).

However, since pulmonary function tests do not respond immediately, even with a good course of treatment, poor or temporarily declining results can be observed in a few months, followed by improvement over a longer period (46).

Risk Stratification and Prognosis

Although the progression and severity of ILD vary among patients and there are concerns regarding adverse events during intensive immunosuppressive treatments, prospective studies have been conducted on patients regardless of severity (67). Furthermore, poor prognostic factors include older age, skin ulcers, hypoxemia, advanced lung disease, and elevated levels of C-reactive protein (CRP), creatine kinase, lactate dehydrogenase (LDH), ferritin, anti-MDA5 titers, and coexistence of anti-Ro52 antibodies, which have been explored for use in the classification of disease severity (12,13,46,47,68,69).

A Japanese multicenter retrospective cohort study (JAMI) involving 497 adult patients with IIM-related ILD demonstrated that anti-MDA5 antibodies, CRP, and KL-6 were independent risk factors for mortality. Consequently, a prognostic model was developed and subsequently validated based on these factors (69), and a cluster analysis of anti-MDA5-positive patients with IIM in China proposed a subtype classification that included differences in anti-MDA5 antibody titers and validated its usefulness in predicting the prognosis (68). In the future, it would be ideal to adapt individualized treatment according to the severity of the disease.

Treatment for Anti-MDA5-positive IIM

Representative remission induction regimens and associated adverse events for anti-MDA5 antibody-positive ILD are shown in Tables 1 and 2, respectively.

Table 2.

Adverse Event during Treatment for Anti-MDA5-positive Interstitial Lung Disease.

Treatment	Regimen	Infection	Other	Reference
Triple immunosuppressive therapy	Combined immunosuppressive regimen (GC, CNI, CY with/without PE)	Total (85%) Bacterial infection (37%) CMV (85%) HSV/VZV (7%) Candidiasis (56%) Aspergillus (7%) PCP (11%) Other fungal infections (4%)	Renal disorder (eGFR: baseline: 98.1±23.9, 52 weeks: 75.3±15.7 mL/min/1.73 m2) DM (70%) Hyperglycemia (74%) Hyperlipidemia (89%) Insomnia (81%) Compression fracture (4%) Femoral head necrosis (4%) Hypertension (33%) TMA (7%) Hemorrhagic cystitis (15%) Electrolyte abnormality (89%) Jaw osteomyelitis/jaw bone necrosis (8%)	(46)
Triple immunosuppressive therapy	Step-up regimen with GC, CNI, CY (historical control)	Total (80%) Bacterial infection (33%) CMV (33%) HSV/VZV (13%) Candidiasis (33%) PCP (13%) Other fungal infections (13%)	Renal disorder (eGFR: baseline: 97.4±26.5, 52 weeks: 67.7±20.2 mL/min/1.73 m2) DM (53%) Hyperglycemia (93%) Hyperlipidemia (87%) Insomnia (67%) Compression fracture (0%) Femoral head necrosis (0%) Hypertension (33%) TMA (0%) Hemorrhagic cystitis (0%) Electrolyte abnormality (87%) Jaw osteomyelitis/jaw bone necrosis (0%)	(46)
JAK inhibitor	TOF, GC, CyA, CY	Total (100%) Bacterial infection (80%) CMV (100%) VZV (60%) Adenovirus (20%) Fungal infection (40%)	Intramuscular bleeding (20%) Lymphoproliferative disease (20%) Pancytopenia (20%) Shock of an unknown cause (20%)	(73)
Rituximab	RTX (low dose), GC	CMV (27%) Respiratory infection (36%)		(86)
Plasmapheresis	PE, GC, IS	Catheter infection (16%)	Anaphylactic shock (33%) Allergy (16%)	(76)
IVIG	IVIG, GC, IS	Infection in 3 months, 25.8% for IVIG vs. 17.6% for non-IVIG		(87)

CMV: cytomegalovirus, CNI: calcineurin inhibitor, CY: cyclophosphamide, CyA: cyclosporine A, DM: diabetes mellitus, eGFR: estimated glomerular filtration rate, GC: glucocorticoid, HSV: herpes simplex virus, IS: immunosuppressant, IVIG: intravenous immunoglobulin, JAK: Janus kinase, MMF: mycophenolate mofetil, PCP: Pneumocystis pneumonia, PE: plasma exchange, RTX: rituximab, TMA: thrombotic microangiopathy, TOF: tofacitinib, VZV: varicella zoster virus

1. Efficacy of Triple Immunosuppressive Therapy with Glucocorticoids, Calcineurin Inhibitors, and Intravenous Cyclophosphamide

Intensive immunosuppressive therapy prior to lung lesion progression is effective in anti-MDA5-positive RP-ILD. Conventional treatments with GCs alone or GCs with additional immunosuppressive drugs (step-up therapy) have demonstrated a poor prognosis, with a six-month survival rate of 28-66% (1,4,70). In contrast, the concomitant administration of GC and immunosuppressive drugs, such as CNIs, from the early stage of the disease seems to be effective (71): the six-month survival rate improved to 75% with triple immunosuppressive therapy with high-dose GC, cyclosporine A (target peak concentration at 2-h: 700-1,000 ng/mL), and IVCY in the early stage of the disease (1). However, several retrospective studies failed to demonstrate the prognostic significance of triple immunosuppressive therapy. This may be due to the lack of a treatment regimen and the retrospective analysis.

A single-arm, multicenter, prospective study of triple immunosuppressive therapy with high-dose GC [prednisolone (PSL) 1 mg/kg/day], tacrolimus (target 12-h trough concentration: 10-12 ng/mL), and IVCY (500-1,000 mg every two weeks) was conducted in Japan (46) (Fig. 2A). Anti-MDA5 titer and ferritin levels in the blood decreased 52 weeks after the start of treatment, and respiratory function and chest HRCT findings improved. The triple immunosuppressive therapy group showed an improved six-month survival rate in comparison to the step-up therapy group (historical control group) (89% vs. 33%, respectively, p＜0.0001) (Fig. 2B). Patients in the triple immunosuppressive therapy group began receiving immunosuppressive drugs approximately 20 days earlier than those in the step-up therapy group did. Plasmapheresis was added to 9 of 27 patients whose respiratory conditions worsened during the treatment course, resulting in a tendency for a higher six-month survival rate in the plasmapheresis group relative to the non-plasmapheresis group (89% vs. 71%, respectively, p＜0.09) (Fig. 2B). During the first 52 weeks of treatment, cytomegalovirus (CMV) reactivation (85%), insomnia (81%), electrolyte abnormalities (89%), and elevated blood glucose (70%) were observed, whereas there were no severe adverse events (Table 2). The eGFR decreased from 98.1±23.9 to 75.3±15 mL/min/1.73 m² at 52 weeks. The results of this study confirmed the efficacy of high-dose GC, tacrolimus, and IVCY combined with plasmapheresis as an additional treatment for RP-ILD with anti-MDA5-positive IIM. However, the careful monitoring of adverse events is crucial.

Figure 2.

Short- and long-term outcomes of the triple immunosuppressive therapy for interstitial lung disease accompanied with anti-MDA5-positive interstitial lung disease. A: Triple immunosuppressive therapy combined with high-dose prednisolone (PSL), oral tacrolimus (TAC), and intravenous cyclophosphamide (IVCY). B: Survival rates of the triple immunosuppressive therapy and historical control groups. A and B were modified from Arthritis Rheumatol. 2020; 72 (3): 488-98. C and D: Recurrence-free rates (C) and drug-free rates (D) of calcineurin inhibitors (CNIs) and glucocorticoids (GCs) after remission for anti-MDA5-RP-ILD treated with triple immunosuppressive therapy (Group T) in comparison to conventional treatments (Group C). Modified from J Rheumatol. 2023; 50 (11): 1454-1461. B-D: Kaplan-Meier test, *p<0.0001, +: censored patients

The long-term prognosis after remission for anti-MDA5-positive RP-ILD is better for patients treated with triple immunosuppressive therapy than for those treated with conventional treatments, including GC monotherapy and step-up therapy (72). A retrospective study in Japan showed relapse rates of 10% and 44% for 10 years after remission in the triple immunosuppressive and conventional therapy groups, respectively (Fig. 2C). CNI/GC discontinuation rates were 36% and 0% in the triple immunosuppressive and conventional therapy groups, respectively (Fig. 2D). Thus, triple immunosuppressive therapy as induction therapy can prevent relapse and lead to drug-free remission.

2. Efficacy of JAK Inhibitors

Tofacitinib, a JAK inhibitor, suppresses type I IFN, type II IFN and IL-2, and has been reported to improve the prognosis. An additional 10 mg/day of tofacitinib for Japanese patients who did not respond to the triple immunosuppressive therapy with PSL (1 mg/kg/day), cyclosporine A, and IVCY (500-1,000 mg every two weeks) resulted in a better twelve-month survival rate in comparison to patients managed without tofacitinib (60% vs. 0%, respectively) (73). Viral (CMV, 100%; varicella-zoster virus (VZV), 60%; adenovirus, 20%), bacterial (80%), and fungal (40%) infections were observed during the treatment.

A single-center, open-label, non-randomized study of tofacitinib in patients with early onset anti-MDA5-positive ILD in China also demonstrated its efficacy (12). Two groups were compared: GC with tofacitinib (10 mg/day) and GC without tofacitinib (conventional treatment, historical control). The six-month survival rate was higher in the GC with tofacitinib group than in the conventional treatment without tofacitinib group (historical control) (100% vs. 78%, respectively). Serum ferritin level, forced vital capacity, diffusing capacity of the lungs for carbon monoxide (DLCO), and CT findings improved in the tofacitinib group. Thus, the prognostic value of JAK inhibitors in patients with early onset disease has been demonstrated, and JAK inhibitors can be used as therapeutic options. However, there is a need for awareness regarding the risk of infection (74).

3. Effectiveness of Apheresis

As the levels of various cytokines in the blood are increased in anti-MDA5-positive RP-ILD, their elimination seems to be effective. Recently, the effectiveness of plasmapheresis (13,46,75,76) and polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) (77,78) in anti-MDA5-positive RP-ILD has been reported.

As described previously, during the course of the triple immunosuppressive therapy, the six-month survival rate tended to be higher in the additional plasmapheresis group than in the non-plasmapheresis group (89% vs. 71%, respectively, p＜0.09) (46).

A retrospective analysis of eight patients with plasmapheresis and five without plasmapheresis for worsening respiratory conditions after triple immunosuppressive therapy with GC, CNI, and IVCY (13). The six-month survival rate was higher in the plasmapheresis group than in the non-plasmapheresis group (63% vs. 0%, respectively).

Another report showed a higher twelve-month survival rate in the plasmapheresis group than in the non-plasmapheresis group in patients refractory to intensive immunosuppressive therapy for anti-MDA5-positive RP-ILD (100% vs. 25%, respectively, p=0.03) (76). Regarding adverse events associated with plasmapheresis, anaphylactic shock (33%), allergy (16%), and catheter infection (16%) were observed and resolved with appropriate treatment.

Although there have been no prospective analyses, early concomitant plasmapheresis appears to be an effective adjuvant therapy for patients with a poor response to initial treatment and progressive respiratory failure.

4. B-cell Depletion Therapy

The effectiveness of rituximab, an anti-CD20 antibody (RTX), has been reported. Adverse events should be noted during RTX treatment. Infusion reactions, including fever, chills, and headache, can occur, making premedication with glucocorticoids and antihistamines advisable (79). Given B-cell depletion, special attention must be paid to opportunistic infections post-administration, such as pneumocystis pneumonia, CMV infection, and VZV infection, along with hepatitis B virus reactivation in previously infected cases (80). Progressive multifocal leukoencephalopathy caused by JC polyomavirus, including fatal cases, has been reported. Furthermore, the exacerbation of autoimmune encephalomyelitis in mice and the onset of psoriasis in humans have been reported following the administration of RTX (81,82).

The effectiveness of additional treatment with RTX in four patients with anti-MDA5-positive RP-ILD who did not respond to high-dose GC therapy or other intensive immunosuppressive therapies was reported in Hong Kong in 2018 (83).

Effective cases using mycophenolate mofetil and rituximab as concomitant medications for GC have been reported (84). A prospective regimen of mycophenolate mofetil, rituximab, plasmapheresis, or PMX-DHP was compared with a conventional therapy group treated with GC, CNI, and IVCY. The 48-week cumulative survival rate was significantly higher in the prospective group in comparison to the conventional group (64% vs. 33%). However, they concluded that careful management of complications, such as opportunistic infections and leukopenia, is essential.

A prospective single-arm study evaluated a combination regimen of methylprednisolone (500 mg for 3 days), rituximab (1 g, twice, 2 weeks apart), and tofacitinib (10 mg, daily) in patients with anti-MDA5-positive RP-ILD (85). As a result, the twelve-month survival rate was 75%, but a high frequency of opportunistic infections was observed.

A retrospective study found that a combination of immunosuppressive drugs with low-dose rituximab (totaling four weekly 100 mg doses) increased survival at 180 days (64% vs. 36%) in comparison to treatment with CY or other non-rituximab immunosuppressants (86). In the RTX group (n=11), B cell subpopulations rapidly and significantly decreased from day 7, and this effect persisted for 180 days. CMV reactivation occurred in three patients (27%) and respiratory infections in four patients (36%). Of the three deaths, two were attributed to ILD relapse precipitated by CMV infection.

5. Intravenous Immunoglobulin

A retrospective analysis in China showed that the six-month survival rate for patients treated with intravenous immunoglobulin (IVIG; 400 mg/kg/day for 5 consecutive days and additional courses 2-4 weeks later) with GC and immunosuppressants was higher than for patients without IVIG (77% vs. 47%, respectively) (87). Within three months, 25.8% of IVIG-treated patients experienced infection in comparison to 17.6% of patients without IVIG (p=0.78). Adverse events associated with IVIG range from minor to serious, encompassing shock, anaphylaxis, liver dysfunction, aseptic meningitis, renal dysfunction, thromboembolism, and the onset or worsening of heart failure.

6. Other Biologics

Novel biological targeting molecules have been developed. CD38 is present on the surface of immune cells, including T, B, and NK cells. It is particularly expressed in activated T cells and plasma cells, where it plays a role in cell differentiation and activation. There have been case reports on the effectiveness of daratumumab, a CD38-targeting biological, for anti-MDA5-positive RP-ILD (88,89).

Teclistamab is a T-cell redirecting bispecific antibody that binds to both the CD3 receptor on the surface of T cells and the B-cell maturation antigen (BCMA) on the surface of plasma cells, thereby activating the immune system. A case report indicated that teclistamab improved the respiratory function and muscle strength of a patient with anti-MDA5 (90).

CD19-targeting CAR-T cell therapy has shown efficacy in other types of IIMs (91). However, its effectiveness against anti-MDA5-positive RP-ILD remains unclear. CD19-targeted CAR-T cell therapy can reset the autoimmune response and maintain long-term remission even after complete B-cell remodeling. Therefore, it may be a promising new treatment, and its long-term efficacy and safety must be established.

Anifrolumab, which inhibits type I IFN activity, has shown efficacy in patients with IIM complicated by SLE (92,93). However, its effectiveness against anti-MDA5-positive RP-ILD remains unclear.

7. Respiratory Support and Surgery

Surviving patients have been reported after lung transplantation for severe respiratory failure and extracorporeal membrane oxygenation (ECMO) as an adjuvant treatment until lung transplantation (11). As these therapies may be useful for severe cases, their efficacy and safety must be evaluated.

8. Evidence of Treatment for Anti-MDA5-positive Juvenile Dermatomyositis

There is currently no established treatment regimen for anti-MDA5-positive JDM-ILD, although cases treated with a combination of steroid pulse therapy with either cyclosporine A or IVCY have been reported (3,53,58,94). While aggressive treatment is necessary for existing respiratory impairment, the appropriateness of adult triple combination immunosuppressive therapy for JDM remains unclear (46,60).

Tofacitinib, a JAK inhibitor, has been reported to be effective in several case studies (95-98). Furthermore, a retrospective study demonstrated the effectiveness of baricitinib in refractory cases (49). Cases of treatment with rituximab have also been reported (99,100). However, further investigations of JAK inhibitors and rituximab are needed.

A retrospective study showed that the cumulative drug-free rate was 50% for 10 years after juvenile-onset patients were in remission with conventional treatment (3). Given that juvenile-onset patients suffer from side effects of steroids and exhibit musculoskeletal damage during the long-term course of the disease, achieving a drug-free state is desirable for a better quality of life (51). Thus, sharing adult treatment experiences with pediatric rheumatologists is important to build treatment evidence.

Conclusion

An early diagnosis and intensive immunosuppressive treatment at an early stage are effective for ILD accompanied by anti-MDA5-positive IIM. Adverse events including infections should be carefully monitored during treatment. It is desirable to elucidate the pathogenesis of the disease, identify indications for intensive treatment, and develop safe and more effective treatments. The next goal is disease stratification and improvement of the long-term prognosis by aiming for drug-free remission.

The authors state that they have no Conflict of Interest (COI).

Funding Statement

HT received research grants from KAKENHI (24K19239). Shimizu Foundation for Immunology and Neuroscience, Japan College of Rheumatology, Nakatomi Foundation, and Ichiro Kanehara Foundation.