SRP54 of black carp negatively regulates MDA5-mediated antiviral innate immunity.

Signal Recognition Particle 54 kDa (SRP54) is a subunit of the signal recognition particle (SRP), a cytoplasmic ribonucleoprotein complex guiding the transportation of newly synthesized proteins from polyribosomes to endoplasmic reticulum. In mammals, it has been reported to regulate the RLR signaling pathway negatively by impairing the association between MAVS and MDA5/RIG-I. However, the role of SRP54 in teleost antiviral innate immune response remains obscure. In this study, the SRP54 homolog of black carp (bcSRP54) has been cloned, and its function in antiviral innate immunity has been elucidated. The CDS of bcSRP54 gene consists of 1515 nucleotides and encodes 504 amino acids. Immunofluorescence (IF) showed that bcSRP54 was mainly distributed in the cytoplasm. Overexpressed bcSRP54 significantly reduced bcMDA5-mediated transcription of interferon (IFN) promoter in reporter assay. Co-expression of bcSRP54 and bcMDA5 significantly suppressed bcMDA5-mediated IFN signaling and antiviral activity, while bcSRP54 knockdown increased the antiviral ability of host cells. In addition, the results of the immunofluorescence staining demonstrated the subcellular overlapping between bcSRP54 and bcMDA5, and the co-immunoprecipitation (co-IP) experiment identified their association. Furthermore, the over-expression of bcSRP54 did not influence the protein expression and ubiquitination modification level of bcMDA5, however, hindered the binding of bcMDA5 to bcMAVS. In summary, our results conclude that bcSRP54 targets bcMDA5 and inhibits the interaction between bcMDA5 and MAVS, thereby negatively regulating antiviral innate immunity, which provides insight into how teleost SRP54 regulates IFN signaling.

Unveiling the Connections Between Melanoma Differentiation-Associated Gene 5 (MDA5)-Positive Dermatomyositis and Its Potential Association With COVID-19: A Report of Two Cases.

Dermatomyositis is a rare inflammatory condition affecting the skin, muscles, and joints. This series of anti-melanoma differentiation-associated gene 5 (anti-MDA5) autoantibody-positive cases highlights a possible link between anti-MDA5-positive dermatomyositis and COVID-19 exposure. A retrospective analysis was performed on anti-MDA5-positive dermatomyositis patients at a district general hospital between January 2021 and July 2023. Information was gathered on the clinical profiles, diagnostics, management, and disease course. The two cases are as follows: (1) A 44-year-old Asian female presented with back pain, tender proximal muscles, symmetrical synovitis, and Gottron's papules, which gradually began after a COVID vaccine and worsened after COVID-19 infection. Despite prompt management, she required finger amputation and a switch to immunomodulators to achieve arthritic disease control. (2) A 49-year-old Caucasian female presented with progressive dyspnea, polyarthralgia, dusky maculopapular rash, and oral ulcers, which began after a COVID vaccine and worsened after COVID-19 infection. Steroids and immunomodulators improved mobility and respiratory symptoms, while biologics subdued her skin symptoms. This case study provides growing evidence for an intriguing association between COVID-19 exposure and anti-MDA5 antibody-positive dermatomyositis. Further research is required to elucidate the underlying pathogenic mechanism. Early involvement of a multidisciplinary team, consideration of symptom variety, infection vigilance, and impact on quality of life are important factors for clinicians to consider when tailoring the management of these patients for optimized outcomes.

Anti-melanoma Differentiation-Associated Gene 5 (Anti-MDA5) Dermatomyositis-Associated Interstitial Lung Disease Complicated by Pneumomediastinum: A Case Report and Literature Review.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) dermatomyositis (DM) is a subset of amyopathic myositis and is associated with unique cutaneous manifestations and rapidly progressive interstitial lung disease (RP-ILD). A rare complication associated with high mortality is the occurrence of pneumomediastinum. We present a case of a 58-year-old female with anti-MDA5 DM-associated interstitial lung disease (ILD) complicated by pneumomediastinum. Treatment with pulse dose steroids and intravenous cyclophosphamide led to clinical improvement and resolution of the pneumomediastinum. Our case emphasizes the recognition of ILD-associated pneumomediastinum in patients with anti-MDA5 DM. Swift diagnosis and aggressive treatment are crucial due to the associated high mortality.

ADAR1: from basic mechanisms to inhibitors.

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded RNA (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency in humans and mice results in profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate RNA sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces the expression of cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), and Z-DNA/RNA binding protein 1 (ZBP1). Immunogenic RNAs 'defused' by ADAR1 may include transcripts from repetitive elements and other long duplex RNAs. Here, we review these recent fundamental discoveries and discuss implications for human diseases. Some tumours depend on ADAR1 to escape immune surveillance, opening the possibility of unleashing anticancer therapies with ADAR1 inhibitors.

An Adolescent Case of Anti-MDA5 Antibody-Positive Juvenile Dermatomyositis With Interstitial Lung Disease Successfully Treated by Multitarget Therapy Avoiding Cyclophosphamide: A Case Report and Literature Review.

Juvenile dermatomyositis (JDM) patients who test positive for the antimelanoma differentiation-associated gene 5 (MDA5) antibody have a poor prognosis because of rapidly progressing interstitial lung disease (ILD). However, agreement on the best treatment for this condition remains elusive. We encountered a 13-year-old girl with anti-MDA5 antibody-positive JDM who presented with arthritis and was already showing signs of ILD when she was admitted to the hospital. While cyclophosphamide (CY) is commonly used, it can cause gonadal disorders and other complications when administered to adolescent females. Consequently, we chose multitarget therapy, which includes tacrolimus and mycophenolate mofetil. Her ILD and skin symptoms gradually improved, and she was able to maintain remission and avoid CY administration for three years. We conducted a thorough literature review to determine the efficacy and safety of multitarget therapy for anti-MDA5 antibody-positive DM and JDM. Multitarget therapy shows promise as a potentially effective and relatively safe treatment. The ability to avoid CY, which is especially important for adolescent patients concerned about fertility preservation, highlights a significant benefit of this multitarget therapy for anti-MDA5 antibody-positive DM and JDM patients.

Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins.

Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.

A Review of Myositis-Associated Interstitial Lung Disease.

There is a well-established relationship between different subsets of idiopathic inflammatory myopathies (IIMs, myositis) and interstitial lung disease (ILD), with lung complications sometimes presenting prior to myopathic manifestations. The subtypes of myositis include those that are strongly associated with ILD, such as polymyositis (PM) and dermatomyositis (DM). Research has shown that in certain patients, these can then be further divided into subtypes using myositis-specific antibodies (MSAs), which are specific for myositis, and myositis-associated antibodies (MAAs), which can be found in myositis in overlap syndromes with other connective tissue diseases (CTDs). Notably, certain MSAs and MAAs are associated with ILD in patients with myositis. The clinical presentations of ILD in patients with myositis can vary widely and can be insidious in onset and difficult to diagnose. As ILD can progress rapidly in some cases, it is essential that clinicians are able to identify and diagnose ILD in patients with myositis. For this reason, the aim of this review is to highlight the clinical features, diagnostic criteria, important histopathologic, laboratory, and radiographic features, and treatment modalities for those patients with myositis-associated ILD.

Asymptomatic and slowly progressive anti-MDA5 ILD: A report of three cases deviating from a notoriously rapidly progressive ILD.

Background: Anti-melanoma differentiation-associated gene 5-positive (anti-MDA5) dermatomyositis (DM) is a rare autoimmune disease associated with rapidly-progressive interstitial lung disease (RP-ILD.) The reported morbidity and 6-month mortality remains high from 33 to 66 % with RP-ILD most often developing within three months of diagnosis. Most cases require aggressive immunosuppression with combination therapy. Asymptomatic or slowly progressive cases of anti-MDA5 ILD are not well described in the literature. We report three cases of Latino patients with asymptomatic or slowly progressive anti-MDA5 ILD.Case descriptions. Case 1: A 54-year-old woman from Honduras with known diagnosis of anti-MDA5 dermatomyositis presented for ILD. She denied respiratory symptoms. Computed tomography (CT) chest showed multifocal patchy areas of scattered groundglass opacities throughout all lobes of the lungs, predominately in a subpleural distribution within the lower lobes. Pulmonary function testing (PFTs) showed mild-to-moderate restriction. She was treated with mycophenolate mofetil monotherapy for her skin manifestations. At 18 months follow-up, she denied respiratory symptoms, and PFTs were normal. Case 2: An 80-year-old man from Cuba was seen in pulmonary clinic to establish care. He was diagnosed with pulmonary fibrosis 11 years earlier with positive anti-MDA5. He denied respiratory symptoms. PFTs showed moderate obstruction and mild to moderate restriction. CT chest showed reduced lung volumes and findings compatible with usual interstitial pneumonia. He was started on nintedanib. Fifteen months following the initial visit, his PFTs remained stable. Follow-up CT chest showed stable pulmonary fibrosis. At all subsequent visits, he reported mild to moderate, slowly progressive dyspnea on exertion and was maintained on nintedanib. Thirteen years after his initial ILD diagnosis, he was diagnosed with pancreatic adenocarcinoma. Case 3: A 70-year-old woman from Peru presented to pulmonary clinic with cough for two months. She also reported pain in several metacarpophalangeal joints. She denied dyspnea. Rheumatologic serologies revealed positive anti-MDA5. PFTs were normal. Her cough was treated with cough suppressants and resolved. At a subsequent visit 8 months after presentation, she denied respiratory symptoms, and her joint pain remained mild. Given her lack of respiratory symptoms and normal PFTs, she was not initiated on ILD-specific treatment. Conclusions: While anti-MDA5 ILD is certainly associated with RP-ILD, clinicians should maintain awareness that there may be cases of asymptomatic or slowly progressive ILD as well.

IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus.

Intron-containing RNA expressed from the HIV-1 provirus activates type 1 interferon in primary human blood cells, including CD4+ T cells, macrophages, and dendritic cells. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with short hairpin RNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte-derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the interferon-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with nontargetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant 2-CARD domain-deletion or phosphomimetic point mutations, indicates that IFIH1 (MDA5) filament formation, dephosphorylation, and association with MAVS are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 (MDA5) and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1 knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes by HIV-1. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 (MDA5), over two orders of magnitude, was revealed by formaldehyde cross-linking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus and that IFIH1 potentially contributes to chronic inflammation in people living with HIV-1, even in the presence of effective antiretroviral therapy.

Serum interleukin-34 levels in dermatomyositis: a potential biomarker for anti-MDA5-antibody-associated interstitial lung disease.

OBJECTIVES: Interleukin (IL)-34 is a hematopoietic cytokine that promotes macrophage activation. Macrophage activation in interstitial lung disease (ILD) in patients with dermatomyositis (DM), especially in those with anti-melanoma differentiation-associated gene 5 (MDA5) antibody suggests the involvement of IL-34 in the disease. However, the association between IL-34 and DM is unknown. In this study, we aimed to determine serum IL-34 levels in DM patients and evaluate their association with DM-ILD. METHODS: We measured serum IL-34 levels in 56 DM patients and 14 age- and sex- matched healthy controls by enzyme-linked immunosorbent assay, and examined their correlation with clinical parameters. In addition, pre- and post-treatment serum IL-34 levels were examined using serum samples from 7 anti-MDA5 antibody-positive DM patients. RESULTS: Serum IL-34 levels were significantly elevated in DM patients, especially in those with anti-MDA5 antibody, compared with healthy controls. In anti-MDA5-antibody-positive DM patients, serum IL-34 levels positively correlated with serum levels of ferritin and anti-MDA5 antibody, which are known biomarkers for rapidly progressive (RP)-ILD. Following combined immunosuppressive therapy, serum IL-34 levels decreased along with ferritin and anti-MDA5 antibody. CONCLUSION: These data suggest that IL-34 may be involved in the development of RP-ILD in anti-MDA5 antibody-positive DM. Serum IL-34 levels can serve as a potential biomarker for RP-ILD in this clinical entity.

Soluble form of the MDA5 protein in human sera.

Viral double-stranded RNA (dsRNA) is sensed by toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5). MDA5 recognizes the genome of dsRNA viruses and replication intermediates of single-stranded RNA viruses. MDA5 also plays an important role in the development of autoimmune diseases, such as Aicardi-Goutieres syndrome and type I diabetes. Patients with dermatomyositis with serum MDA5 autoantibodies (anti-CADM-140) are known to have a high risk of developing rapidly progressive interstitial lung disease and poor prognosis. However, there have been no reports on the soluble form of MDA5 in human serum. In the present study, we generated in-house monoclonal antibodies (mAbs) against human MDA5. We then performed immunohistochemical analysis and sensitive sandwich immunoassays to detect the MDA5 protein using two different mAbs (clones H27 and H46). As per the immunohistochemical analysis, the MDA5 protein was moderately expressed in the alveolar epithelia of normal lungs and was strongly expressed in the cytoplasm of lymphoid cells in the tonsils and acinar cells of the pancreas. Interestingly, soluble MDA5 protein was detectable in the serum, but not in the urine, of healthy donors. Soluble MDA5 protein was also detectable in the serum of patients with dermatomyositis. Immunoblot analysis showed that human cells expressed a 120 kDa MDA5 protein, while the 60 kDa MDA5 protein increased in the supernatant of peripheral mononuclear cells within 15 min after MDA5 agonist/double-strand RNA stimulation. Hydrogen deuterium exchange mass spectrometry revealed that an anti-MDA5 mAb (clone H46) bound to the epitope (415QILENSLLNL424) derived from the helicase domain of MDA5. These results indicate that a soluble MDA5 protein containing the helicase domain of MDA5 could be rapidly released from the cytoplasm of tissues after RNA stimulation.

Effectiveness of generic tofacitinib in idiopathic inflammatory myositis (IIM)-a retrospective analysis from Indian Myositis Registry (MyoIN).

OBJECTIVES: Determine domain-based-outcomes and steroid-sparing efficacy of generic tofacitinib in IIM. METHODS: This is a multicenter retrospective study wherein clinical phenotype, autoantibody profile, prior immunosuppressives, and outcomes at 3, 6, and 12 months were retrieved for IIM patients prescribed tofacitinib. Overall clinical response was assessed as complete or partial remission as per physician judgment. Changes in cutaneous and calcinosis domain were recorded as per physician global assessment (PGA), lung domain as per medical research council (MRC) dyspnea scale, and muscle strength by Manual Muscle Testing-8 (MMT-8). RESULTS: Forty-two patients of IIM with mean age 38.7 ± 16 years; (76.2% (N = 32) women), median duration of illness 48 (19;88) months were included. Commonest indication for initiating tofacitinib was either for refractory or as steroid sparing for cutaneous domain (N = 25/42, 59.5%) followed by calcinosis (N = 16/42, 38%). Overall complete and/or partial remission was achieved in 23/37 (64.8%), 30/35 (85.7%), and 29/30 (96.6%) patients at 3, 6, and 12 months, respectively. At 12-month follow-up, there was a reduction in prednisolone dose, with absolute decrease from a daily dose of 17.5 mg (IQR 5;50) to 2.5 mg (IQR 0;5) (p < 0.001). Individual domain assessments revealed improvement in cutaneous domain [16/25 (64%)] and calcinosis [6/15 (40%)]. Adverse effects included herpes zoster (N = 2/42, 4.8%) and dyslipidemia (N = 4/42, 9.5%). CONCLUSIONS: Treatment with generic tofacitinib significantly reduces the daily dose of corticosteroids and is effective in cutaneous domain including calcinosis in IIM. KEY POINTS: • This multicenter retrospective study is the first real-world data from India, elucidating steroid sparing efficacy of generic tofacitinib in patients with inflammatory myositis. • Domain-based outcome assessment suggests good clinical improvement especially in cutaneous domain, even those with refractory disease. • Modest benefits were evident in calcinosis, but its effect on the muscle and pulmonary domain appears limited.

Celiac disease prevalence in patients with idiopathic inflammatory myopathies, a cross-sectional study.

Up to 30% of patients with celiac disease (CD) suffer from concurrent autoimmune disease, compared to 3% of the general population. The association between CD and the current clinical phenotypes of inflammatory myopathies (IIM) patients has not been thoroughly addressed. Assess the CD features among patients with IIM and their relationship with the clinical phenotype and the myositis specific (MSA) and associated antibodies (MAA). For this cross-sectional study, we recruited 99 adult patients classified as IIM from a tertiary center in Mexico. We assessed serum MSA, MAA, and CD-associated autoantibodies (IgA anti-tissue transglutaminase (tTG) and both IgA and IgG anti-deaminated gliadin peptide (DGP)). Patients with highly suggestive serology for CD were then tested for IgG anti-endomysium antibodies, and a duodenal biopsy was performed. 70.7% of patients were positive for at least one antibody. Nine duodenal biopsies were taken, revealing findings compatible with celiac disease in two cases. Subjects with anti-MDA5 antibodies were more likely to have positive anti-tTG IgA antibodies (OR 6.76, 95% CI 1.85-24.62, P = 0.013) and suggestive CD serology (OR 6.41, 95% CI 1.62-25.29, P = 0.009). Patients with anti-Mi2 antibodies were more likely to have positive anti-DGP IgG antibodies (OR 3.35, 95% CI 1.12-9.96, P = 0.039), while positivity for these autoantibodies was less frequent in patients with anti-NXP2 antibodies (OR 0.22, 95% CI 0.06-0.80, P = 0.035). There is a higher prevalence of serologic and definite CD in patients with IIM compared to the general population. Identifying this subgroup of patients may have prognostic and therapeutic implications. Key points • The study estimated a serological celiac disease (CD) prevalence of 70.7% in patients with idiopathic inflammatory myopathies (IIM) and a biopsy-confirmed prevalence of 2%, suggesting that IIM patients should be considered a high-risk population for CD. • We identified a significant association between serological CD and the presence of anti-MDA5 and anti-Mi2 antibodies, suggesting a potential justification for celiac disease screening in this specific subgroup of patients. • The impact of gluten-free diets on IIM patients with serological markers of CD remains untested and warrants further investigation through prospective, randomized studies.

[Diagnosis of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis led by sarcoplasmic myxovirus resistance protein A expression on muscle pathology].

A 44-year-old woman with autism spectrum disorder developed bulbar symptoms and generalized muscle weakness 7 months before referral. Six months before, she was administered glucocorticoid for liver involvement. During the course, while she presented alopecia, skin ulcers, and poikiloderma, hyperCKemia was observed only twice. Due to complications including cardiac involvement and hearing loss as well, we suspected mitochondrial disease and performed a muscle biopsy. The muscle pathology showed sarcoplasmic myxovirus resistance A (MxA) expression with scattered pattern. Since anti-melanoma differentiation-associated gene 5 (MDA5) antibody was detected, we diagnosed the patient with anti-MDA5 antibody-positive dermatomyositis (DM). We reinforced immunosuppressive therapy, and her clinical symptoms and liver involvement were improved. When we diagnose a case of anti-MDA5 antibody-positive DM who is difficult to make clinical diagnosis, it may be valuable to evaluate sarcoplasmic MxA expression on muscle pathology.

Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy.

Colorectal cancer is the second most prevalent and deadly cancer worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for the treatment of solid tumors. However, less than 5 % of colorectal cancer patients respond to immune checkpoint therapy. Thus, it is of great scientific significance to develop "potentiators" for immune checkpoint therapy. In this study, we found that knocking down different DNMT and HDAC isoforms could increase the expression of IFNs in colorectal cancer cells, which can enhance the effectiveness of immune checkpoint therapy. Therefore, the combined inhibition of DNMT and HDAC cloud synergistically enhance the effect of immunotherapy. We found that dual DNMT and HDAC inhibitors C02S could inhibit tumor growth in immunocompetent mice but not in immunocompromised nude mice, which indicates that C02S exerts its antitumor effects through the immune system. Mechanistically, C02S could increase the expression of ERVs, which generated the intracellular levels of dsRNA in tumor cells, and then promotes the expression of IFNs through the RIG-I/MDA5-MAVS signaling pathway. Moreover, C02S increased the immune infiltration of DCs and T cells in microenvironment, and enhanced the efficacy of anti-PD-L1 therapy in MC38 and CT26 mice model. These results confirmed that C02S can activate IFNs through the RIG-I/MDA5-MAVS signaling pathway, remodel the tumor immune microenvironment and enhance the efficacy of immune checkpoint therapy, which provides new evidence and solutions for the development of "potentiator" for colorectal cancer immunotherapy.

Tacrolimus Personalized Therapy based on CYP3A5 Genotype in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases, especially anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin) -outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all phase IIM patients (p = 0.001, 0.013, 0.002, and < 0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all phase MDA5+ DM patients (p = 0.007, 0.001, 0.036, and < 0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/d to attain the target Cmin, while nonexpressers required 0.046 mg/kg/d (p = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.