Interstitial lung disease and myositis.

PURPOSE OF REVIEW: In patients with myositis, interstitial lung disease (ILD) is one of the major causes of morbidity and mortality. Given the limited evidence, there is an urgent need to refine the treatment for myositis-ILD. This review aims to highlight recent updates on the management of myositis-associated ILD, focusing on screening, risk stratification, and treatment. RECENT FINDINGS: Asian race and/or residence, dermatomyositis, mechanic's hand, antisynthetase antibodies, and antimelanoma differentiation-associated gene 5 antibodies are risk factors for ILD development. Patients with such risk factors should be screened for ILD using high-resolution computed tomography. Various prediction models for mortality or rapidly progressive ILD (RP-ILD) in patients with myositis-ILD have been proposed, but validation of these models in multiple independent studies is required. Academic societies in Japan, the United Kingdom, and the United States have proposed tentative treatment algorithms for myositis-ILD on the basis of the presence or absence of RP-ILD. SUMMARY: Knowledge on myositis-ILD risk stratification, potentially useful for personalized management approaches in clinical practice, is accumulating. However, further global joint efforts are necessary to build a strong evidence base for consensus algorithms for myositis-ILD.

Clinical phenotyping in patients with anti-synthetase antibodies using cluster analysis.

Objectives: To characterize clinically distinct subgroups among unselected patients with anti-synthetase antibodies using cluster analysis. Methods: This study evaluated patients with anti-synthetase antibodies registered to two independent cohorts; 106 consecutive patients from a prospective, single-centre cohort of the Scleroderma/Myositis Centre of Excellence (SMCE) were used as a derivation cohort and 125 patients from the Multicentre Retrospective Cohort of Japanese Patients with Myositis-Associated Interstitial Lung Disease (JAMI) were used as a validation cohort. Anti-synthetase antibodies were identified by RNA immunoprecipitation. A multiple correspondence analysis followed by hierarchical clustering was performed to aggregate the patients into homogeneous subgroups. Subsequently, a simple-to-use classification tree was generated using classification and regression tree analysis. Results: Three clusters were identified in the SMCE cohort: cluster 1 (n = 48), the interstitial pneumonia with autoimmune features/amyopathic dermatomyositis cluster, associated with older age at diagnosis and a higher frequency of malignancy; cluster 2 (n = 46), the DM cluster, corresponded to a younger age at diagnosis with a higher prevalence of myositis, arthritis, DM pathognomonic rashes, mechanic's hands and fever; and cluster 3 (n = 12), the SSc cluster, characterized by chronic interstitial lung disease. There was no significant difference in overall survival or progression-free survival between the clusters. A simple classification tree using myositis and RP was created in the SMCE cohort. Clusters 1 and 2 were successfully reproduced and the classification tree demonstrated favourable performance in the JAMI cohort. Conclusion: Patients with anti-synthetase antibodies were classified into three distinct phenotypes, indicating substantial heterogeneity within this patient group.

Lung ultrasound in the assessment of interstitial lung disease in patients with connective tissue disease: Performance in comparison with high-resolution computed tomography.

OBJECTIVE: To investigate clinical relevance of performing lung ultrasound (LUS) in patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) in comparison with high-resolution computed tomography (HRCT). METHODS: This single-centre study enrolled eligible patients with CTD-ILD from the prospective LUS registry. Total B-lines were detected by assessment at 14 sites via LUS. Forced vital capacity, diffusing lung capacity for carbon monoxide (DLCO), DLCO/alveolar volume, 6-minute walking distance, and the ILD-GAP index were used as ILD prognostic parameters. Correlations were examined using single and multiple regression analyses. RESULTS: Sixty-seven patients were enrolled, including 29 with idiopathic inflammatory myopathy or anti-synthetase syndrome, 25 with systemic sclerosis (SSc), 10 with rheumatoid arthritis, and 3 with mixed connective tissue disease. The total number of B-lines correlated with ILD extent on HRCT in patients with CTD-ILD (r = 0.66; P < 0.001), particularly in patients with SSc-ILD (r = 0.78; P < 0.001). Total B-lines and ILD extent on HRCT showed comparable correlations with prognostic parameters, while multiple regression analysis revealed the limited benefit of performing LUS in addition to HRCT in predicting correlations with prognostic factors. CONCLUSIONS: LUS serves as an alternative tool for assessing the severity and prognosis of patients with CTD-ILD.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Dissociating Autoantibody Responses against Ro52 Antigen in Patients with Anti-Synthetase or Anti-MDA5 Antibodies.

We aimed to dissociate the autoantibody response against the Ro52 protein in patients with anti-synthetase or anti-melanoma differentiation-associated gene 5 (MDA5) antibodies to explore the potential roles of different anti-Ro52 autoantibody responses in disease subclassification. This study used a single-center, prospective myositis cohort involving 122 consecutive patients with anti-synthetase antibodies identified by RNA immunoprecipitation (RNA-IP) and 34 patients with anti-MDA5 antibodies detected using enzyme immunoassay (EIA). Anti-Ro52 antibodies were measured using commercial EIA kits, while anti-Ro/SSA antibodies were identified using RNA-IP. Clinical features and outcomes were stratified according to two different patterns of autoantibody responses against Ro52, including "isolated anti-Ro52", defined by positive anti-Ro52 and negative anti-Ro/SSA antibodies, and "anti-SSA-Ro52", defined by positive anti-Ro52 and anti-Ro/SSA antibodies. Isolated anti-Ro52 positivity was the most prevalent autoantibody response in patients with both anti-synthetase (40/122; 32.8%) and anti-MDA5 antibodies (8/34; 23.5%). Isolated anti-Ro52 or anti-SSA-Ro52 positivity was associated with Gottron's sign in patients with anti-synthetase antibodies, while in patients with anti-MDA5 antibodies, isolated anti-Ro52 positivity was associated with respiratory insufficiency at initial presentation and poor overall survival. Isolated anti-Ro52 positivity could be a potential biomarker for patient stratification; however, the clinical significance of dissociating isolated anti-Ro52 positivity from overall anti-Ro52 positivity was not evident.

The Role of Environmental Factors in the Development of Idiopathic Inflammatory Myopathies: a Narrative Review.

PURPOSE OF REVIEW: This review aims to evaluate recent findings on the role of environmental factors in the development and clinical presentation of idiopathic inflammatory myopathies (IIMs). RECENT FINDINGS: A targeted literature review was conducted to identify reports relevant to the association between environmental factors and IIMs published over the past three years. There has been an increasing number of publications dealing with the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination with the development of IIMs, highlighting the significant role of the antiviral immune response in the pathogenesis of the disease. Traditional environmental factors associated with the pathogenic process of IIM subclassifications included drugs such as statins and immune checkpoint inhibitors, ultraviolet radiation, smoking, air pollutants, and vitamin D deficiency. Correlations of seasonality and residence with the onset of certain IIM subtypes suggest a potential role of environmental triggers in the pathogenic process. An interplay between genetic predisposition and various environmental factors might contribute to the development of IIMs as well as the heterogeneous clinical and serological presentation of IIMs. The growing evidence on the role of environmental factors in the development of IIMs provides important clues to elucidate the pathophysiology of these disease entities. The mechanisms underlying the interactions between genetic predisposition and environmental factors should be investigated in the future.

Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments.

OBJECTIVES: To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM). METHODS: Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24. RESULTS: No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis. CONCLUSIONS: UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study. TRIAL REGISTRATION NUMBER: NCT03981744.

New paradigm in the treatment of myositis-associated interstitial lung disease.

INTRODUCTION: Interstitial lung disease (ILD) is the leading cause of mortality in idiopathic inflammatory myopathies or myositis. Clinical characteristics, including the course of ILD, rate of progression, radiological and pathohistological morphologies, extent and distribution of inflammation and fibrosis, responses to treatment, recurrence rate, and prognosis, are highly variable among myositis patients. A standard practice for ILD management in myositis patients has not yet been established. AREAS COVERED: Recent studies have demonstrated the stratification of patients with myositis-associated ILD into more homogeneous groups based on the disease behavior and myositis-specific autoantibody (MSA) profile, leading to better prognoses and prevention of the burden of organ damage. This review introduces a new paradigm in the management of myositis-associated ILD based on research findings from relevant literature selected by a search of PubMed as of January 2023, as well as expert opinions. EXPERT OPINION: Managing strategies for myositis-associated ILD are being established to stratify patients based on the severity of ILD and the prediction of prognosis based on the disease behavior and MSA profile. The development of a precision medicine treatment approach will provide benefits to all relevant communities.

Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review.

Objective: Severe digital ischemia, including digital ulcers and gangrene, is considered rare in patients with antisynthetase antibodies. This study aimed to elucidate the clinical features of antisynthetase-positive patients complicated with digital ulcers and/or gangrene using a systematic literature review and case series in a single-center cohort. Methods: A systematic literature review was conducted to identify reports describing antisynthetase-positive cases with digital ulcers and/or gangrene. Our cohort of consecutive patients with antisynthetase antibodies was stratified by the history of severe digital ischemia. Demographic and clinical features and outcomes in patients with severe digital ischemia identified in the systematic literature review and our cohort were compared with those in patients without severe digital ischemia in our cohort. Results: The systematic literature review revealed 12 antisynthetase-positive patients with severe digital ischemia from one case series and eight case reports. Seven (7%) of 100 patients with antisynthetase antibodies in our cohort had a record of severe digital ischemia. Severe digital ischemia was often found at presentation and was associated with the classification of systemic sclerosis with or without myositis overlap. Clinical features associated with severe digital ischemia in antisynthetase-positive patients included Raynaud's phenomenon (p < 0.001), digital pitting scars (p = 0.001), and nailfold capillary abnormality (p = 0.02). Outcomes of severe digital ischemia were generally favorable with vasodilators. Conclusion: Severe digital ischemia is an overlooked complication in antisynthetase-positive patients. Antisynthetase antibodies should be measured in patients presenting with digital ulcers or gangrene, especially in those with systemic sclerosis phenotype and features associated with antisynthetase antibodies in the absence of systemic sclerosis-specific autoantibodies.

Abatacept downregulates Fcγ receptor I on circulating monocytes: a potential therapeutic mechanism in patients with rheumatoid arthritis.

BACKGROUND: Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis. METHODS: Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined. RESULTS: CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1ß, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex. CONCLUSIONS: The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production.

Mortality Risk Stratification Using Cluster Analysis in Patients With Myositis-Associated Interstitial Lung Disease Receiving Initial Triple-Combination Therapy.

Objective: To stratify patients with polymyositis/dermatomyositis-associated interstitial lung disease (ILD) who were initially treated with an intensive regimen consisting of high-dose corticosteroids, a calcineurin inhibitor, and intravenous cyclophosphamide (triple-combo therapy) into subgroups based on mortality outcomes by a cluster analysis using a large-scale multicenter retrospective cohort of Japanese patients with myositis-associated ILD (JAMI). Methods: Two-step cluster analysis of preclustering and subsequent hierarchical clustering was conducted in 185 patients who received triple-combo therapy in an unbiased manner. Initial predictors for mortality previously reported in patients with myositis-associated ILD were used as variables and included age, sex, disease duration, classification of myositis, requirement of supplemental oxygen, anti-aminoacyl tRNA synthetase (ARS) antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, and serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6). The cluster model was further applied to 283 patients who received conventional regimens consisting of corticosteroids with or without a single immunosuppressive agent (dual-combo therapy or monotherapy). Cumulative survival rates were compared using Kaplan-Meier analysis, and the log-rank test was used to test for significant differences between two groups. Results: We developed a cluster model consisting of 6 clusters, which were categorized by age at onset, clinically amyopathic dermatomyositis, CRP, KL-6, requirement of supplemental oxygen, anti-ARS antibody, and anti-MDA5 antibody. This model was judged to be of good quality based on the silhouette measure of cohesion and separation of 0.6. These clusters were regrouped into three subsets based on low (<10%), moderate (10-50%), and high (>50%) mortality rates. The performance of the clustering was generally replicated in patients who received initial dual-combo therapy or monotherapy. Survival benefits of triple-combo therapy over dual-combo therapy or monotherapy were not observed in any of the clusters. Conclusion: We successfully developed a cluster model that stratified patients with myositis-associated ILD who were treated with initial triple-combo therapy into subgroups with different prognoses, although this model failed to identify a patient subgroup that showed survival benefits from triple-combo therapy over dual-combo therapy or monotherapy.

Antiviral proinflammatory phenotype of monocytes in anti-MDA5 antibody-associated interstitial lung disease.

OBJECTIVE: To evaluate upstream and downstream regulators leading to macrophage activation and subsequent cytokine storm in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD). METHODS: We conducted an integrated miRNA-mRNA association analysis using circulating monocytes from 3 patients with anti-MDA5-associated ILD and 3 healthy controls and identified disease pathways and a regulator effect network by Ingenuity Pathway Analysis (IPA). The expression of relevant genes and proteins was verified using an independent validation cohort, including 6 patients with anti-MDA5-associated ILD, 5 with anti-aminoacyl tRNA synthetase antibody-associated ILD, and 6 healthy controls. RESULTS: IPA identified 26 matched pairs of downregulated miRNA and upregulated mRNAs and revealed that canonical pathways mediated by type I IFN signalling and C-C motif ligand 2 (CCL2) were responsible for the pathogenic process (P < 0.05 for all pathways). The regulatory network model identified IFN-ß; Toll-like receptors 3, 7, and 9; and PU.1 as upstream regulators, while the downstream effect of this network converged at the inhibition of viral infection. mRNA and protein expression analysis using validation cohort showed a trend towards the increased expression of relevant molecules identified by IPA in patients with anti-MDA5-associated ILD compared with those with anti-aminoacyl tRNA synthetase antibody-associated ILD or healthy controls. The expression of all relevant genes in monocytes and serum levels of CCL2 and IFN-ß declined after treatment in survivors with anti-MDA5-associated ILD. CONCLUSION: An antiviral proinflammatory network orchestrated primarily by activated monocytes/macrophages might be responsible for cytokine storm in anti-MDA5-associated ILD.

Utility of Ultrasonography in Assessing Periaortitis Associated with Retroperitoneal Fibrosis: A Case Report.

Periaortitis is a rare vascular manifestation and is often associated with retroperitoneal fibrosis. Herein, we describe a case of periaortitis accompanied by retroperitoneal fibrosis in a patient who developed acute kidney insufficiency due to bilateral ureteral stenosis. Ultrasonography at presentation detected thickness of the outer layer of the bilateral common iliac artery and right internal and external iliac arteries, consistent with periaortitis. Moreover, follow-up ultrasound images revealed subsiding of the thickness of the arterial wall in response to treatment with corticosteroids. Because of its noninvasiveness and handiness, ultrasonography has become popular for the assessment of large vessels in clinical practice, particularly monitoring for affected lesions. Computed tomography, magnetic resonance imaging, and positron emission tomography are currently used for the diagnosis and monitoring of periaortitis, but in this case, ultrasonography was utilized in the diagnosis and monitoring of periaortitis as a supportive imaging modality, as the use of contrast agents was contraindicated because of renal insufficiency.

Tertiary lymphoid structures in the primary tumor site of patients with cancer-associated myositis: A case-control study.

Objective: To investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity. Methods: Cancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area. Results: Six CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls. Conclusion: The adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

Should we reconsider the definition of elderly-onset rheumatoid arthritis in an ageing society?

OBJECTIVES: The management of elderly-onset rheumatoid arthritis (EORA) is challenging due to progressive functional disability, increased comorbidities, and high drug-related risks. EORA is defined as disease onset after 60 years since 1985. We assessed whether this cut-off age was optimal in a progressively ageing society. METHODS: This study used two cohorts of consecutive rheumatoid arthritis (RA) patients: the Nippon Medical School (NMS) cohort (n = 204) and the Keio cohort (n = 296). Clinical findings independently correlated with the age of RA onset were selected as 'EORA features' from previously reported EORA characteristics using univariable and multivariable regression analyses. Receiver operating characteristic curve analysis was conducted to determine the cut-off age that best selected patients with all EORA features. RESULTS: Acute onset, negative anti-cyclic citrullinated peptide antibody, and high erythrocyte sedimentation rate were selected as 'EORA features' in both cohorts. Patients with all EORA features were more numerous with age and almost exclusively older than 65 years. The optimal EORA cut-off age was 73 years with an area under the curve (AUC) of 0.82 in the NMS cohort and 68 with an AUC of 0.93 in the Keio cohort. In the NMS cohort, Health Assessment Questionnaire-Disability Index and comorbidities in patients with disease onset between 60 years and the projected cut-off age were similar to those in younger-onset RA, but differed from those in patients with disease onset older than the projected cut-off age. CONCLUSION: The optimal EORA cut-off age was greater than the conventional definition, but this needs to be validated in different patient populations.

2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Infratentorial onset of progressive multifocal leukoencephalopathy in a patient with systematic lupus erythematosus complicated with lymphoma: a case report.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by reactivation of JC virus (JCV). Typical PML shows confluent, bilateral but asymmetric, subcortical lesions in the supratentorial white matter on magnetic resonance imaging (MRI). We report here a 50-year-old woman with systemic lupus erythematosus complicated with lymphoma who developed PML with atypical brain MRI findings limited to the infratentorial area at presentation. She presented with numbness on the right side of the face, including her tongue, clumsiness of the right hand, and gait disturbance, after completion of remission induction therapy for lymphoma, including rituximab. Brain MRI demonstrated a solitary lesion limited to the cerebellum and brainstem, but a definitive diagnosis could not be made from cerebrospinal fluid study or tentative histologic evaluation of brain biopsy specimens. Despite methylprednisolone pulse therapy, her neurological deficits progressively worsened. One month later, in-depth analysis of her cerebrospinal fluid and brain biopsy specimens confirmed the presence of JCV. Eventually, the localised unilateral crescent-shaped cerebellar lesions on MRI expanded to the contralateral cerebellum, middle cerebellar hemisphere, pons, and midbrain and finally developed multifocal invasion into the white matter of the cerebral hemispheres. Our case suggests that PML could first present with a solitary infratentorial lesion in immunocompromised patients.

Risk Prediction Modeling Based on a Combination of Initial Serum Biomarker Levels in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: To establish predictive models for mortality in patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) using a combination of initial serum biomarker levels. METHODS: The Multicenter Retrospective Cohort of Japanese Patients with Myositis-Associated ILD (JAMI) database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risk factors predictive of all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and those without anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between subgroups using the Breslow test. RESULTS: In the derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels were identified as independent risk factors for mortality in both anti-MDA-5-positive and anti-MDA-5-negative patients. We then developed a prediction model based on anti-MDA-5 antibody status, CRP level, and KL-6 level, termed the "MCK model," to identify patients at low (<15%), moderate (15-50%), or high (≥50%) risk of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti-MDA-5-positive patients (P < 0.01 for low versus moderate risk and P = 0.03 for moderate versus high risk) and in anti-MDA-5-negative patients (P < 0.001 for low versus moderate risk). The utility of the MCK model was replicated in the validation cohort. CONCLUSION: Our findings indicate that an evidence-based risk prediction model using CRP and KL-6 levels combined with anti-MDA-5 antibody status might be useful for predicting prognosis in patients with PM/DM-ILD.