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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.

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.

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.

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 (

Objectives Galectin-3 is involved in various biological activities, including immune activations and fibrosis. Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases of unknown aetiology, often complicated by interstitial lung disease (ILD). The aim of this study was to evaluate the expression of galectin-3 in sera and tissues of patients with IIM and assess the associations of galectin-3 with patient characteristics and disease activity. Results Serum galectin-3 levels were significantly higher in IIM patients than in healthy controls. The serum galectin-3 levels positively correlated with serum levels of inflammatory markers and proinflammatory cytokines/chemokines and the Myositis Intention-to-Treat Activity Index. Stratification analysis revealed that patients with IIM-associated ILD (IIM-ILD) had significantly higher levels of serum galectin-3 than those without IIM-ILD. In addition, patients with acute/subacute interstitial pneumonia had significantly higher levels of serum galectin-3 than those with chronic interstitial pneumonia. Furthermore, serum galectin-3 levels in IIM-ILD patients correlated with the radiological assessments of parenchymal lung involvement and treatment response. Immunohistochemical analysis revealed that galectin-3 was expressed in inflammatory cells of myositis and dermatitis sections, whereas in ILD sections, galectin-3 was expressed in interstitial fibrosis and inflammatory cells. Conclusion Galectin-3 may be involved in the pathogenesis of inflammatory and fibrotic conditions in IIM and can serve as a potential biomarker of disease activity, especially in patients with IIM-ILD.

Objective To clarify the incidence, risk factors, and impact of malignancy in patients with PM/DM-associated interstitial lung disease (ILD). Methods This study used data from 497 patients with PM/DM-associated ILD enrolled in a multicentre, retrospective and prospective cohort of incident cases. Cancer-associated myositis (CAM) was defined as malignancy diagnosed within 3 years before or after PM/DM diagnosis. Demographic and clinical information was recorded at the time of diagnosis, and data about the occurrence of mortality and malignancy was collected. Results CAM was identified in 32 patients with PM/DM-associated ILD (6.4%). Patients with CAM were older (64 vs 55 years, P < 0.001), presented with arthritis less frequently (24% vs 49%, P = 0.01), and showed a lower level of serum Krebs von den Lungen-6 (687 vs 820 IU/l, P = 0.03) than those without CAM. The distribution of myositis-specific autoantibodies, including anti-melanoma differentiation–associated gene 5, anti-aminoacyl tRNA synthetase, and anti-transcriptional intermediary factor 1-γ antibodies, did not differ between the groups. Survival analysis demonstrated that CAM patients had a poorer survival than non-CAM patients (P = 0.006), primarily due to excess deaths by concomitant malignancy, while mortality due to ILD-related respiratory failure was similar between the groups (P = 0.51). Conclusion Concomitant malignancy can occur in patients with PM/DM-associated ILD, and has significant impact on mortality. Older age, lack of arthritis, and a lower level of serum Krebs von den Lungen-6 at diagnosis are predictors of concomitant malignancy.

A 47-year-old man was referred to our hospital with a 1-month history of fever and dyspnea after inhalation of insecticide in a confined space. We diagnosed rapidly progressive interstitial pneumonia. High-dose methylprednisolone, tacrolimus, and intermittent infusion of cyclophosphamide were administered. His condition rapidly deteriorated; therefore, extracorporeal membrane oxygenation therapy was performed. Unfortunately, he died 69 days after admission. Although typical skin findings suggestive of dermatomyositis were absent, anti-melanoma differentiation-associate gene (anti-MDA5) antibody was positive. Our findings suggest that in patients with hyperferritinemia and rapidly progressive interstitial lung disease (RP-ILD) demonstrating random ground glass shadows and peripheral consolidations by high-resolution computed tomography (HRCT) even if skin manifestations related to dermatomyositis are not complicated, we should assume anti-MDA5 antibody-positive interstitial pneumonia. Keywords: Anti-melanoma differentiation-associated gene 5 antibody, Rapidly progressive interstitial pneumonia, Clinical amyopathic dermatomyositis, Extracorporeal membrane oxygenation

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-β; 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-β 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.

ObjectivesTo investigate whether the onset of polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung disease (ILD) is influenced by season and residence in the context of myositis-specific autoantibodies.MethodsFor patients with PM/DM-associated ILD enrolled in a multicentre cohort, 365 and 481 patients were eligible for seasonal and geographical analysis, respectively, based on the availability of reliable clinical information. The patients were divided into three groups: (1) anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive patients, (2) anti-aminoacyl tRNA synthetase (anti-ARS) antibody-positive patients and (3) patients negative for those antibodies. Seasonality was assessed by the Rayleigh test. Distance from residence to the nearest waterfront was measured on Google Map and was compared between groups by the exact Wilcoxon rank-sum test.ResultsIn anti-MDA5-positive patients, the disease developed more frequently in October–March (p=0.03), whereas a seasonal relationship was not found in the remaining two patient groups. Residence at disease onset in anti-MDA5-positive patients was significantly closer to the waterfront, especially to freshwater, compared with that in anti-ARS-positive or anti-MDA5-/ARS-negative patients (p=0.003 and 0.006, respectively).ConclusionsAnti-MDA5-associated ILD occurred predominantly from October to March in individuals residing near freshwater, suggesting an environmental influence on the onset of this disease subset.

Background Some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV. Results Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n = 18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r = 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset. Conclusions In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV.

The patient was a 62-year-old man with anticitrullinated protein antibody-positive rheumatoid arthritis (RA) and a history of repeated respiratory tract infections and organizing pneumonia for eigh...

Hughes–Stovin syndrome (HSS) is an extremely rare condition characterised by pulmonary artery aneurysms and deep vein thrombosis (DVT). We report the case of a 34-year-old Senegalese man who initially presented with fever, hemoptysis, and cough. Radiological and laboratory evaluation revealed right pulmonary artery aneurysms, intense inflammatory reaction, and renal dysfunction with protein and occult blood in urine. Vasculitis-like polyarteritis nodosa was suspected, and the patient was treated with oral high-dose prednisolone (PSL) followed by intravenous cyclophosphamide (IVCY). In the course of treatment, he developed bilateral leg edema, and DVT was revealed; he was finally diagnosed with HSS. As the findings of thrombi in the inferior vena cava extend to the level of the renal vein, the cause of renal dysfunction was suspected to be renal vein thrombosis. Continuing treatment with oral PSL and IVCY successfully improved his condition, resulting in remission.

We herein report a rare case of a 66-year-old woman who had synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome with marked sternal osteitis and bilateral pleural effusions. SAPHO syndrome was diagnosed based on the characteristic features of a hyperostotic sternum and thoracic spine. The inflammatory changes of sternal osteitis and involvement of the adjacent soft tissue were assumed to be the cause of the pleural effusions. The effusions decreased during the natural course of the disease and resolved after methotrexate therapy. The pain dramatically decreased with oral tramadol. Physicians should consider the possibility of SAPHO syndrome in patients with anterior chest pain and pleural effusions.

Subtyping myositis is helpful in the management of patients with idiopathic inflammatory myopathy (IIM). Myositis-specific and myositis-associated autoantibodies are powerful prognostic predictors of clinical manifestations, organ involvement, and outcome in this heterogeneous group of autoimmune diseases. Autoantibody assessment is helpful in managing these challenging IIM patients, including the identification of concomitant malignancy, interstitial lung disease (ILD), and refractory disease.

Recently identified and well-characterized myositis-specific autoantibodies (MSAs) include anti-transcription intermediary factor 1γ (TIF1-γ), anti-nuclear matrix protein 2 (NXP2), and anti-melanoma differentiation-associated gene 5 (MDA5). These antibodies are found in juvenile and adult patients with dermatomyositis (DM) with severe cutaneous involvement in the presence or absence of clinically apparent myositis. Anti-TIF1-γ and anti-NXP2 are associated with concomitant malignancy in adult patients, especially older individuals, and have no link to interstitial lung disease (ILD). On the other hand, patients with anti-MDA5 antibody frequently have ILD, which is often rapidly progressive, in both juvenile and adult patients. These MSAs have unique clinical and prognostic features and may be seen in amyopathic DM. Therefore, their identification is useful for predicting future clinical manifestations and outcomes.

Objective The aim of this study was to clarify predictive factors for sustained remission in adult patients with PM/DM, particularly focusing on stratification by myositis-specific autoantibodies (MSAs). Methods A total of 162 adult patients with PM/DM who were followed up for >1 year after diagnosis were retrospectively enrolled. MSAs were evaluated comprehensively in 102 patients whose sera were available. Sustained remission was defined as no evidence of disease activity (active skin rash, active myositis or active interstitial lung disease) for longer than a 6-month continuous period while undergoing myositis therapy or no medication. Clinical data were reviewed in patients’ medical charts Results The sustained remission rate for all patients was 58% during the median follow-up period at 4 years. With regard to MSAs, the achievement rate of sustained remission among MSA-negative patients was significantly higher than that for patients with anti-aminoacyl-tRNA synthetase (P = 0.004), anti-melanoma differentiation-associated gene 5 (P = 0.037) or anti-transcriptional intermediary factor 1-γ (P = 0.013) antibodies. MSA-negative status (odds ratio 5.84, P = 0.009) and absence of severe muscle weakness requiring assistance at diagnosis (odds ratio 43.6, P < 0.001) were independent factors associated with sustained remission in multivariate analysis. Cumulative remission rates were significantly higher (P < 0.001) in patients with both the MSA-negative status and absence of severe muscle weakness at diagnosis than the others. Conclusion MSA-negative status and the absence of severe muscle weakness requiring assistance at diagnosis are independent predictive factors for sustained remission in adult PM/DM patients.

Patient: Male, 67 Final Diagnosis: Unclassified vasculitis Symptoms: Fever • ocular pain • erythema • chest pain • headache Medication: — Clinical Procedure: Biopsy Specialty: Rheumatology Objective: Rare disease Background: Systemic vasculitides constitute heterogenous conditions affecting many organs and systems through blood vessel inflammation. Although there are some classifications for vasculitis, several vasculitides are “unclassified” because they cannot be clearly assigned to one of the known entities. Case Report: We report an autopsy case of a 67-year-old Japanese man who presented with fever, ocular pain, erythema, chest pain, and headache. The disease caused episcleritis, thrombophlebitis, extensive deep vein thrombosis, multiple pulmonary nodules and masses, hypertrophic pachymeningitis, and hyper-intensity areas in brain parenchyma on magnetic resonance images. Histopathology of the pulmonary nodule confirmed vasculitis affecting medium-to-small veins and arteries without necrotizing vasculitis or granulomatous inflammation. We diagnosed the patient with unclassified vasculitis based on the clinicopathological characteristics. Steroids in combination with immunosuppressants were used, but the disease was refractory and relapsing. The disease activity was eventually controlled with rituximab, but the patient died of bronchopneumonia. On autopsy, lung and brain findings indicated healed vascular inflammation. Conclusions: This is the first case report of unclassified vasculitis, which is characterized as medium-to-small-sized arteritis and phlebitis, causing episcleritis, thrombophlebitis, deep vein thrombosis, pulmonary vasculitis, and intracranial vasculitis. The clinical conditions share some similarities with granulomatosis with polyangiitis and Behçet’s disease; however, they meet no classification criteria of any specific vasculitis. More cases need to be analyzed to confirm our findings.

The presence of anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differential-associated gene 5 (MDA5) is strongly related to interstitial lung disease (ILD) in patients with dermatomyositis (DM). Several studies suggest a potential relationship between ILD and anti-small ubiquitin-like modifier activating enzyme (SAE) antibody in DM patients, but detailed clinical characteristics of anti-SAE-associated ILD still remain unknown. We have experienced 2 cases who were positive for anti-SAE antibody, who presented with ILD in the context of clinically amyopathic DM. These 2 patients had the following common ILD characteristics: an insidious course with preserved pulmonary function; a limited extent of pulmonary lesions with subpleural peripheral-dominant small ground glass opacity/consolidation on high-resolution computed tomography; and a favorable treatment response. These findings suggest that anti-SAE-associated ILD is unique in terms of clinical and imaging features and differs from ILD associated with anti-ARS or anti-MDA5 antibody.

We clarify clinical characteristics of patients with immune checkpoint inhibitor (ICI)-induced myositis. In 13 of 15 cases with ICI-induced myositis, the type of malignancy was melanoma. Eight, 4, and 3 patients received anti-PD-1 alone, anti-CTLA4 alone, and a combination of those, respectively. The mean period to the onset of ICI-induced myositis from the initiation of ICI was 4 weeks. Myocarditis was a complication in five patients. Seven of the patients died. The causes of death were myocarditis in three patients, respiratory muscle paralysis in two patients, and cancer progression in two patients. In patients without myocarditis or respiratory muscle paralysis, the prognosis for myositis was favorable with normalization of the CK levels occurring upon the cessation of ICI and the administration of immunosuppressive agents. Myocarditis and respiratory muscle paralysis are the major causes of death as immune-related adverse events in patients with ICI-induced myositis.

Objective.It has been reported that organizing pneumonia (OP) develops when patients with rheumatoid arthritis (RA) are treated with biologic disease-modifying antirheumatic drugs (bDMARD). However, the clinical characteristics and pathophysiology of OP in RA remain unknown in patients treated with bDMARD. We investigated the clinical characteristics and cytokine profiles of patients with RA-OP treated with bDMARD or conventional synthetic DMARD (csDMARD).Methods.Twenty-four patients with RA who had developed OP were enrolled. These patients included 12 treated with bDMARD (bDMARD-OP subset) and 12 treated with csDMARD (csDMARD-OP subset). We compared the clinical characteristics and cytokine profiles between the patients with OP (OP subset, n = 24) and non-OP patients (non-OP subset, n = 29).Results.There was no significant difference in clinical characteristics between the OP subset and the non-OP subset. Four patients developed OP within 2 months of bDMARD administration. In the other 8 patients, OP developed more than 1 year after the initiation of bDMARD. OP improved with corticosteroid treatment in all bDMARD-OP patients. After OP improved, bDMARD were readministered in 6 patients, and no OP recurrence was observed in any of these patients. Our multivariate analysis revealed that serum levels of interferon-α (IFN-α), interleukin (IL)-1β, IL-6, IL-8, and interferon-γ–inducible protein 10 were significantly associated with the development of OP, although these cytokines tended to be lower in the bDMARD-OP subset than in the csDMARD-OP subset.Conclusion.OP is unlikely to be fatal in patients treated with bDMARD or csDMARD. IFN-α and proinflammatory cytokines are associated with the pathophysiology of OP in RA.

Objective.The physical function of PM/DM patients after remission induction therapy remains unknown adequately. The aim of our study was to evaluate the present status of physical dysfunction and to clarify the clinical manifestations and myositis-specific autoantibodies (MSAs) associated with physical dysfunction after treatment in PM/DM.Methods.We obtained clinical data including the age at disease onset, gender, disease duration, laboratory data prior to initial treatment, and the specific treatment administered. We evaluated disease activity and physical dysfunction after treatment using the core set provided by the International Myositis Assessment and Clinical Studies Group.Results.57% of the 77 enrolled patients with PM/DM had troubles in daily living after treatment. At the enrolment, disease activity evaluated by physicians was only revealed in 20% of patients. In a multivariate analysis, the age at disease onset, female gender, and CK levels before treatment were significantly associated with the severity of physical dysfunction after treatment. Anti-SRP positivity was associated with more severe physical dysfunction after treatment than anti-ARS or anti-MDA5.Conclusions.Half of the PM/DM patients showed physical dysfunction after treatment. Age at disease onset, gender, CK level before treatment, and anti-SRP were significant predictors associated with physical dysfunction after treatment in PM/DM.

Background:Anti-Ro/SS-A (anti-SS-A) antibody is one of myositis-associated antibodies, and is found in patients with anti-synthetase antibodies1. Anti-SS-A antibody targets the complex consisting of Ro52 and Ro60 proteins coupled with cytoplasmic non-coding Y-RNAs. Autoantibody against Ro52 uncoupled with Y-RNAs (anti-uncoupled Ro52) is also present in patients with a variety of connective tissue diseases, including myositis2. However, the majority of previous studies used enzyme-linked immunoassay (EIA) for detection of anti-Ro52 antibodies, resulting in failure to discriminate between anti-Ro52 antibodies coupled and uncoupled with Y-RNAs. The prevalence and clinical significance of anti-uncoupled Ro52 antibodies still remain unclear in patients with anti-synthetase antibodies.Objectives:To elucidate clinical relevance of anti-uncoupled Ro52 antibodies in a cohort of anti-synthetase syndrome employing RNA immunoprecipitation assay (RNA-IP) in combination with EIA.Methods:This is a single-center, cross-sectional study involving 80 patients positive for anti-synthetase antibodies by RNA-IPP. Complete clinical information was obtained from a medical chart review. Serum samples were obtained at first visit and stored at -20°C until use. Anti-SS-A and anti-SS-B antibodies were detected by RNA-IP, and anti-Ro52 and anti-Ro60 antibodies were measured by commercial EIA kits (ORGENTIC, Mainz, Germany). Autoantibodies that immunoprecipitated Y-RNAs regardless of results of anti-anti-Ro52 or anti-Ro60 EIAs were regarded as anti-SS-A antibody, while antibodies that did not immunoprecipitate Y-RNAs but reacted with anti-Ro52 antibodies by EIA were regarded as anti-uncoupled Ro52 antibody. Student’s t-test, Mann-Whitney’s U test, and Fisher’s exact test were employed to compare the clinical features between each group. Cumulative survival rates were compared using log-rank test.Results:In our cohort of 80 patients with anti-synthetase antibody, mean age at diagnosis was 61 ± 12 years, and 76% were female. Clinical diagnosis was classic dermatomyositis (cDM) in 11, clinically amyopathic dermatomyositis (CADM) in 21, polymyositis (PM) in 11, systemic sclerosis (SSc) in 3, myositis-SSc overlap in 5, interstitial lung disease (ILD) alone in 29, and unclassified in 3. The antigenic specificity of anti-synthetase antibodies included Jo-1 in 19, PL-7 in 12, PL-12 in 9, EJ in 21, OJ in 4, and KS in 16. Anti-SS-A anti-SS-B antibodies were found in 14 (17%) and 2 (2.5%) patients, respectively. The presence of anti-Ro60 and anti-SS-A antibodies was almost concordant (P < 0.0001), although the presence of anti-Ro52 and anti-SS-A antibodies was not correlated (P = 0.8). This was primarily because of high prevalence (40%) of autoantibodies to uncoupled Ro52. Interestingly, prevalence of anti-uncoupled Ro52 antibodies was different among antigenic specificities of anti-synthetase antibodies: high in Jo-1 (58%) and EJ (55%), and low in PL-7 (8%) and OJ (0%). Gottron’s sign/papule was more frequent in patients with anti-uncoupled Ro52 than in those without (61% versus 28%, P = 0.005), resulting in clinical diagnosis of cDM or CADM more common in patients with anti-uncoupled Ro52 than in those without (59% versus 26%; P = 0.003). The prevalence and extent of ILD tended to be greater in anti-uncoupled Ro52-positive versus negative patients, but difference did not reach statistical significance. There were no differences in cumulative survival rates between patients stratified by the presence or absence of anti-uncoupled Ro52 antibodies.Conclusion:Autoantibodies to uncoupled Ro52 were commonly found in patients with anti-synthetase antibodies. Anti-Ro52 positivity might be useful for subclassifying anti-synthetase syndrome.References:[1]McHugh NJ et al.Nat Rev Rheumatol. 2018;14(5): 290-302.[2]Schulte-Pelkum J et al.Autoimmun Rev. 2009;8(7): 632-7.Disclosure of Interests:Akira Yoshida: None declared, Yuka Okazaki: None declared, Takahisa Gono Speakers bureau: Astellas, and Medical and Biological Laboratories, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim)

Background Lung diseases, such as airway disease and interstitial lung disease (ILD), are often complicated in patients with rheumatoid arthritis (RA). The presence of those pre-existing lung diseases is one of the poor prognostic factors and risk factors for infectious pneumonia in patients with RA. There have been several concerned issues regarding pulmonary complications in RA patients with pre-existing lung diseases during treatment with disease-modifying antirheumatic drugs (DMARDs) because of infectious pneumonia or acute exacerbation in ILD, occasionally resulting in fatal outcome. Objectives We identified risk factors for serious pulmonary complications in patients with pre-existing lung disease during treatment with DMARDs in RA. Methods This study enrolled consecutive 487 RA patients at our hospital from 2005 to 2016 retrospectively. 110 of those 487 patients had pre-existing lung disease at the first visit to our hospital. At first, we divided those 110 patients into two subsets, one with development of serious pulmonary complication and the other without that during observational periods. We defined hospitalisation due to lung disease as a serious pulmonary complication regardless of the causes. Demographic and clinical data at enrollment as well as treatment regimens were collected by review of medical charts. We conducted a univariate analysis to compare the differences of clinical characteristics between the subsets. In multivariate analysis, the Cox proportional hazard model was employed to identify factors independently associated with serious pulmonary complication. The explanatory variables were chosen based on candidates (p Results In 110 RA patients with pre-existing lung disease, the median age and disease duration at enrollment was 70 and 3 years, and 71% were female. Rheumatoid factor and anti-cyclic citrullinated protein antibody (anti-CCP) were detected in 97 (88%) and 95 (86%) patients. Methotrexate (MTX), sulfasalazine (SSZ), bDMARDs and corticosteroid were prescribed in 37 (34%), 48 (44%), 42 (38%) and 65 (59%) patients. During the median observation periods of 11 months, 17 (15%) patients had serious pulmonary complications due to pulmonary infection in 11, exacerbation of ILD in 5, and drug-induced pneumonia in 1. The univariate analysis identified candidate variables for serious pulmonary complications as follows: use of MTX and bDMARDs, and no use of SSZ. In multivariate analysis, use of bDMARDs (HR 2.9, 95% CI 0.99–9.0; p=0.05) was identified as the independent risk factor. In 42 patients during treatment with bDMARDs, the univariate analysis identified candidate variables as follows: elder age, male, higher levels of anti-CCP, use of MTX, and no use of SSZ. In multivariate analysis, the higher levels of anti-CCP (HR 1.002, 95% CI 1.0003–1.004; p=0.0007) and no use of SSZ (HR 441.8, 95% CI 1.1–4658460.2; p=0.04) were identified as the independent risk factors. Conclusions Serious pulmonary complications should be more careful for RA patients with pre-existing lung disease during treatment with bDMARDs, particularly those with higher levels of anti-CCP or no use of SSZ. Disclosure of Interest None declared

Background Cancer-associated myositis (CAM) is believed to be rarely complicated by interstitial lung disease (ILD), and, thus, detailed clinical characteristics of CAM in patients with polymyositis (PM)/dermatomyositis (DM)-associated ILD are not well known. Objectives To clarify the incidence, risk factors, and impact on survival of malignancy in patients with PM/DM-associated ILD, using a large cohort data. Methods We used 497 patients with PM/DM-associated ILD enrolled in a multicentre retrospective cohort of incident cases from 44 institutions across Japan (JAMI). CAM was defined as malignancy diagnosed within 3 years before or after PM/DM diagnosis. Demographic data and clinical characteristics were recorded at the time of diagnosis, and follow-up survival and malignancy data were collected prospectively. Results Thirty-two patients with CAM (6.4%) were identified. Patients in the CAM group were older (64.3 vs 55.1 years, p Conclusions In patients with PM/DM-associated ILD, older age at diagnosis and lack of arthritis are predictors for concomitant malignancy, which leads to a reduced survival. Disclosure of Interest Y. Kaneko Speakers bureau: Astellas, T. Nunokawa: None declared, Y. Taniguchi: None declared, Y. Yamaguchi: None declared, T. Gono: None declared, K. Masui: None declared, A. Kawakami: None declared, Y. Kawaguchi: None declared, S. Sato Grant/research support from: a patent on anti-MDA5 antibody-measuring kit, M. Kuwana Grant/research support from: Astellas, Speakers bureau: Astellas, Japan Blood Products Organisation, Medical and Biological Laboratories

Background Concomitant malignancy is one of the prognostic factors in patients with myositis,1 but clinical parameters for mortality still remain unknown in patients with cancer-associated myositis (CAM). Objectives Initial predictors for mortality were examined using a multicenter cohort of CAM patients. Methods This retrospective study enrolled 67 consecutive patients diagnosed as having CAM in 3 referral hospitals between 1995 and 2017. Clinical data at diagnosis of myositis as well as treatment regimens and outcomes of myositis and malignancy were collected by review of medical charts. Myositis-specific autoantibodies (MSAs) were comprehensively detected using RNA immunoprecipitation (IP), enzyme-linked immunosorbent assay, and IP-immunoblotting. We initially conducted a univariate analysis to select variables that were different between survivors and dead cases. In multivariate analysis, the Cox proportional hazard model with backward selection method (p>0.20) was employed to identify factors independently associated with mortality. Explanatory variables were chosen based on the following three models. The Model 1 included age at diagnosis of myositis, gender and candidate variables (p Results The median age at diagnosis of myositis was 63 years, and 62% were female. MSAs were detected in 47 patients: anti-TIF1-γ in 27, anti-ARS in 6, anti-MDA5 in 5, anti-Mi-2 in 3, anti-NXP2 in 3, anti-SAE in 2, and anti-SRP in 1. During the median observation period of 2 years, 19 (28%) of 67 CAM patients were dead due to tumour in 16, ILD in 1, and an unknown cause in 2. The univariate analysis identified significant poor prognostic factors (p Conclusions Male and progression of malignancy at diagnosis of myositis were identified as predictors of survivals in CAM patients. Reference [1] Callen JP. Dermatomyositis. Lancet2000;355:53–7. Disclosure of Interest H. Kadota: None declared, T. Gono: None declared, Y. Yamaguchi: None declared, E. Watanabe: None declared, Y. Okazaki: None declared, Y. Nakajima: None declared, S. Kobayashi: None declared, Y. Shirai: None declared, M. Takeno: None declared, C. Terai: None declared, M. Kuwana Grant/research support from: Astellas, Speakers bureau: Astellas and Japan Blood Products Organisation

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is complicated in approximately 10% of RA patients. High titers of rheumatoid factor or anti-citrullinated protein antibodies (ACPAs), smoking, male gender, older age, longer disease duration, and higher articular disease activity are factors associated with the development of RA-ILD. Genetic factors such as human leukocyte antigen and peptidyl-arginine deiminase (PADI) and environmental factors such as smoking and periodontal disease could be associated with the activation of autoimmunity against citrullinated proteins, the synthesis of ACPAs, and the development of RA or RA-ILD. Metalloproteinase 7 and interferon-r-inducible protein 10 are serum novel biomarkers for the identification of RA-ILD, although surfactant protein A (SP-A), SP-D, and KL-6 are useful conventional biomarkers for the evaluation of RA-ILD. Novel antibodies against the PADI enzyme isoforms 3 and 4 or citrullinated heat shock protein (Hsp) 90a and Hsp90b are associated with RA-ILD and could be useful for predicting the development of RA-ILD. ILD is one of the main causes of mortality in RA. Therefore, prompt management of ILD in RA is necessary. To provide a better prognosis for RA-ILD patients, more efforts need to be made to determine the pathophysiology and the biomarkers for RA-ILD and the causal relationship between the development of ILD and DMARDs.

Rheumatoid arthritis (RA) is an immune-mediated disease that primarily affects joints. In the 2000s, numerous novel antirheumatic agents, called biological disease-modifying antirheumatic drugs (bDMARDs) as well as methotrexate, have becom available worldwide. These developments in treatment have resulted in RA remission or low disease activity in greater than 50% of RA patients. This recent progress has allowed RA patients attain improved physical function and prognosis. However, treatment-related events, such as infections, have occurred and occasionally caused severe or fatal outcomes in RA patients. Thus, clinicians must pay attention to complications during treatment with corticosteroids and/or DMARDs, especially bDMARDs. Approximately 50% of the causes of death in RA patients treated with bDMARDs involve respiratory disease, including pneumonia and interstitial lung disease. Therefore, clinicians should manage these pulmonary complications promptly. In this book, we will describe the current status of knowledge about lung disease in RA and would suggest the best form of management of lung disease in RA patients for clinicians, including general practitioners, rheumatologists, respirologists, radiologists, and pathologists. We hope that this book will prove helpful to all types of medical staff and clinicians who take care of RA patients.