Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. METHODS: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. RESULTS: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). CONCLUSIONS: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

Differences and similarities in cytokine profiles of macrophage activation syndrome in systemic lupus erythematosus and adult-onset Still's disease.

To clarify the differences and similarities in the cytokine profiles of macrophage activating syndrome (MAS) between systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD). The study participants included 9 patients with MAS-SLE, 22 with non-MAS-SLE, 9 with MAS-AOSD, and 13 with non-MAS-AOSD. Serum cytokine levels were measured using a multiplex bead assay. Cytokine levels were compared between patients with SLE and AOSD with/without MAS. Moreover, cytokine patterns were examined using principal component analysis (PCA) and cluster analysis. IL-6, IL-8, IL-18, and TNF-α levels were elevated in patients with SLE and AOSD. IFN-α levels were elevated in SLE, whereas IL-1ß and IL-18 levels were elevated in AOSD. In SLE, IFN-α and IL-10 levels were higher in MAS than in non-MAS and controls. PCA revealed distinctive cytokine patterns in SLE and AOSD, SLE with IFN-α and IP-10, AOSD with IL-1ß, IL-6, and IL-18, and enhanced cytokine production in MAS. PCA and cluster analysis showed no differences in cytokine patterns between the MAS and non-MAS groups. However, serum ferritin levels were correlated with IFN-α levels in SLE. Cytokine profiles differed between SLE and AOSD but not between MAS and non-MAS. MAS is induced by the enhancement of underlying cytokine abnormalities rather than by MAS-specific cytokine profiles. Type I IFN may be involved in MAS development in patients with SLE.

Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis.

Objective: We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment. Methods: Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed. Results: Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection. Conclusion: Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Longterm Outcomes of 188 Japanese Patients with Eosinophilic Granulomatosis with Polyangiitis.

OBJECTIVE: Patients with eosinophilic granulomatosis with polyangiitis (EGPA) frequently experience relapses, which lead to cumulative organ damage. In this retrospective observational study, we aimed to reveal the risk factors for relapse in EGPA. METHODS: A total of 188 Japanese patients with EGPA diagnosed between 1996 and 2015 were identified from medical records in 10 hospitals. The diagnosis was based on the American College of Rheumatology 1990 criteria or Lanham's criteria. Baseline characteristics, treatments, asthma exacerbation, and relapses were evaluated by retrospective chart review. RESULTS: The median followup period was 56 months. The median age at disease onset was 59.7 years. At the disease onset, 95.2% of the patients had a history of bronchial asthma and 44.7% were positive for antineutrophil cytoplasmic antibodies. The cumulative survival and relapse-free survival rates at 5 years were 89.6% and 64.0%, respectively. Multivariate analysis with 2 models, proportional hazards, and competing risk models, was performed to identify the factors associated with relapse. The proportional hazards model identified azathioprine (AZA) maintenance therapy and high eosinophil counts at onset as independent factors with lower relapse risks, and high immunoglobulin E (IgE) levels at onset as a risk factor for relapse. The competing risk model identified no statistically significant factors. CONCLUSION: Although potential benefit of AZA maintenance therapy in preventing relapse of EGPA was suggested by the proportional hazards model, there was a discrepancy in the results between the models. Eosinophil counts and IgE levels at onset were also identified as candidates of factors associated with relapse in EGPA.

Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells.

Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naïve CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6-manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naïve mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies.

Molecular biological analysis in a patient with multiple lung adenocarcinomas.

The utility of molecular biological analysis in lung adenocarcinoma has been demonstrated. Herein we report a rare case presenting as multiple lung adenocarcinomas with four different EGFR gene mutations detected in three lung tumors. After opacification was detected by routine chest X-ray, the patient, a 64-year-old woman, underwent chest computed tomography which revealed a right lung segment S4 ground-glass nodule (GGN). Follow-up computed tomography revealed a 42 mm GGN nodule with a 26 mm nodule (S6) and a 20 mm GGN (S10). Histopathology of resected specimens from the right middle and lower lobes revealed all three nodules were adenocarcinomas. Four EGFR mutations were detected; no three tumors had the same mutations. Molecular biological analysis is a promising tool for the diagnosis of primary tumors in patients with multiple lung carcinomas of the same histotype, enabling appropriate treatment.

Hyperplasia of Lymphoid Follicles and Lymphangiectasia in the Parietal Pleura in Bucillamine-induced Yellow Nail Syndrome.

Yellow nail syndrome (YNS) pleurisy is often difficult to control, and pathological examinations have rarely been reported. We herein report a case of bucillamine-induced YNS in which histopathology of the parietal pleura revealed hyperplasia of the lymphoid follicles and lymphangiectasia. Even after the discontinuation of bucillamine, the pleurisy and lymphedema showed no change. Based on the histopathological findings showing similarity to rheumatoid pleurisy, we administered corticosteroid treatments, and both the pleurisy and lymphedema improved. The findings in the present case suggest that, in bucillamine-induced YNS, pleurisy may be related to inflammation caused by rheumatoid arthritis in addition to abnormalities in lymphatic vessels.

Intensive immunosuppressive therapy for endogenous lipoid pneumonia associated with rheumatoid arthritis.

Endogenous lipoid pneumonia is an uncommon inflammatory pulmonary disease that is caused by lipids from an endogenous source, the treatment for which has not been established. We report the first case of endogenous lipoid pneumonia presenting as lung consolidation and which was associated with rheumatoid arthritis. Treatment was successful with intensive immunosuppressive therapy. When a physician finds lung consolidation in a patient with active rheumatic disease, lipoid pneumonia should be considered.

Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells.

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.

Cancer association as a risk factor for anti-HMGCR antibody-positive myopathy.

OBJECTIVE: To show cancer association is a risk factor other than statin exposure for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody-positive (anti-HMGCR Ab+) myopathy. METHODS: We analyzed the clinical features and courses of 33 patients (23 female and 10 male) with anti-HMGCR Ab+ myopathy among 621 consecutive patients with idiopathic inflammatory myopathies. RESULTS: Among the 33 patients, 7 (21%) were statin-exposed and 26 were statin-naive. In relation with cancer, there were 12 patients (statin-exposed, n = 4) with cancers detected within 3 years of myopathy diagnosis (cancer association), 3 patients (all statin-naive) with cancers detected more than 3 years before myopathy diagnosis (cancer history), 10 cancer-free patients followed up for more than 3 years (all statin-naive), and 8 patients without cancer detection but followed up for less than 3 years (statin-exposed, n = 3). Therefore, 12 patients with cancer association (36%) formed a larger group than that of 7 statin-exposed patients (21%). Among 12 patients with cancer association, 92% had cancer detection within 1 year of myopathy diagnosis (after 1.3 years in the remaining patient), 83% had advanced cancers, and 75% died of cancers within 2.7 years. Of interest, 1 patient with cancer history had sustained increase in creatine kinase level over 12 years from cancer removal to the development of weakness. CONCLUSIONS: Patients with cancer association formed a large group with poor prognosis in our series of patients with anti-HMGCR Ab+ myopathy. The close synchronous occurrence of cancers and myopathies suggested that cancer association is one of the risk factors for developing anti-HMGCR Ab+ myopathy.

Anti-TIF1-γ antibody and cancer-associated myositis: A clinicohistopathologic study.

OBJECTIVE: We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti-transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. METHODS: We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[-] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. RESULTS: Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(-) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(-) and exhibited no dC5b-9 or VFs. CONCLUSIONS: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(-) CAM.

Clinical features of organizing pneumonia associated with rheumatoid arthritis.

OBJECTIVES: To clarify the clinical features of organizing pneumonia (OP) associated with rheumatoid arthritis (RA) and to determine whether development of OP is related to RA activity. METHODS: A cross-sectional study was conducted, in which medical records of 499 consecutive RA patients who visited our hospital during one month were reviewed. OP was diagnosed by pathological findings by trans-bronchial biopsy or by clinical features (typical computed tomography findings, no causative agents, good response to glucocorticoids, and lack of response to antibiotics). RESULTS: Among 499 patients, OP was found in 19 patients and the estimated prevalence was 1.9-4.8%. No differences in clinical features were noted between the OP and non-OP groups. The mean age of OP development was 57.2 years and the period from the onset of RA to OP ranged from -4 to +34 years. Although 14 patients presented OP after the onset of RA, two developed OP before RA and three developed OP simultaneously with RA. Patients receiving tumor necrosis factor inhibitors also developed OP. RA disease activity just before onset of OP was low in 8 of 14 RA cases. At the onset of OP, only two patients showed exacerbations of arthritis, whereas most patients presented with fever and serum C-reactive protein (CRP) elevations. Glucocorticoids were effective for OP in all patients who received them. Relapse occurred in 4 of 19 cases. CONCLUSIONS: OP develops in approximately 4% of RA patients, which occurs independently from arthritis activity and at any time in RA patients.

Detection of inflammatory lesions by f-18 fluorodeoxyglucose positron emission tomography in patients with polymyositis and dermatomyositis.

OBJECTIVE: To evaluate the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the management of patients with inflammatory myopathy. We examined whether FDG-PET scanning detects myositis or extramuscular lesions in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: FDG-PET imaging was performed in 24 patients with active inflammatory myopathy (PM, 11; DM, 13). The images were read by radiologists in a blinded manner. FDG uptake into muscles was judged positive when the intensity of muscles was higher than or equal to that of the liver. As controls, FDG imaging findings of patients with a lung mass and without muscle diseases were used. To investigate associations between FDG-PET findings and clinical/laboratory findings, the patients' medical records were reviewed retrospectively. RESULTS: Increased FDG uptake in muscles was found in 8 of 24 (33%) patients. In 67 of 69 (97%) controls without muscle diseases, no muscle FDG uptake was detected. The sensitivity of FDG-PET to detect myositis was lower than that of electromyogram (EMG), magnetic resonance imaging, and muscle biopsy. There were no significant differences in clinical manifestations between patients with and without increased FDG uptake in muscles, although patients with FDG muscle uptake had a tendency to have extended myositis with endomysial cell infiltration. FDG-PET detected neoplasms in patients with associated malignancy. FDG uptake in lungs was found in 7 of 18 patients with interstitial lung disease. CONCLUSION: FDG-PET imaging has limited usefulness for the evaluation of myositis in patients with PM/DM because of its low sensitivity, although it might be useful for detection of malignancy in these patients.

Systemic sclerosis complicated by arrhythmogenic right ventricular dysplasia that was misinterpreted as pulmonary arterial hypertension.

A 58-year old Japanese woman who had been diagnosed with and managed for systemic sclerosis (SSc) with pulmonary arterial hypertension died suddenly. However, the autopsy revealed marked right ventricular dilatation, and the myocardium had been replaced by fatty tissue. These findings were consistent with arrhythmogenic right ventricular dysplasia (ARVD). A literature search identified nine cases of SSc with ARVD in Japan, including this case; this number is significantly higher than the value estimated from the prevalences of ARVD and SSc in Japan, suggesting an association between these two rare diseases.

Rituximab was effective on refractory thrombotic thrombocytopenic purpura but induced a flare of hemophagocytic syndrome in a patient with systemic lupus erythematosus.

We report the case of a patient with systemic lupus erythematosus (SLE) who first revealed hemophagocytic syndrome (HPS), which was treated successfully with glucocorticoid and intravenous cyclophosphamide. The patient then demonstrated refractory thrombotic thrombocytopenic purpura (TTP) with normal a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13 activity that responded well to rituximab. After rituximab treatment, the patient showed a flare of HPS that was controlled by additional intravenous cyclophosphamide treatment. This case showed that TTP with normal ADAMTS-13 activity is B-cell dependent and indicated that B-cell depletion might exacerbate some autoimmune conditions in SLE.