Reika Maezawa

Systemic lupus erythematosus complicating autoimmune pulmonary alveolar proteinosis that was worsened by immunosuppressive therapy.

A 26-year-old Japanese woman developed autoimmune pulmonary alveolar proteinosis (PAP) during glucocorticoid therapy for systemic lupus erythematosus (SLE). Intensive immunosuppressive therapy worsened the PAP. De-escalation of immunosuppressive therapy improved the PAP. Autoimmune PAP is rarely associated with systemic autoimmune diseases, and the present case is the first case of autoimmune PAP associated with SLE. Moreover, the present case suggests that immunosuppressive therapy should be avoided or used carefully for the treatment of patients with anti-GM-CSF antibody, such as those with autoimmune PAP.

Clinical features of organizing pneumonia associated with rheumatoid arthritis

Abstract 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.

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.

Dr. Owada, et al, reply

To the Editor: We thank Dr. Pipitone, et al for their interest1 in our article2. Pipitone, et al reported high sensitivity of active myositis by 18F fluorodeoxyglucose positron emission tomography (FDG-PET) imaging3 compared with that in our study, when they defined active myositis based on the ratio of standardized uptake values of proximal muscles to that of the liver. Moreover, they reported that the … Address correspondence to Dr. K. Kurasawa, 880 Kita-Kobayashi, Mibu, Tochigi 321-0293, Japan. E-mail: kurasawa{at}dokkyomed.ac.jp

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.

FRI0134 Cluster analysis of pulmonary lesions in rheumatoid arthritis (ra); airway disease is shared and critical pulmonary abnormality in ra

Background Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects joints and various organs including the lung. The pulmonary involvement is critical for prognosis of the patients and decision of the treatment. Moreover, the pulmonary involvement showed various abnormalities such as interstitial pneumonia (ILD) and airway disease (AD). Importantly, a pulmonary abnormality coexists with other ones in RA patients. There have been large numbers of studies on the prevalence of pulmonary abnormalities and clinical features of patients with these lesions. However, it remains to be elucidated what existence pattern of pulmonary abnormalities RA patients have. Objectives To reveal the existence pattern of the pulmonary abnormalities in RA patients using cluster analysis, and to clarify the clinical features of patients with multiple pulmonary abnormalities. Methods Subjects were consecutive 208 RA patients who were treated with bDMARDs as the first one from Feb. 2004 to Sep. 2015 in our department and received HRCT scan before and after the therapy. Pulmonary abnormalities were classified into 4 categories (ILD, nodular lesions, AD and other) and 20 lesions such as ground-glass opacity, reticular pattern, bronchiolitis and bronchiectasis and were examined their existence and distribution. Cluster analysis was conducted according to the existence of the lesions by Ward method. Clinical features were analyzed through reviewing medical records. Results Subjects were 208 RA cases (M/F; 64/144, mean age 59.2 year-old, disease duration 13.1 years). Pulmonary lesions were found in 146 (70.2%) of RA patients before treatment Imaging findings were 81of ILD (39%),45 of nodular lesion (21.6%) and 115 of AD (55%). Cluster analysis showed 6 clustered (Fig.), 1; no pulmonary lesions, 2; AD without bronchoectasia, 3; AD with bronchoectasia, 4; AD with curved linear opacities, 5; AD with nodular lesions, and 6; reticular pattern with AD. AD was common abnormalities and coexisted with other pulmonary lesions in RA. AD was found in 79%, 78% and 71% of patients with pulmonary abnormalities, ILD and nodular lesions, respectively. AD alone, AD with ILD, and AD with nodular pattern were found in 16.3%, 8.6% and 28.9%, respectively, while patients without pulmonary lesions were 29.8% in RA. AD was frequently associated with ILD and nodule compare to non-AD. No differences were found in gender, smoking history, disease duration and disease activity between patients with and without AD. New emergence or exacerbation of pulmonary abnormalities developed in AD patients compared to those without pulmonary abnormalities or AD. No significant differences were found in clinical features, among AD alone, AD with ILD and AD with nodules. Conclusions Pulmonary abnormalities were found in 70% in RA. AD was found in 55% of RA patients and coexisted with other pulmonary lesions such as ILD and nodular lesions. Patients with AD frequently showed newly emerging or worsening pulmonary lesions, regardless of the coexistence of other pulmonary lesions. Thus, AD is shared and critical pulmonary abnormality in RA. Disclosure of Interest None declared

Intensive immunosuppressive therapy for endogenous lipoid pneumonia associated with rheumatoid arthritis

Abstract 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.

FRI0063 Non- Neutralizing Autoantibody Against GM-CSF in Connective Tissue Diseases and its Association with Pulmonary Involvements

Background Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor, particularly for differentiation of alveolar macrophage, and immune modulator including inflammation. Neutralizing autoantibodies against GM-CSF antibodies cause pulmonary alveolar proteinosis (PAP). We have previously reported a SLE patient with anti-GM-CSF antibody (Ab) and PAP (Lupus 2013;22, 1060). However, it remains unknown whether there exist autoantibodies against GM-CSF in connective tissue disease (CTD) patients without PAP. Objectives To determine whether anti-GMF autoantibody is detected in sera from CTD patients. If so, to determine whether the antibody has neutralizing activity and to clarify the clinical features of patients with the antibody. Methods Subjects were 245 CTD patients (SLE; 63, DM/PM; 49, RA; 106, vasculitis; 27) and 34 healthy controls. A EIA system to detect anti-GM-CSF Abs was developed; GM-CSF was coated on the plate that was then blocked with BSA, diluted serum with PBS was added, and after washing the Ab was detected by anti-IgG Ab. To avoid non-specific binding, the optic density (OD) of the Ab was calculated as follows; OD (GM-CSF coated well) -OD (GM-CSF negative well). The neutralizing activity of the Ab was examined through inhibition of CD11b expression on neutrophils by GM-CSF; neutrophils were incubated in media with GM-CSF (5ng/ml) and serum from the subjects, and CD11b expression was examined using flowcytometry. Association of clinical features with the Ab was assessed by reviewing medical records. Results Anti-GM-CSF Ab was detected in 60% of CTD (frequencies of positivity: SLE; 70%, DM/PM; 57%, RA; 57%, vasculitis 55%) (Fig.1). PAP was not found in all cases except one SLE that has been reported previously. Neutralizing activity was not detected except the case of SLE with PAP. Pulmonary involvements including interstitial lung disease, bronchial disease and pleuritis was frequently found in RA patients positive for the Abs compared to negative patients (positive 47%, vs negative 18%; p<0.001). Similarly, pulmonary involvements were found in SLE patients with the Abs (positive 25%, vs negative 5%; p=0. 04). In DM/PM, no differences were found in frequencies of of pulmonary involvements between the Ab positive and negative groups, because more than 80% of the patients had lung involvements.Therapy decreased titers of the Ab in SLE and RA. Conclusions Non-neutralising Autoantibody against GM-CSF was frequently detected in CTD patients, particularly those with pulmonary involvements. These findings suggest that the autoantibody, which might work as carrier protein of GM-CSF, plays roles in the development of CTDs, especially pulmonary involvements in RA and SLE. Disclosure of Interest None declared

FRI0151 Clinical features of organizing pneumonia associated with rheumatoid arthritis; development of organizing pneumonia is not related to disease activity of arthritis

Background Organizing pneumonia (OP), different name: bronchiolitis obliterans with organizing pneumonia (BOOP), is a form of interstitial lung diseases characterized by presence of buds of granulation tissue in bronchiole and alveoli. Radiographic feature of OP is diffuse alveolar opacities which are similar to bacterial pneumonia and tumors. There are two types of OP; cryptogenic OP and secondary OP. Secondary OP is associated with many entities such as infection, drugs and connective tissue diseases including RA. However, clinical features of OP in patients with RA remain unclear Objectives To clarify clinical features of OP associated with RA, particularly, to determine whether the development of OP is related to disease activity of arthritis. Methods To determine prevalence of OP, we reviewed medical records of consecutive 499 RA patients who visited our hospital in Dec 2010. For analysis of clinical features of OP, we analyzed medical records of 24 RA patients with OP; 19 extracted by the above screening and additional 5 who admitted our hospital because of OP in 2011-12. OP was diagnosed by pathological findings or typical pulmonary imaging with clinical features (migration pulmonary infiltrates/ no response to antibiotics and good response to glucocorticoid). Results Among 499 RA patients, patients with history of OP were 19 (3.8%) cases, while prevalence of interstitial pneumonia and with bronchoectasia/bronchiolitis were 13.0% and 6.0%, respectively. Among 24 patients, male was8 and female was 16. Age of the onset of OP was 60.5 ± 9.6 year (mean ± sd). RA preceded OP in 16 patients (67%), while OP developed simultaneously with RA in 3 patients, and occurred before the onset of RA in 3 cases. The interval between the onset of RA and OP was 11.6 ± 12.8 years. Positivity of RF and anti-CCP antibody were found in 18/24 and 14/17, respectively. At the onset of OP, 18 patients were treated for RA, 11 and 7 of them received MTX and d TNF inhibotors, respectively. The disease activity of RA was high in 4, moderate in4, low in 9, and CR in 1 case. Only 3 patients showed exacerbation of arthritis. Respiratory symptoms and fever were found in 14 and 18 out of 24 OP patients. All patients revealed alveolar opacities, multiple lung lesions were found in half of the cases, and spontaneous resolution of the lung infiltrates was found in 9 cases. antibiotics weres ineffective for OP and glucocorticoid dramatically improved OP. Relapse of OP was found in 5 patients without exacerbation of arthritis. Conclusions OP is not a rare pulmonary complication in RA which develops in 4% in RA. OP develops in patients whose disease activity was controlled or in those treated with TNF inhibitors, successfully. These findings suggest that OP in RA might be TNF- independent and have different pathogenesis from arthritis. Disclosure of Interest None Declared

THU0255 Marked increase in serum KL-6 and SP-D levels during 1st 4 weeks after tratment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis

Background Interstitial pneumonia (IP) is a serious complication associated with polymyositis (PM) and dermatomyositis (DM). Predictive factors for poor prognosis have not been fully identified. KL-6 and surfactant protein D (SP-D) are biomarkers for existence and severity of IP. Clinical usefulness of these markers in IP in PM/DM has not been fully evaluated. Objectives To identify poor prognostic factors for IP in PM/PM. and to determine whether serum KL-6/SP-D levels predict patients with IP in PM/DM. Methods Consecutive 50 PM/DM (P: 17, DM 33) patients with active IP, 6 of whom were died of respiratory failure, were enrolled in this study. Active IP was defined as IP that was judged as requiring intensive immunotherapy for IP by physicians managing patients, based on worsening dyspnea and, expanding ground glass opacities in HR-CT or decreasing PaO2. Serum KL-6 and SP-D levels were measured before treatment for IP and every 2-4 weeks after starting therapy. To find correlation between KL-6/SP-D levels and clinical feature including prognosis, medical records were reviewed retrospectively. Results Serum KL-6 and SP-D levels were elevated in patients with active IP compared to those with inactive IP or without IP. Serum KL-6 and SP-D levels at the diagnosis of active IP were within normal range in 26% and 44% of patients with active IP, respectively. KL-6 and SP-D levels at the time of diagnosis failed to predict prognosis. Serum Kl-6 levels were increased up to 3 month after starting treatment and then decreased gradually to base lines, whereas SP-D levels were at peaks within 1st 4 weeks after the treatment and decreased rapidly to normal levels. In patients with poor prognosis showed in marked increased in KL-6/SP-D levels. Comparison of clinical features between patients with poor and good prognosis showed significant difference in Kl-6 levels at 1st 4 weeks and increase of KL-6 and SP-D levels during during 1st 4 weeks, increased AaDO2 levels before treatment and existence of alveolar opacities. Multivariate logistic regression analysis showed only increase in KL-6/SP-D levels during during 1st 4 weeks as a poor prognostic factor. Cut off levels determined by ROC analysis were 1.70 and 1.75 of increase ratio of KL-6 and SP-D levels at 2-4 weeks after treatment to those at 0 week, respectively. Increase of KL-6 during 1st 4 weeks over 800U/ml was a poor prognostic factor. Conclusions Increase in serum Kl-6/SP-D levels during 1st 4 weeks after starting therapy, but not their levels at any one time point, predicts poor prognosis. When marked increased of KL-6 and SP-D levels during the 1st 4 weeks, patients have risks of poor prognosis and additional therapy should be considered. Disclosure of Interest None Declared