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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.

Acute lupus myocarditis and pulmonary arterial hypertension (PAH) are rare complications associated with systemic lupus erythematosus (SLE). No previous reports have shown the coexistence of these disorders. Here we present a 41-year-old patient with SLE who concurrently developed severe acute lupus myocarditis and PAH with digital gangrene as an initial manifestation. Acute lupus myocarditis and PAH were successfully treated with prednisolone and intravenous cyclophosphamide pulse therapy (600-700 mg × 6) along with anticoagulant therapy. Catheter-directed thrombolysis was required for digital gangrene caused by vasculitis. Concurrent development of these rare disorders may represent a common mechanism such vasculitis as an underlining cause of SLE.

Administration of four once-weekly doses of 375 mg/m2 rituximab (RTX) is commonly used as remission induction therapy for ANCA-associated vasculitis (AAV). Low-dose RTX has been recently shown to produce closely similar results to conventional treatments in other autoimmune diseases. However, the therapeutic potential of this approach in AAV remains largely unknown. Here, we analyzed the efficacy and tolerability of high- and low-dose regimens of RTX in patients with AAV. We retrospectively examined AAV patients who met the classification algorithm of Watts et al. from 2006 to 2016. Patients were divided into high- (HD) and low-dose (LD) RTX groups. HD-RTX was the original regimen while LD-RTX consisted of two once-weekly doses of 375 mg/m2. Cumulative complete remission (CR) rates for 1 year were compared, and serial changes in peripheral B cell counts and serious adverse events were monitored. Apart from a higher percentage of elderly patients in the LD group (p

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients...

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Additional file of Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis

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Interstitial lung disease (ILD) is a major complication and a prognostic factor of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).1 The prevalence of ILD is higher in Japanese AAV as compared with European populations.1 In a Japanese inception cohort study, 45.0% of patients with microscopic polyangiitis (MPA) were complicated by ILD.2 Such ethnic difference suggests a role for genetic background in the development of AAV-associated ILD (AAV-ILD). Single nucleotide polymorphism (SNP) rs35705950(G/T) in the promotor region of MUC5B, encoding mucin 5B, is a strong genetic factor for idiopathic pulmonary fibrosis (IPF). The risk allele T was associated with overexpression of mucin 5B in the lung.3 Recently, rs35705950 has been associated with rheumatoid arthritis-associated ILD (RA-ILD).4 Here, we examined whether rs35705950 is associated with AAV-ILD in case-control and case–case association studies. About 474 Japanese patients with AAV and 842 healthy Japanese controls were recruited at rheumatology or nephrology centres based on the clinical diagnosis of AAV, and classified according to the European Medicines Agency algorithm.5 The patients were examined for the presence or absence of ILD using CT or high-resolution CT (HRCT) by site investigators. 163 patients were reported positive and 264 negative for ILD (see online supplementary table S1,S2). This study was conducted in accordance with the Declaration of Helsinki.### Supplementary data [annrheumdis-2018-214263supp001.htm] Genotyping was performed using TaqMan SNP Genotyping Assays (Assay ID: C\__\_|1582254\_20) (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Odds ratios (ORs), 95% confidence intervals …

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

Aim This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients. Methods We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using 99m thallium (99m Tl) and 123 I-β-methyl-P-iodophenyl-pentadecanoic acid (123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of 123 I-BMIPP from that of 99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing 99m Tl and 123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis. Results Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases. Conclusions Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients.

This report describes a rare case of recurrent bilateral focal myositis and its successful treatment via methotrexate. A 38-year-old man presented myalgia of the right gastrocnemius in May 2005. Magnetic resonance imaging showed very high signal intensity in the right gastrocnemius on short-tau inversion recovery images. A muscle biopsy revealed inflammatory CD4+ cell-dominant myogenic change. Focal myositis was diagnosed. The first steroid treatment was effective. Tapering of prednisolone, however, repeatedly induced myositis relapse, which progressed to multiple muscle lesions of both lower limbs. Initiation of methotrexate finally allowed successful tapering of prednisolone, with no relapse in the past 4 years.

BACKGROUND Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P

Adult-onset Still's disease (AOSD) is an inflammatory disorder characterised by sustained fevers, arthritis, and skin involvement. Interstitial lung disease (ILD) is a rare manifestation, and its clinical characteristics have yet to be determined.We sought to examine the clinical characteristics of AOSD-associated ILD. We retrospectively investigated 78 patients diagnosed as AOSD. ILD was diagnosed based on chest high-resolution computed tomography (HRCT). Clinical characteristics were compared between patients with and without ILD. Relapse was defined as sustained fevers, re-emergence of arthritis, and skin involvement after remission. We further investigated the pathological features of ILD on available samples.Patients with ILD, found in 9 of 78 (11.5 %), had older age of onset (mean age 62.6) than those without ILD (mean age 38.8) (p0.01). The 3-year survival rates were comparable between patients with ILD (92.5%) and those without ILD (88.9%) (p=0.23). Patients with ILD had a higher cumulative rate of haemophagocytic syndrome (HPS) and relapse than those without (p0.0001 and p=0.009, respectively). Chest HRCT showed marked thickening of the interlobular septa, the bronchovascular bundles, or the visceral pleura in all cases. There was no honeycomb or volume loss. Pulmonary pathological findings revealed marked thickening of the visceral pleura and the interlobular septa.Patients with ILD might have higher risks for HPS and relapse. Careful observation and appropriate therapeutic intervention might be needed.

This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients.We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy usingOf 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases.Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients.

To clarify whether patients with connective tissue disease (CTD)-associated borderline mean pulmonary artery pressure (mPAP) have distinctive hemodynamic characteristics from those with normal mPAP and whether pathogenesis is as heterogeneous as manifest pulmonary hypertension (PH). Seventy-five CTD patients who underwent right heart catheterization (RHC) from 2008 through 2016 were retrospectively analyzed. We compared between-group differences in clinical and hemodynamic findings: normal mPAP (n = 35), borderline mPAP (n = 15), and PH (n = 25). A therapeutic intervention trial based on RHC results was performed in nine patients. The values of tricuspid regurgitation pressure gradient (TRPG) in patients with borderline mPAP were comparable at rest but became higher after exercise compared to those with a normal mPAP (P = 0.01). Pulmonary artery wedge pressure in patients with borderline mPAP was higher than in those with normal mPAP (P

To characterize clinical features of polymyositis/dermatomyositis (PM/DM) patients with different anti-aminoacyl transfer RNA synthetase (ARS) antibodies and their association with anti-Ro52.Autoantibodies in sera from 97 Japanese patients (36 PM, 56 DM, and 5 clinically amyopathic DM), who satisfied Bohan and Peter or modified Sontheimer's criteria, were characterized by immunoprecipitation and enzyme-linked immunosorbent assay. Clinical information was from medical records. Features associated with different anti-ARS and anti-Ro52 antibodies were analyzed.The prevalence of anti-ARS was similar to other studies (Jo-1, 22%; EJ, 4%; OJ, 1%; PL-12, 1%), except for a high prevalence of anti-PL-7 (12%), which allowed us to characterize patients carrying this specificity. Serum creatine kinase 3000 IU/l was less common in anti-PL-7-positive patients (57%) than anti-Jo-1-positive patients (18%) (p = 0.0328) and was not found in anti-EJ-positive individuals. Interstitial lung disease was common in anti-ARS-positive patients (97%) (p0.0001 vs. 48% in anti-ARS-negative). Anti-Ro52 antibodies were frequently detected with anti-ARS (59%) (57% in anti-Jo-1, 67% in anti-PL-7) (vs. 21% in anti-ARS-negative, p0.0002). Anti-Ro52 was associated with overlap syndrome (26%) (vs. 7% in anti-Ro52-negative, p = 0.0119).Patients with different anti-ARS in combination with anti-Ro52 appear to be associated with distinctive clinical subsets.

A 49-year-old woman with primary Sjögren syndrome initially developed pulmonary venous hypertension (PVH) due to heart failure with preserved ejection fraction. Endomyocardial biopsy specimens showed mild myocardial fibrosis. Pulmonary arterial hypertension (PAH) was revealed after the treatment with diuretics. During the treatment for PAH using upfront combination with pulmonary vasodilators and immunosuppressants, the patient developed combined disease with PAH and PVH. A careful hemodynamic assessment is necessary in such cases.

Introduction: This retrospective study investigated the concurrence rate and clinical characteristics of recently developed malignancies with microscopic polyangiitis (MPA). Materials and Methods: The subjects included 42 Japanese MPA cases (16 males and 26 females) that had been newly admitted to the hospital. Recent occurrences of malignancy de 昀ned as malignancies diagnosed upon admission and up to two years prior to admission) and the presence of organ lesions were evaluated. As a control, recent occurrences of malignancy in 126 patients with rheumatoid arthritis (RA) were evaluated in a similar manner. Results: Recently developed malignancies occurred s gn 昀c ntl more often in the MPA group (19.0%) than in the RA group (6.3%; odds ratio (OR), 3.47 [95% CI, 1.21–9.93]; Fisher’s exact test, p = 0.029). All MPA-asso‐ ciated malignancies were solid cancers, and none were from hematopoietic origin. With regard to characteriza‐ tion of organ lesions, MPA cases with malignancies exhibited peripheral neuropathy s gn 昀c ntl more often (75% vs. 32.4%; OR, 6.27; 95% CI, 1.09–36.25; p = 0.045) and glomerulonephritis less often (37.5% vs. 82.4%; OR, 0.13; 95% CI, 0.02–0.69; p = 0.020) than MPA cases without malignancies. Skin lesions were ob‐ served in approximately 50% of cases, and there was no s gn 昀c nt difference between MPA groups with and without malignancies (26.5%; OR, 2.78; 95% CI, 0.57–12.51; p value, 0.236). Conclusion: MPA coincided with malignancies at a higher ratio than did RA. Therefore, it is recommended that those admitted for MPA should be thoroughly screened for malignancies.

Objective.The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).Methods.Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections.Results.The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1–8.5).Conclusion.One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.

Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.

Background Borderline mean pulmonary artery pressure (PAP) (21–24 mmHg) may comprise a transition phase from normal pulmonary hemodynamic condition to pulmonary arterial hypertension (PAH), which is one of the fatal complications in connective tissue diseases (CTD) [1]. The accumulated evidence is not enough to conclude that treatment for PAH in this stage may be associated with improving clinical outcomes. On the other hand, CTD-associated PH is caused by various cardiopulmonary comorbidities. It is possible that borderline mean PAP, like overt PH, is caused not only by pulmonary vasculopathy but also by cardiac and pulmonary complications [2]. Objectives To clarify whether patients with borderline mean PAP associated with CTD have distinctive hemodynamic characteristics from those with normal mean PAP and its underlining pathogenesis is heterogeneous as those with manifest PH. Methods We retrospectively investigated 76 CTD patients who underwent right heart catheterization from 2008 through 2016. Of the 76 patients, 25 (33%) and 16 (21%) had manifest PH and borderline mean PAP, respectively. The rest of the 35 patients had normal mean PAP. Systemic sclerosis was the most common CTD among the enrolled patients (61%), followed by MCTD (16%). Hemodynamic characteristics and findings after exercise echocardiography in patients having normal mean PAP, borderline mean PAP, and PH were compared. We also determined the validity of therapeutic intervention. Results The values of tricuspid regurgitation pressure gradient (TRPG) were comparable between patients with borderline (31.1±7.8 mmHg) and normal mean PAP (28.3±6.9 mmHg) (P=0.1572) but its value became significantly higher in patients with borderline mean PAP (39.1±8.0 mmHg) than in those with normal mean PAP (32.8±7.4 mmHg) after exercise echocardiography (P=0.0391). Pulmonary arterial wedge pressure was significantly elevated in patients with borderline mean PAP (12±3 mmHg) compared with that in normal mean PAP (7±3 mmHg) (P Conclusions The pathogenesis of borderline mean PAP, clearly distinctive from normal mean PAP, was heterogeneous as that of manifest PH in CTD patients. Though the clinical course may be altered with appropriate therapeutic intervention, repeated assessment is needed. References Kovacs G, Olschewski H. Borderline pulmonary pressures in scleraderma - “a pre-pulmonary arterial hypertension” condition? Arthritis Res Ther 2015; 17: 123, 015–0649–7. Kovacs G, Avian A, Tscherner M, et al. Characterization of patients with borderine pulmonary arterial pressure. Chest 2014; 146: 1486–93. Disclosure of Interest None declared

Background Cardiac involvement is a manifestation of systemic sclerosis (SSc) that contributes to significant mortality and morbidity. Since many SSc patients with cardiac involvement are asymptomatic and it may progress silently, early diagnosis is still challenging. The perfusion-metabolic mismatch in cardiac scintigraphy indicates functional abnormality due to myocardial injury and has been expected to detect early cardiac involvement in various diseases. However, its clinical utility has been poorly evaluated in patients with SSc. Objectives To evaluate clinical utility of perfusion and myocardial fatty acid metabolism mismatch in SSc patients without cardiac failure. Methods All patients who visited St. Marianna University Hospital from 2009 to 2015 and performed cardiac scintigraphy using 99m Tl and 123 I-BMIPP were retrospectively evaluated. Patients who fulfilled American Collage of Rheumatology classification criteria of SSc and systemic lupus erythematosus (SLE) were selected. We subtracted %uptake of metabolism ( 123 I-BMIPP) from that of perfusion ( 99m Tl) on each 17 myocardial segments standardized by American Heart Association. We compared sum of all the scores and each score in 3 coronary artery regions between patients with SSc and SLE. Furthermore, we evaluated incidence of cardiac death or cardiac failure depending on the scores of each coronary artery regions. Results Among 177 patients, we analyzed the data in 22 cases with SSc and 23 with SLE. The sum of all mismatch scores was not significantly different between the 2 groups (p=0.37). The mismatch score of left anterior descending coronary artery (LAD) region was significantly higher in SSc than SLE (p=0.05) (Figure 1A). We next divided SSc patients into 2 groups depending on degree of the LAD mismatch score and found the group with low score had higher incidence of cardiac death or cardiac failure (p=0.04) than that with high score (Figure 1B). Conclusions The low mismatch score in LAD region of cardiac scintigraphy could be associated with cardiac death or cardiac failure in SSc patients. Since myocardial fibrosis might replace viable cardiomyocytes leading to loss of ventricular volume, metabolic defect by scintigraphy might be less detectable. Disclosure of Interest None declared

The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p

The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionized the treatment of inflammatory arthritides. The increase in the use of biologic agents coupled with expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. Biological therapies appear to have a place in the therapeutic strategy for ANCA-associated systemic vasculitides, at least for patients whose disease is refractory to conventional therapy. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. However, the precise indications for TNF-alpha inhibitors or anti-CD20 monoclonal antibodies have not yet been defined. These biologics must be prescribed extremely cautiously and only in trial settings, especially in view of the adverse effects. (*English Translation of J Jpn Coll Angiol, 2009, 49: 75-79).

Background Lupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV. Methods Eighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years. Results Forty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients’ disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Objective Microscopic polyangiitis (MPA) is necrotizing vasculitis of unknown etiology. We analyzed the serum peptide profile of MPA to find a biomarker for this disease. Methods Serum peptides from 33 patients with MPA, 7 with granulomatosis with polyangiitis (Wegener's), 7 with Churg-Strauss syndrome, 6 with giant cell arteritis, and 25 with systemic lupus erythematosus (SLE) were comprehensively analyzed by mass spectrometry. Peptide function on human microvascular endothelial cells (HMVECs) was examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Results A total of 102 serum peptides were detected from the 78 patients. One of the peptides, peptide 1,523, showed significantly higher ion intensity in MPA (mean ± SD 46.8 ± 39.3 arbitrary units [AU]) than in the other systemic vasculitides (14.1 ± 12.2 AU) (P < 0.05) or in SLE (17.0 ± 12.1 AU) (P < 0.05). In MPA, peptide 1,523 showed significantly higher ion intensity before treatment than 1 week (P < 0.05) and 6 weeks (P < 0.05) after the initiation of treatment. Peptide 1,523 was identified as 13 C-terminal amino acid residues of apolipoprotein A-I (Apo A-I) and was designated “AC13.” Validation of AC13 ion intensity using another MPA cohort (n = 14) similarly showed significantly higher ion intensity (90.1 ± 167.9 AU) compared to 14 patients with rheumatoid arthritis (8.6 ± 5.4 AU) (P < 0.01) and 14 healthy subjects (11.8 ± 6.1 AU) (P < 0.01). Serum concentrations of Apo A-I and high-density lipoprotein cholesterol were down-regulated in MPA before treatment and returned to their normal ranges 6 weeks after the initiation of treatment (both P < 0.01). Stimulation of HMVECs with AC13 significantly up-regulated secretion of interleukin-6 (IL-6) (P < 0.05) and IL-8 (P < 0.01). Conclusion AC13, a candidate biomarker for MPA, may be useful for monitoring disease activity and may exacerbate vascular inflammation through up-regulation of proinflammatory cytokines.

Objective We recently developed an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue. This study was undertaken to use that model to investigate the role of prostaglandin E2 (PGE2) and its receptor subtypes in the development of pannus growth and osteoclast activity in rheumatoid arthritis (RA). Methods Inflammatory cells that infiltrated pannus from patients with RA were collected without enzyme digestion and designated synovial tissue–derived inflammatory cells. Their single-cell suspensions were cultured in medium alone to observe an aberrant overgrowth of inflammatory tissue in vitro. Levels of cytokines produced in culture supernatants were measured using enzyme-linked immunosorbent assay kits. Osteoclast activity was assessed by the development of resorption pits in calcium phosphate–coated slides. Results Primary culture of the synovial tissue–derived inflammatory cells resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks, during which tumor necrosis factor α, PGE2, macrophage colony-stimulating factor, and matrix metalloproteinase 9 were produced in the supernatant. This aberrant overgrowth was inhibited by antirheumatic drugs including methotrexate and infliximab. On calcium phosphate–coated slides, synovial tissue–derived inflammatory cells showed numerous resorption pits. In the presence of inhibitors of endogenous prostanoid production such as indomethacin and NS398, exogenous PGE1 and EP4-specific agonists significantly inhibited all these activities of synovial tissue–derived inflammatory cells in a dose-dependent manner. Addition of indomethacin, NS398, or EP4-specific antagonist resulted in the enhancement of these cells' activities. EP2-specific agonist had a partial effect, while EP1- and EP3-specific agonists had no significant effects. Conclusion These results suggest that endogenous PGE2 produced in rheumatoid synovium negatively regulates aberrant synovial overgrowth and the development of osteoclast activity via EP4.

Objective Acute-onset diffuse interstitial lung disease (AoDILD) in patients with rheumatoid arthritis (RA) has been a serious concern, especially for those under treatment with biological agents which may affect the presentation and outcome of AoDILD, including Pneumocystis pneumonia (PCP). Therefore, we conducted a retrospective, multi-center study of AoDILD in RA patients receiving biological agents. Methods Patients who developed AoDILD while receiving biological agents (infliximab, etanercept, adalimumab and tocilizumab) were enrolled in the study. Definite PCP was defined as patients who showed either P. jirovecii organisms in their respiratory samples by microscopic examination, or positive tests for both P. jirovicii DNA-PCR with respiratory samples and an elevated serum 1,3-β-D-glucan level above the cut-off value. Probable PCP was defined as either a positive test for P. jirovicii PCR or an elevated serum β-D-glucan level. Chest HRCT findings were evaluated and scored by two board-certified radiologists. Results The final diagnoses for 26 patients examined were definite PCP for 13 patients, probable PCP for 11, and methotrexate-associated pneumonitis in 2 patients. Definite and probable PCP cases were clinically indistinguishable. Generalized, diffuse ground-glass opacity (GGO) is the characteristic HRCT finding in patients with definite or probable PCP, which was different from our previous findings in RA patients, mostly without biologics, showing GGO distributed in a panlobular or multilobular manner. The clinical outcome was favorable by treatment with trimethoprim-sulfamethoxazole and glucocorticoids. Conclusion The possibility of PCP should be intensively investigated in RA patients developing AoDILD while receiving biological agents.

Intravenous immunoglobulin (IVIG) therapy was administered to 15 patients who were refractory to traditional steroid therapy [eight with polymyosis (PM), seven with dermamyosis (DM)] to evaluate its efficacy. Serum creatine kinase (CK) significantly decreased from week 1, and manual muscle test scores (MMT) and activities of daily living (ADL) significantly increased from week 2. Efficacy rates were 93.3% (14/15 patients) as assessed using the MMT score, 80.0% (12/15 patients) using the ADL score, and 100% (15/15 patients) using the serum CK level. When changes in the serum CK level over two four-week periods, one before IVIG therapy (from week -4 to week 0) and one after IVIG therapy (from week 0 to week 4), were transformed to natural logarithms, the four-week change after IVIG therapy was significantly greater than that before IVIG therapy. The estimated duration of the serum CK level remaining normal in 50% of the patients after IVIG therapy was 334.5 days. Adverse reactions were observed in seven of 16 patients (43.8%) during the study period, but none of the adverse reactions were considered to be serious or required emergency treatment. In conclusion, the present study indicates that IVIG therapy is effective for steroid-resistant PM/DM.

Objective To elucidate the clinical and radiological features of Pneumocystis pneumonia (PCP) in patients with rheumatoid arthritis (RA), compared with methotrexate (MTX) pneumonitis in RA and Pneumocystis pneumonia in acquired immunodeficiency syndrome (AIDS). Subjects and Methods Retrospective analysis of 14 PCP cases in RA (RA-PCP), 10 MTX pneumonitis cases in RA (MTX-P) and 11 PCP cases in AIDS (AIDS-PCP) from 9 centers in the Kanto area in the last 6 years. Results Compared with AIDS-PCP, both RA-PCP and MTX-P developed more rapidly, showing higher serum CRP and lower plasma β-D-glucan levels, and more severe oxygenation impairment. In most of the RA-PCP cases, a high dose of corticosteroid was administered as adjunctive therapy, resulting in a favorable outcome. The mortality was 14% in RA-PCP, 0% in AIDS-PCP and 0% in MTX-P cases. In RA-PCP patients the CD4 cell count showed only mild suppression, not reaching the predisposing level for PCP in HIV infection, suggesting that there are risk factors for RA-PCP other than immunosuppression. Radiologic analysis revealed some characteristic patterns of each disease. In MTX-P, diffuse homogeneous ground glass opacity (GGO) with sharp demarcation by interlobular septa (type A GGO) was found in 70%, while in AIDS-PCP diffuse, homogeneous or nonhomogeneous GGO without interlobular septal boundaries (type B GGO) was predominant (91%). In RA-PCP, type A GGO was found in 6 cases and type B GGO in 5 cases, showing the complex nature of this disease. Conclusion RA-PCP differed considerably from AIDS-PCP clinically and radiologically. Clinically it occurred without severe immunosuppression, and showed characteristic aspects, with more intense inflammation and less parasite burden. Radiologically it mimicked MTX-P in some cases sharing the conspicuous CT features of MTX-P, rendering the distinction of these two disorders difficult.

To describe co-existence of left heart abnormalities among case series of connective tissue disease (CTD) patients who showed pre-capillary pulmonary hypertension (PH) as well as borderline mean pulmonary arterial pressure (mPAP).From 2010 through 2012, 49 CTD patients suspected to have PH by exercise Doppler echocardiography underwent right heart catheterization. We retrospectively searched for left heart diseases from the available data on Doppler echocardiography, cardiac magnetic resonance imaging (MRI), scintigraphy, and endomyocardial biopsy.Among 49 patients, 11 and 2 had pre- and post-capillary PH, respectively, and another 10 had borderline mPAP. Six of 11 patients with pre-capillary PH showed low pulmonary vascular resistance (PVR) (≤ 240 dynes•sec•cm(- 5)) and low diastolic pulmonary gradient (7 mmHg). Seven of 10 patients with borderline mPAP had normal PVR (160) suggesting the presence of left heart abnormalities. Other abnormal findings included increased left atrial volume index and E/E' on Doppler echocardiography, delayed contrast enhancement by MRI, patchy area of hypoperfusion on thallium scintigraphy, and fibrosis in endomyocardial biopsy.The present case series suggested some contribution of left heart abnormalities to the increase in mPAP among CTD patients with pre-capillary PH as well as borderline mPAP.

The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1.The mean age of the 7 patients was 57 (range, 34-71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract infection, sepsis, and cytomegalovirus infection. Two patients died due to recurrent infections and airway obstruction, caused by an AAV lesion.Rituximab had a beneficial effect on refractory AAV in Japanese patients, but several adverse effects occurred during rituximab treatment.

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

It is well known that cervical spondylosis in athetoid cerebral palsy results from abnormal muscle tension. However there is no information on low back pain in athetoid cerebral palsy. Sixty-one athetoid cerebral palsy workers were investigated by questionnaire.Forty-one (67.2%) athetoid cerebral palsy workers had low back pain in daily life. X-ray examination was performed on 29 athetoid cerebral palsy workers. Lumbar spondylolyses were shown in 17 (58.6%). Endplate lesions of the lumbar vertebral body were found in 91 vertebras (53.5%). There were no significant differences between age and occurrence of low back pain or spondylolyses. These results suggest that abnormal athetoid mortion is related to the occurrence of the spondylolyses.

Study objectives: We described the features seen on serial high-resolution CT scans of nonspecific interstitial pneumonia (NSIP) that was associated with polymyositis (PM) and dermatomyositis (DM), and we correlated the changes in the CT scan findings with those of pulmonary function test results. Design, setting and patients: Serial CT scans of 14 patients with histologically proven NSIP and PM/DM from two university hospitals were evaluated retrospectively (follow-up period, 3 to 61 months; mean follow-up period, 27.6 months). Using initial and follow-up CT scan findings, the extent of each type of opacity and the total area of increased opacity were calculated and correlated with the results of pulmonary function tests. Measurements and results: The predominant findings on the initial CT scans were of reticular and/or ground-glass opacities with or without consolidation. Reticular and ground-glass opacities predominated in the lower zone of each lung, and consolidation predominated at the lung periphery. Thirteen patients showed significant improvement of the total area of increased opacity (p r = −0.650; p = 0.031). Ground-glass and reticular opacities also were improved significantly in 11 and 13 patients, respectively. The decrease in the extent of ground-glass opacity correlated inversely with the changes in FVC ( r = −0.758; p = 0.0119) and diffusion capacity for carbon monoxide ( r = −0.669; p = 0.0448). In one patient, ground-glass opacity progressed, and death occurred after 3 months. Traction bronchiectasis was seen in 12 patients, and it improved in four patients after treatment. Honeycomb lung was not noted in any patient during follow-up. Conclusions: With treatment, serial CT scans of PM/DM patients with NSIP showed significant improvement in the abnormal opacities, and radiographic progression of lung fibrosis was limited. The CT scan features and clinical course of NSIP in PM/DM patients were relatively uniform, and this constitutes a subset of NSIP.

To characterize thin-section computed tomographic (CT) findings of pathologic subgroups of nonspecific interstitial pneumonia (NIP) in a sizeable number of patients.The study included 55 cases of pathologically proven NIP. The 55 cases were categorized histologically into four grades: grade 1, interstitial inflammation without fibrosis (n = 6); grade 2, interstitial inflammation predominating over fibrosis (n = 16); grade 3, fibrosis predominating over inflammation (n = 5); and grade 4, fibrosis only (n = 28). Two independent observers evaluated the presence, extent, and distribution of various CT findings. Thin-section CT findings and histologic grades were compared by using the Spearman rank correlation coefficient. Observer agreement was assessed.Areas with ground-glass attenuation and architectural distortion were present in all 55 patients. Traction bronchiectasis and intralobular reticular opacities were seen in 52 and 48 patients, respectively. The extent of traction bronchiectasis (r = 0.68; P.001) and intralobular reticular opacities (r = 0.35; P.05) correlated with the histologic grade. Honeycombing was seen in 12 (43%) of 28 patients with grade 4 NIP and in three (11%) of the remaining 27 patients (chi(2) test, P.001). There was good agreement between the observers for the presence (kappa = 0.7-1.0) and extent (Spearman rank correlation; r = 0.87-0.98; P.001) of various abnormalities.The extent of traction bronchiectasis and intralobular reticulation at thin-section CT correlates with increased fibrosis in NIP. Honeycombing is seen almost exclusively in patients with fibrotic NIP.

Background Exercise-induced pulmonary hypertension (PH) is considered as an early preclinical functional phase of resting PH in systemic sclerosis (SSc). In this study, we investigated the prevalence of exercise-induced PH in patients with SSc and evaluated the influence of pulmonary vascular reserve on exercise-induced PH. Methods This prospective study included 568 SSc patients. The patients with interstitial lung disease and those with left ventricular dysfunction were excluded (n = 50); finally, 518 patients underwent simple exercise echocardiography using a Master's two-step. Systolic pulmonary artery pressure (SPAP), the ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') and pulmonary vascular resistance (PVR) were measured before and after exercise. ΔPVR (the difference between rest and post) was used for the assessment of pulmonary vascular reserve. All patients were stratified into the no exercise-induced PH (SPAP