Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment.

OBJECTIVES: Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. METHODS: We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. RESULTS: LPD patients were categorized into two groups: patients who regressed spontaneously (n = 19) and those who needed chemotherapy (n = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. CONCLUSIONS: Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.

Combined disease with pulmonary arterial hypertension and pulmonary venous hypertension revealed after treatment of heart failure with preserved ejection fraction in a case with primary Sjögren syndrome.

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.

Clinical subsets associated with different anti-aminoacyl transfer RNA synthetase antibodies and their association with coexisting anti-Ro52.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%) (p < 0.0001 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, p < 0.0002). Anti-Ro52 was associated with overlap syndrome (26%) (vs. 7% in anti-Ro52-negative, p = 0.0119). CONCLUSIONS: Patients with different anti-ARS in combination with anti-Ro52 appear to be associated with distinctive clinical subsets.

Left heart abnormalities in connective tissue disease patients with pre-capillary pulmonary hypertension as well as borderline mean pulmonary arterial pressure.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Hypoxia-induced endogenous prostaglandin E2 negatively regulates hypoxia-enhanced aberrant overgrowth of rheumatoid synovial tissue.

OBJECTIVE: During isometric exercise, the synovial joint tissue is prone to hypoxia, which is further enhanced in the presence of synovial inflammation. Hypoxia is also known to induce inflammatory cascades, suggesting that periodic hypoxia perpetuates synovitis in rheumatoid arthritis. We previously established an ex vivo cellular model of rheumatoid arthritis using the synovial tissue-derived inflammatory cells, which reproduced aberrant synovial overgrowth and pannus-like tissue development in vitro. Using this model, we investigated the regulatory mechanism of synovial cells against hypoxia in rheumatoid arthritis. METHODS: Inflammatory cells that infiltrated synovial tissue from patients with rheumatoid arthritis were collected without enzyme digestion, and designated as synovial tissue-derived inflammatory cells. Under normoxia or periodic hypoxia twice a week, their single-cell suspension was cultured in medium alone to observe an aberrant overgrowth of inflammatory tissue in vitro. Cytokines produced in the culture supernatants were measured by enzyme-linked immunosorbent assay kits. RESULTS: Primary culture of the synovial tissue-derived inflammatory cells under periodic hypoxia resulted in the attenuation of the spontaneous growth of inflammatory tissue in vitro compared to the culture under normoxia. Endogenous prostaglandin E2 (PGE2) production was enhanced under periodic hypoxia. When endogenous PGE2 was blocked by indomethacin, the aberrant tissue overgrowth was more enhanced under hypoxia than normoxia. Indomethacin also enhanced the production of tumor necrosis factor-α (TNF-α), macrophage colony-stimulating factor (M-CSF), and matrix metalloproteinase-9 (MMP-9) under periodic hypoxia compared to normoxia. The EP4-specific antagonist reproduced the effect of indomethacin. Exogenous PGE1 and EP4-specific agonist effectively inhibited the aberrant overgrowth and the production of the inflammatory mediators under periodic hypoxia as well as normoxia. CONCLUSIONS: The enhancing effect of periodic hypoxia on the aberrant overgrowth of rheumatoid synovial tissue was effectively down-regulated by the simultaneously induced endogenous PGE2.

Long-term survival, causes of death, and prognostic factors for mortality in patients with microscopic polyangiitis and those with anti-neutrophil cytoplasmic antibody-positive interstitial lung disease: A single-center retrospective study.

AIM: To elucidate the clinical features, long-term survival, and prognostic factors for mortality among patients with microscopic polyangiitis (MPA), including those with anti-neutrophil cytoplasmic antibody-positive interstitial lung disease (ILD) (ANCA-ILD), which could be a subset of its variant phenotype. METHODS: We retrospectively included 76 consecutive patients between 2006 and 2014, diagnosed with MPA according to the European Medicines Agency algorithm using the Chapel Hill Consensus Conference definitions or ANCA-ILD. ILD was classified as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia pattern using chest computed tomography. RESULTS: The mean (standard deviation) age of the patients (female, 68%) was 69 (12) years. The median (interquartile range) follow-up period was 68 (33-95) months. Comorbid ILD and glomerulonephritis were observed in 44 (58%) (68% UIP) and 54 (71%) patients, respectively. Comorbid ILD was associated with low survival (P = .0563). There were 17 (39%) and 5 (16%) deaths in the ILD and non-ILD groups, respectively (P = .0404). In the ILD group, 6 and 5 of the deaths were attributed to infection and ILD progression, respectively. In the non-ILD group, 1 and 2 patients expired from subsequently developed ILD and aspiration pneumonia, respectively. Age ≥ 70 years (hazard ratio = 2.78; 95% confidential interval 1.15-6.70) and UIP (3.95; 1.60-9.77) were independent risk factors for mortality. CONCLUSION: Age ≥ 70 years and ILD with a UIP pattern were associated with high mortality, owing to susceptibility to infection and ILD progression. A more effective and less toxic treatment is required for progressive ILD.

Cutaneous polyarteritis nodosa associated with HLA-B39-positive undifferentiated spondyloarthritis in a Japanese patient.

We present the case of a 43-year-old man diagnosed with HLA-B39-positive spondyloarthritis who developed cutaneous lesions consistent with cutaneous polyarteritis nodosa (CPN). Previous studies indicated an elevated incidence of HLA-B39 in HLA-B27-negative Japanese patients with spondyloarthritis. This case suggested that CPN may also occur in association with forms of HLA-B39-positive spondyloarthritis. The rarity of this association is emphasized. Therapy with corticosteroid and methotrexate improved both the cutaneous lesions and the clinical symptoms of spondyloarthritis.

Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis.

The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0-21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort.

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

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

Nintedanib for the treatment of systemic sclerosis-associated interstitial lung disease.

INTRODUCTION: Interstitial lung disease (ILD) is a leading cause of death in patients with systemic sclerosis (SSc). Nonspecific immunosuppressants have been the first-line treatment for SSc-associated ILD (SSc-ILD). Nintedanib, an oral triple kinase inhibitor targeting profibrotic pathways, has been employed for the treatment of idiopathic pulmonary fibrosis and has recently received marketing approval in the United States and Japan, based on the results of a placebo-controlled randomized controlled trial. In this clinical trial, nintedanib delayed the progression of SSc-ILD compared with placebo. AREAS COVERED: This review covers current pharmacotherapies for SSc-ILD, drug profiles of nintedanib, and efficacy and safety profiles of nintedanib in patients with idiopathic pulmonary fibrosis and SSc-ILD observed in randomized controlled trails. EXPERT OPINION: Currently, we have two treatment options for SSc-ILD, i.e., immunosuppressants and antifibrotic agents. However, appropriate utilization of antifibrotic agents in clinical practice remains challenging, i.e., in which cases they are to be used, timing of use, how to use them properly, and whether in combination with immunosuppressants.

Concurrent onset of acute lupus myocarditis, pulmonary arterial hypertension and digital gangrene in a lupus patient: a possible role of vasculitis to the rare disorders.

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.

Low-dose rituximab as induction therapy for ANCA-associated vasculitis.

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 < 0.01), the 17 patients with HD-RTX and 11 patients with LD-RTX showed no significant differences in clinical characteristics, including Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), and the initial dose of glucocorticoid. On 1-year observation, cumulative CR rates did not significantly differ (p = 0.20). Further, peripheral B cell counts and incidence of serious adverse events also did not differ. Cumulative CR rate did not significantly differ between LD and HD groups. Further study is warranted to confirm these results.

Hemodynamic heterogeneity of connective tissue disease patients with borderline mean pulmonary artery pressure and its distinctive characters from those with normal pulmonary artery pressure: a retrospective study.

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 < 0.0001) and comparable to those with PH. Each of the three patients was treated for pre-capillary and post-capillary disease and two for interstitial lung disease (ILD). During the mean follow-up period of 40 months, mPAP or TRPG normalized in all patients treated for pre-capillary and post-capillary disease. One patient with severe ILD developed to PH and died from it. CTD patients with borderline mPAP, the underlining pathogenesis of which is heterogeneous as PH, have distinctive hemodynamic characteristics from those with normal mPAP. Whether a specific treatment targeting the inflammatory process or local hemodynamics may alter the clinical course to PH is a topic for future research.

Rhabdomyolysis in a Patient with Polyarteritis Nodosa.

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.

Lack of partial renal response by 12 weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV.

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 < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3. CONCLUSIONS: Lack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI.

Role of non-protein amino acid L-canavanine in autoimmunity.

Association of SLE and alfalfa was first reported in a volunteer who developed lupus-like autoimmunity while ingesting alfalfa seed for a hypercholesterolemia study. This was corroborated with studies in monkeys fed with alfalfa sprout that developed SLE. Re-challenge with L-canavanine relapsed the disease. Arginine homologue L-canavanine, present in alfalfa, was suspected as a cause. L-canavanine can be charged by arginyl tRNA synthetase to replace L-arginine during protein synthesis. Aberrant canavanyl proteins have disrupted structure and functions. Induction or exacerbation of SLE by alfalfa tablets reported in a few cases remains controversial. Epidemiological studies on the relationship between alfalfa and SLE are sparse. In mice, NZB/W F1, NZB, and DBA/2 mice fed with L-canavanine show exacerbation/triggering of the SLE, however, BALB/c studies were negative. L-canavanine incorporation may be more efficient in the presence of inflammation or other conditions that can cause arginine deficiency. The L-canavanine induced apoptotic cells can be phagocytosed and a source of autoantigens processed by endosomal proteases. Endogenous canavanyl proteins are ubiquitinated and processed via proteasome. Incorporation of L-canavanine into proteasome or endosome can also cause disruption of antigen processing. Alfalfa/L-canavanine-induced lupus will be an interesting model of autoimmunity induced by the modification of self-proteins at the translational level.

Induction of lupus-related specific autoantibodies by non-specific inflammation caused by an intraperitoneal injection of n-hexadecane in BALB/c mice.

A single intraperitoneal (i.p.) injection of pristane, incomplete Freund's adjuvant (IFA), or the adjuvant oil squalene, but not high molecular weight medicinal mineral oils, induces lupus-related autoantibodies to nRNP/Sm and -Su in non-autoimmune strains of mice. This ability appears to be associated with the low molecular weight and adjuvanticity of hydrocarbon. n-Hexadecane (C(16)H(34)), which is present in petroleum, has adjuvant activity and induces arthritis in rodents like other lupus-inducing oils. In addition to dietary exposure to n-hexadecane in mineral oils, exposure also occurs via inhalation of oil mist, jet fuel, or diesel exhaust or by absorption through the skin. Since n-hexadecane is a low molecular weight adjuvant hydrocarbon oil similar to other lupus-inducing hydrocarbons, the present study examined whether it can also induce lupus-related autoantibodies in mice. Female BALB/cJ mice received a single i.p. injection of 0.5 ml of n-hexadecane, pristane, or saline (control). Pathology and serology (immunoglobulin levels, autoantibodies by immunofluorescence, immunoprecipitation, and ELISA) were examined 3 months later. Unexpectedly, all n-hexadecane-treated mice, but none in the other groups, developed inflammatory ascites within 2.5 months. n-Hexadecane induced hypergammaglobulinemia (IgG1, IgG2a), antinuclear (titer>1:160, 67%) and -cytoplasmic antibodies (58%) and autoantibodies to nRNP/Sm (25%), Su (33%), ssDNA (83%), and chromatin (100%). Therefore, non-specific inflammation caused by n-hexadecane resulted in the production of a limited set of specific autoantibodies. These previously unrecognized immunological effects of n-hexadecane may have implications in monitoring human exposure to hydrocarbons and in the pathogenesis of autoimmune diseases.

Simple exercise echocardiography using a Master's two-step test for early detection of pulmonary arterial hypertension.

BACKGROUND: Early detection of pulmonary arterial hypertension (PAH) is indispensable, although, echocardiography at rest alone does not provide sufficient evidence for it. Here, this study aimed to investigate the usefulness of simple exercise echocardiography using a Master's two-step test for detecting early PAH. METHODS: This study included 52 connective tissue disease patients who had mild symptoms in World Health Organization functional classification 2, suspected as having early PAH, and underwent exercise echocardiography and right heart catheterization. Echocardiography was performed before and after the Master's two-step exercise test; the study patients were classified into the non-PAH (mean pulmonary arterial pressure <25 mmHg, n=37) or PAH (mean pulmonary arterial pressure ≥25 mmHg, n=15) groups. RESULTS: Rest systolic pulmonary artery pressure estimated using echocardiography did not significantly differ between the two groups; however, a significant difference in post-exercise systolic pulmonary artery pressure was found (non-PAH, 58.8±10.8 mmHg; PAH, 80.2±14.3 mmHg, p<0.0001). The multiple logistic regression analysis indicated post-exercise systolic pulmonary artery pressure as an independent predictor of PAH (p=0.013). The area under the curve by post-exercise systolic pulmonary artery pressure was 0.91 for PAH. Post-exercise systolic pulmonary artery pressure ≥69.6 mmHg predicted PAH with the sensitivity of 93% and the specificity of 90%. CONCLUSIONS: Simple exercise echocardiography using the Master's two-step test could detect PAH in mildly symptomatic connective tissue disease patients. The usefulness of this method should be verified for the early detection of PAH.

Autoantibodies to transcription intermediary factor TIF1ß associated with dermatomyositis.

INTRODUCTION: Myositis specific autoantibodies are associated with unique clinical subsets and are useful biomarkers in polymyositis/dermatomyositis (PM/DM). A 120 kD protein recognized by certain patients with DM was identified and clinical features of patients with this specificity were characterized. METHODS: The 120 kD protein recognized by a prototype serum was purified and identified by mass spectrometry and immunological methods. Autoantibody to this 120 kD protein was screened in sera from 2,356 patients with various diagnoses from four countries, including 254 PM/DM, by immunoprecipitation of 35S-methionine labeled K562 cell extracts. Clinical information of patients with this specificity was collected. RESULTS: The 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1ß (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti-TIF1ß positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1ß were identified; all are women, one each in a Japanese, African American, Caucasian, and Mexican individual. Three had a diagnosis of DM and one case was classified as having an undifferentiated connective tissue disease with an elevated CPK but without significant muscle symptoms. This individual also had a history of colon cancer, cervical squamous metaplasia and fibroid tumors of the uterus. Myopathy was mild in all cases and resolved without treatment in one case. The anti-TIF1ß specificity was not found in other conditions. CONCLUSIONS: Anti-TIF1ß is a new DM autoantibody associated with a mild form of myopathy. Whether it has an association with malignancy, as in the case of anti-TIF1γ, or other unique features will need to be evaluated in future studies.

Longterm survival and associated risk factors in patients with adult-onset idiopathic inflammatory myopathies and amyopathic dermatomyositis: experience in a single institute in Japan.

OBJECTIVE: To analyze clinical characteristics, survival, causes of death, and risk factors associated with mortality in patients with adult-onset idiopathic inflammatory myopathies (IIM) in Japan. METHODS: We retrospectively investigated 197 patients diagnosed with adult-onset IIM at our hospital from 1984 to 2009 according to Bohan and Peter criteria for polymyositis (PM)/dermatomyositis (DM) and modified Sontheimer's criteria for clinically amyopathic DM (ADM). RESULTS: Survival in the whole group at 1, 5, and 10 years was 85%, 75%, and 67%, respectively. Mortality in cancer-associated myositis was the worst (25% at 5 yrs), followed by clinically ADM (61% at 5 yrs) and primary DM (77% at 5 yrs). Primary DM had significantly low survival compared to primary PM (91% at 5 yrs; p = 0.0427). Among the 53 patients who died were 6 patients with ADM (11%) and 20 patients with primary DM (38%). Interstitial lung disease (ILD) was the main cause of death in clinically ADM (71%) and primary DM (60%), most of which occurred within the first few months. Fewer patients died in primary PM (9%) and overlap myositis (13%). Independent risk factors for death were older age (HR 1.031; 95% CI 1.009-1.053) and skin ulcers (HR 3.018; 95% CI 1.340-6.796) in the whole group and ILD with mild serum creatine kinase levels (< 500 IU/l; HR 3.537; 95% CI 1.260-9.928) in primary DM. CONCLUSION: Survival of clinically ADM and primary DM was low, mainly due to fatal ILD, compared to primary PM. Establishing therapeutic strategy for ILD may improve the survival in our patient population.