Yoshioki Yamasaki

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.

Citrulline Dependence of Anti-Cyclic Citrullinated Peptide Antibodies in Systemic Lupus Erythematosus as a Marker of Deforming/Erosive Arthritis

Objective. Anti-cyclic citrullinated peptide (CCP) antibodies are a serological marker for rheumatoid arthritis (RA); up to 10%–15% of patients with systemic lupus erythematosus (SLE) are also positive. While anti-CCP in RA is citrulline-dependent, anti-CCP in some other diseases is citrulline-independent and reacts with both CCP and the unmodified (arginine-containing) cyclic arginine peptide (CAP). We investigated the citrulline dependence of anti-CCP and its significance in the arthritis of SLE. Methods. IgG anti-CCP was compared by ELISA to anti-CAP in sera from patients with SLE (n = 335) and RA (n = 47) and healthy controls (n = 35). SLE patients were divided into 5 groups based on their joint involvement: subset I: deforming/erosive arthritis (n = 20); II: arthritis fulfilling (or likely fulfilling) American College of Rheumatology criteria for RA but without erosions (n = 18); III: joint swelling but not fulfilling RA criteria (n = 39); IV: arthritis without documented joint swelling (n = 194); and V: no arthritis (n = 58). Results. Anti-CCP (> 1.7 units) was found in 68% (32/47) of patients with RA and 17% (55/329) of those with SLE. It was more common in SLE patients with deforming/erosive arthritis (38%). High anti-CCP (> 10 units) was found in RA (26%) and deforming/erosive SLE (12%). High anti-CCP/CAP ratios (> 2, indicating a selectivity to CCP) were found in 91% of anti-CCP-positive RA and 50% of anti-CCP-positive SLE patients with deforming/erosive arthritis. Patients from subset II did not have high anti-CCP/CAP. Conclusion. Citrulline dependence or high levels (> 10) of anti-CCP were common in SLE patients with deforming/erosive arthritis, while most anti-CCP in SLE patients was citrulline-independent. This may be useful in identifying a subset of SLE patients with high risk for development of deforming/erosive arthritis.

Clinical implication of autoantibodies in patients with systemic rheumatic diseases

Autoantibodies have been used extensively as a useful biomarker in systemic lupus erythematosus and other autoimmune rheumatic diseases. Antinuclear antibodies by immunofluorescence are a standard clinical test to screen for evidence of systemic autoimmunity. Different specific autoantibodies are associated with particular diagnoses, symptoms, unique syndromes, subsets of the disease and clinical activity. They are produced prior to the onset of clinical manifestations and have predictive value. This review focuses on a critical re-evaluation of the clinical significance of autoantibodies. Disease subsets defined by autoantibodies, coexistence of disease marker antibodies, and problems in testing and interpreting results are examined. Clinical approaches in differential diagnosis of antinuclear antibodies and the significance of antinuclear antibodies in healthy individuals are also discussed.

Autoantibodies to transcription intermediary factor (TIF)1β associated with dermatomyositis

IntroductionMyositis 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.MethodsThe 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.ResultsThe 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1β (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti-TIF1β positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1β 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-TIF1β specificity was not found in other conditions.ConclusionsAnti-TIF1β 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.

Autoantibodies against the replication protein A complex in systemic lupus erythematosus and other autoimmune diseases

Replication protein A (RPA), a heterotrimer with subunits of molecular masses 70, 32, and 14 kDa, is a single-stranded-DNA-binding factor involved in DNA replication, repair, and recombination. There have been only three reported cases of anti-RPA in systemic lupus erythematosus (SLE) and Sjögren syndrome (SjS). This study sought to clarify the clinical significance of autoantibodies against RPA. Sera from 1,119 patients enrolled during the period 2000 to 2005 were screened by immunoprecipitation (IP) of 35S-labeled K562 cell extract. Antigen-capture ELISA with anti-RPA32 mAb, immunofluorescent antinuclear antibodies (ANA) and western blot analysis with purified RPA were also performed. Our results show that nine sera immunoprecipitated the RPA70–RPA32–RPA14 complex and all were strongly positive by ELISA (titers 1:62,500 to 1:312,500). No additional sera were positive by ELISA and subsequently confirmed by IP or western blotting. All sera showed fine speckled/homogeneous nuclear staining. Anti-RPA was found in 1.4% (4/276) of SLE and 2.5% (1/40) of SjS sera, but not in rheumatoid arthritis (0/35), systemic sclerosis (0/47), or polymyositis/dermatomyositis (0/43). Eight of nine patients were female and there was no racial predilection. Other positive patients had interstitial lung disease, autoimmune thyroiditis/hepatitis C virus/pernicious anemia, or an unknown diagnosis. Autoantibody specificities found in up to 40% of SLE and other diseases, such as anti-nRNP, anti-Sm, anti-Ro, and anti-La, were unusual in anti-RPA-positive sera. Only one of nine had anti-Ro, and zero of nine had anti-nRNP, anti-Sm, anti-La, or anti-ribosomal P antibodies. In summary, high titers of anti-RPA antibodies were found in nine patients (1.4% of SLE and other diseases). Other autoantibodies found in SLE were rare in this subset, suggesting that patients with anti-RPA may form a unique clinical and immunological subset.

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 Masters 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 Masters 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 Masters 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.

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

Abstract 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 Sontheimers 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.

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.

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

Abstract 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.

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.