Ayako Nishino

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy

Objectives Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. Methods Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. Results Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb–IV). Conclusions While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function

Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin‐dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN).

Serum interferon-α is a useful biomarker in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis

Abstract Objective. We have tried to clarify the clinical importance of the measurement of serum type-I interferon (IFN) in patients with anti-melanoma differentiation-associated gene 5 Ab (MDA5 Ab)-positive dermatomyositis (DM). Methods. We studied 30 patients with DM: 10 were anti-MDA5 Ab-positive and 20 were anti-MDA5 Ab-negative. At each patients initial visit, serum IFN-α, IFN-β, interleukin 18 (IL-18), ferritin, and the titer of anti-MDA5 Ab were measured using enzyme-linked immunosorbent assays (ELISAs). The associations between the IFNs and with the other variables were examined. Results. Rapidly progressive interstitial lung disease (RPILD) was confirmed in 10 patients, most of whom were complicated in the anti-MDA5 Ab-positive DM patients. The presence of clinically amyopathic dermatomyositis (CADM) as well as the serum concentrations of IFN-α and ferritin was significantly higher in the anti-MDA5 Ab-positive DM patients. Serum concentration of IL-18 did not differ between anti-MDA5 Ab-positive and anti-MDA5 Ab-negative groups; however, a positive correlation was found between IFN-α and IL-18 in the anti-MDA5 Ab-positive DM patients (r = 0.8139, p = 0.0146). Conclusion. Serum IFN-α can be used as a useful biomarker in patients with anti-MDA5 Ab-positive DM, which may reflect the presence of RPILD.

Synovial inflammation assessed by ultrasonography correlates with MRI-proven osteitis in patients with rheumatoid arthritis

OBJECTIVE The aim of this study was to explore whether assessment of synovial inflammation by ultrasonography correlates with MRI-proven osteitis in patients with RA. METHODS Thirty RA patients who fulfilled 2010 RA classification criteria and were naive to DMARDs, including biologics and glucocorticoids, were consecutively enrolled in this study. Grey scale (GS) and power Doppler (PD) images of articular synovitis and bone erosion in both wrist and MCP joints were evaluated by the method proposed by the European League Against Rheumatism. MRI-proven osteitis of the identical sites was also evaluated within 3 days using the RA MRI scoring system (RAMRIS). The Cochran-Armitage test and Spearmans correlation coefficient were used to investigate the correlation of each US finding with MRI-proven osteitis. RESULTS MRI-proven osteitis was found in 8.3% of MCP joints and 48.3% of wrist joints. Its prevalence was increased in the joints where the GS or PD grade of articular synovitis was 2 or 3. In addition, MRI-proven osteitis was found preferentially in the joints positive for bone erosion on US. A clear correlation was demonstrated between the GS or PD grade of articular synovitis or the presence of US bone erosion and RAMRIS osteitis score in both MCP joints and wrist joints. CONCLUSION Our data indicate that joint injury assessed by US correlates with MRI-proven osteitis in patients with RA.

Lupus nephritis IgG induces the expression of calcium/calmodulin‐dependent kinase type IV in podocytes and alters their function

Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin‐dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN).

IgG4-related epididymo-orchitis associated with bladder cancer: possible involvement of BAFF/BAFF-R interaction in IgG4-related urogenital disease

We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.

Magnetic Resonance Imaging Bone Edema at Enrollment Predicts Rapid Radiographic Progression in Patients with Early RA: Results from the Nagasaki University Early Arthritis Cohort.

Objective. To clarify whether magnetic resonance imaging (MRI) bone edema predicts the development of rapid radiographic progression (RRP) in the Nagasaki University Early Arthritis Cohort of patients with early-stage rheumatoid arthritis (RA). Methods. Patients with early-stage RA (n = 76) were enrolled and underwent 1.5-T MRI of both wrists and finger joints. Synovitis, bone edema, and bone erosion were evaluated using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS). RRP was defined as an annual increment > 3 at 1 year by the Genant-modified Sharp score of plain radiographs. A multivariate logistic regression analysis was performed to establish the risk factors for RRP. Results. Median disease duration at enrollment was 3 months. RRP was found in 12 of the 76 patients at 1 year. A univariate analysis revealed that matrix metalloprotease-3, RAMRIS bone edema score, and RAMRIS bone erosion score were associated with RRP. Multivariate logistic regression analyses demonstrated that the RAMRIS bone edema score at enrollment (5-point increase, OR 2.18, 95% CI 1.32–3.59, p = 0.002) was the only independent predictor of the development of RRP at 1 year. A receiver-operating characteristic analysis identified the best cutoff value for RAMRIS bone edema score as 5. RRP was significantly rare among the patients with a RAMRIS bone edema score < 5 at enrollment (2 from 50 patients). Conclusion. Our findings suggest that MRI bone edema is closely associated with the development of RRP in patients with early-stage RA. Physicians should carefully control the disease activity when MRI bone edema is observed in patients with early RA.

Antineutrophilic cytoplasmic antibody-associated vasculitis with hypocomplementemia has a higher incidence of serious organ damage and a poor prognosis.

Abstract A relationship between antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and complement has been shown, and complement has an important role in the pathogenesis of AAV. The clinical characteristics of AAV with hypocomplementemia still remain unclear. We conducted an observational study of 81 patients with AAV (median onset age 71 years; 58% female). Using medical records, we analyzed the patients’ baseline variables, laboratory data, clinical symptoms, and therapeutic outcomes after treatments including episodes of relapses, initiation of dialysis, and death. We defined hypocomplementemia as the state in which at least one of the following was lower than the lower limit of the normal range: complement 3 (C3), complement 4 (C4), and total complement activity (CH50). Sixteen patients (20%) had hypocomplementemia at their diagnosis of AAV. Compared to the AAV patients without hypocomplementemia (n = 65), those with hypocomplementemia had significantly higher rates of the occurrence of skin lesions (8 [50%] vs. 8 [12%], P = 0.002), diffuse alveolar hemorrhage (DAH) (6 [38%] vs. 5 [8%], P = 0.006), and thrombotic microangiopathy (TMA) (3 [19%] vs. 0 [0%], P = 0.007). The AAV patients with hypocomplementemia had significantly lower platelet levels (16.5 × 104 vs. 24.9 × 104 cells/&mgr;L, P = 0.023) compared to those without hypocomplementemia. More positive immune complex deposits in renal biopsy specimens were seen in the AAV patients with hypocomplementemia than in those without hypocomplementemia (4 [80%] vs. 2 [18%], P = 0.036). Assessed by a log-rank test, hypocomplementemia at disease onset was significantly associated with death (P = 0.033). Hypocomplementemia in AAV at the disease onset was a risk factor for the serious organ damage, and a life prognostic factor. It is thus very important to pay attention to the levels of complement at the diagnosis of AAV.

Soluble α-klotho is a potential biomarker associated with neuropsychiatric systemic lupus erythematosus.

A reduced level of the single-pass transmembrane protein α-Klotho is known to be associated with neuronal damage. We investigated whether α-Klotho in cerebrospinal fluid (CSF) could be a candidate marker for the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE). We analyzed the laboratory data, symptoms and radiological image findings of 34 NPSLE patients. Patients with SLE without neuropsychiatric manifestations (SLE) (n=25), and patients with viral meningitis (VM) (n=19), multiple sclerosis (MS) (n=20) or neuromyelitis optica (NMO) (n=20) were included as controls. The multivariable analyses revealed that lower CSF α-Klotho level, lower serum anti-Smith antibodies (U/mL) and higher serum C3 (mg/dL) were significant factors for predicting NPSLE. The CSF α-Klotho levels of the NPSLE patients were inversely correlated with the level of granulocyte/macrophage-colony stimulating factor. Our data suggested that the determination of CSF α-Klotho levels will contribute to the diagnosis of NPSLE and help elucidate the mechanisms underlying this disease.

Upregulation of Thrombospondin 1 Expression in Synovial Tissues and Plasma of Rheumatoid Arthritis: Role of Transforming Growth Factor-β1 toward Fibroblast-like Synovial Cells

Objective. To investigate the role of thrombospondin 1 (TSP-1) in RA. Methods. Expression of TSP-1 in synovial tissues was determined by immunohistochemistry. Expression of TSP-1 in rheumatoid fibroblast-like synovial cells (FLS) was investigated by quantitative real-time PCR and ELISA. Correlations among the plasma TSP-1 and other variables in patients with RA were examined. Results. Expression of TSP-1 was increased in rheumatoid synovial tissues. Transforming growth factor-β1 (TGF-β1) clearly increased TSP-1 expression in FLS on both mRNA and protein levels. Changes in plasma TSP-1 were associated with those in 28-joint Disease Activity Score-erythrocyte sedimentation rate and plasma TGF-β1. Conclusion. TSP-1 might be critically involved in the disease process of RA through the TGF-β1/TSP-1 axis.