Yasuhiro Katsumata

Increased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis

OBJECTIVES Acute/subacute interstitial pneumonia (A/SIP) is an intractable and fatal complication of DM. Since a useful indicator predicting the complication of A/SIP has not been found, the aim of this study was to determine whether serum ferritin is a potential predictive indicator of the occurrence of A/SIP in 64 patients with DM. METHODS Of the total patients enrolled, 19 had A/SIP, 24 had chronic interstitial pneumonia and 21 were without interstitial lung disease (ILD). Clinical manifestations and laboratory data were obtained from medical records on admission. RESULTS Serum ferritin levels were extremely high in patients with DM with A/SIP. It was significantly higher in DM with A/SIP than that in DM without A/SIP (median 790 vs 186 ng/ml; P < 0.0001). The cumulative survival rate for 6 months was 62.7% in patients with DM with A/SIP. Moreover, the cumulative survival rate was significantly (P = 0.016) lower in the group with ferritin levels > or =1500 ng/ml than the rate in the group with ferritin levels <1500 ng/ml. CONCLUSIONS Serum ferritin can be useful as a predictor of the occurrence of A/SIP and correlates with the prognosis of A/SIP in DM. The intensive treatment using combination therapy with various immunosuppressant agents should be chosen for patients with ILD with DM showing hyperferritinaemia, especially levels >1500 ng/ml.

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

The aberrant production of precursor IL-1α (pre-IL-1α) in skin fibroblasts that are derived from systemic sclerosis (SSc) is associated with the induction of IL-6 and procollagen, which contributes to the fibrosis of SSc. However, little is understood about how intracellular pre-IL-1α regulates the expression of the other molecules in fibroblasts. We report here that pre-IL-1α can form a complex with IL-1α-binding proteins that is translocated into the nuclei of fibroblasts. Immunoprecipitation that used anti-human IL-1α Ab and 35S-labeled nuclear extracts of fibroblasts showed three specific bands (≈31, 35, and 65 kDa). The 31-kDa molecule was identified as pre-IL-1α, and the 35- and 65-kDa molecules might be pre-IL-1α-binding proteins. A partial sequencing for the 10 aa from the N-terminals of the molecules showed 100% homology for HAX-1 (HS1-associated protein X-1) and IL-1 receptor type II (IL-1RII). Suppression of the genes of HAX-1 or IL-1RII induced the inhibitory effects of IL-1 signal transduction, including production of IL-6 and procollagen, by fibroblasts. In particular, pre-IL-1α was not translocated into the nucleus by an inhibition of HAX-1. These findings reveal that nuclear localization of pre-IL-1α depends on the binding to HAX-1 and that biological activities might be elicited by the binding to both HAX-1 and IL-1RII in SSc fibroblasts.

Clinical manifestations of neurological involvement in primary Sjögren’s syndrome.

The aim of this study was to evaluate neurological manifestations of primary Sjögren’s syndrome (pSS) and investigate the etiology and pathogenesis of peripheral and central nervous complications in pSS. Thirty-two patients with pSS were enrolled in the present study, 20 of whom had neurological involvement plus sicca symptoms. The clinical features were evaluated by neurological examinations including nerve conduction study, magnetic resonance imaging, cerebrospinal fluid, and electroencephalogram. The frequency of fever was significantly higher (P = 0.006) in pSS with neurological involvement than in pSS without neurological involvement. There was no statistical significance in other factors between the two groups. Peripheral nervous system (PNS), central nervous system (CNS), and both PNS and CNS involvements were revealed in 14, 3, and 3 patients, respectively. Optic neuritis and trigeminal neuralgia were revealed frequently in cranial neuropathy. Anti-aquaporin 4 antibody was detected in one patient with optic neuritis. Of the nine patients with polyneuropathy, eight patients presented pure sensory neuropathy including small fiber neuropathy (SFN). pSS with SFN appeared to have no clinically abnormal features, including muscle weakness and decreasing deep tendon reflex. Skin biopsy revealed epidermal nerve fiber degenerated in one pSS patient with pure sensory neuropathy who was diagnosed as having SFN. Our observations suggest that a number of mechanisms can be attributed to neurological involvements in pSS rather than just the mechanisms previously described (i.e., vasculitis and ganglioneuronitis). Presumably, specific autoantibodies may directly induce injury of the nervous system.

Anti‐C1q antibodies are associated with systemic lupus erythematosus global activity but not specifically with nephritis: A controlled study of 126 consecutive patients

OBJECTIVE Several studies have shown that anti-C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti-C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-C1q antibodies and clinical and serologic parameters of SLE. METHODS An enzyme-linked immunosorbent assay kit was used to measure anti-C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti-C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti-C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed. RESULTS Anti-C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti-C1q antibodies were significantly (P < 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti-C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti-C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti-double-stranded DNA antibodies, C3, C4, CH50, and C1q (P < 0.0001 for all comparisons). Moreover, anti-C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097). CONCLUSION These findings indicate that anti-C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.

Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus

OBJECTIVE The aim of this study is to establish a detection method for anti-N-methyl-d-aspartate receptor subunit 2A (NR2A) antibody and to evaluate the relationship between anti-NR2A antibody and various organ involvement in SLE. METHODS Serum anti-NR2A antibody was measured by ELISA using a peptide with a core of either DWEYS or DWDYS as autoantigen. Additionally, clinical characteristics were compared between 27 anti-NR2A antibody-positive (P group) and 80 antibody-negative (N group) SLE patients using DWDYS peptide. RESULTS The optical density (OD) values of anti-NR2A antibody using DWDYS and DWEYS peptides correlated significantly (r = 0.94, P < 0.0001). The median OD value was significantly higher (P < 0.0001) with DWDYS. Additionally, the SLEDAI was significantly higher (P = 0.023) in the P group. The frequency of neuropsychiatric SLE (NPSLE) was significantly higher (P = 0.0002) in the P group, although the frequencies of serositis and nephritis were not statistically significant. Significant correlations were found between anti-NR2A antibody and leucocyte count (r(s) = -0.31, P = 0.001) and haemoglobin (r(s) = -0.42, P < 0.0001), although no correlation was found between anti-NR2A antibody and the titre of anti-dsDNA antibody. NPSLE was the most significant independent variable (P = 0.0008) associated with anti-NR2A antibody positivity, as estimated by multiple linear regression analysis. CONCLUSION Serum anti-NR2A antibody can be associated with the complication of NPSLE and may indicate the involvement of non-nervous tissue. The use of peptides that include DWDYS is preferable to detect anti-NR2A antibody in ELISA.

Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus: possible involvement in excessive interferon-γ and anti-double-stranded DNA antibody production

Inducible co-stimulator (ICOS) is the third member of the CD28/cytotoxic T-lymphocyte associated antigen-4 family and is involved in the proliferation and activation of T cells. A detailed functional analysis of ICOS on peripheral blood T cells from patients with systemic lupus erythematosus (SLE) has not yet been reported. In the present study we developed a fully human anti-human ICOS mAb (JTA009) with high avidity and investigated the immunopathological roles of ICOS in SLE. JTA009 exhibited higher avidity for ICOS than a previously reported mAb, namely SA12. Using JTA009, ICOS was detected in a substantial proportion of unstimulated peripheral blood T cells from both normal control individuals and patients with SLE. In CD4+CD45RO+ T cells from peripheral blood, the percentage of ICOS+ cells and mean fluorescence intensity with JTA009 were significantly higher in active SLE than in inactive SLE or in normal control individuals. JTA009 co-stimulated peripheral blood T cells in the presence of suboptimal concentrations of anti-CD3 mAb. Median values of [3H]thymidine incorporation were higher in SLE T cells with ICOS co-stimulation than in normal T cells, and the difference between inactive SLE patients and normal control individuals achieved statistical significance. ICOS co-stimulation significantly increased the production of IFN-γ, IL-4 and IL-10 in both SLE and normal T cells. IFN-γ in the culture supernatants of both active and inactive SLE T cells with ICOS co-stimulation was significantly higher than in normal control T cells. Finally, SLE T cells with ICOS co-stimulation selectively and significantly enhanced the production of IgG anti-double-stranded DNA antibodies by autologous B cells. These findings suggest that ICOS is involved in abnormal T cell activation in SLE, and that blockade of the interaction between ICOS and its receptor may have therapeutic value in the treatment of this intractable disease.

Frequency of Class III and IV Nephritis in Systemic Lupus Erythematosus Without Clinical Renal Involvement: An Analysis of Predictive Measures

Objective. To determine the frequency of International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis in patients with systemic lupus erythematosus (SLE) without clinical renal involvement. Methods. We investigated the renal pathology of 195 patients with SLE, including 86 patients without clinical renal involvement. Results. Lupus nephritis other than class I was found in 58% of the patients without clinical renal involvement, and class III and IV nephritis was found in 15% of these patients. To reveal the predictive measures involved in class III or IV lupus nephritis, we explored the clinical measures in patients with SLE who did not have clinical renal involvement. Anti-dsDNA antibody titers were significantly higher (p = 0.0266) and C3 values were significantly lower (p = 0.0073) in patients with class III or IV lupus nephritis than in patients without class III or IV lupus nephritis. The sensitivity and specificity values were 77% and 73%, respectively, for cutoff levels of both 40 IU/ml for anti-dsDNA antibodies and 55 mg/dl for C3 (OR 8.8, p = 0.0011). Conclusion. The frequency of nephritis, including ISN/RPS class III and IV, was unexpectedly high in SLE patients without clinical renal involvement. ISN/RPS class III or IV lupus nephritis could be hidden in patients with SLE who present both a high titer of anti-dsDNA antibody and a low concentration of C3, even when they have clinically normal urinary findings and renal function.

Clinical Manifestations of Adult‐Onset Still's Disease Presenting With Erosive Arthritis: Association With Low Levels of Ferritin and Interleukin‐18

Adult‐onset Stills disease (AOSD) is a clinical entity with a heterogeneous etiology. We have encountered patients with AOSD who had severe polyarthritis and who fulfilled the classification criteria for rheumatoid arthritis (RA); however, most patients with AOSD typically exhibit mild arthritis. In this study, we proposed 2 clinical subsets of AOSD and investigated the clinically significant characteristics of the 2 subtypes.

Role of innate immunity in a murine model of histidyl–transfer RNA synthetase (Jo-1)–mediated myositis†

OBJECTIVE Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis. METHODS Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization. RESULTS Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling. CONCLUSION Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.

Brief Report: Association of HLA–DRB1*0101/*0405 with susceptibility to anti–melanoma differentiation–associated gene 5 antibody–positive dermatomyositis in the Japanese population

OBJECTIVE The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody positivity. Anti-MDA-5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti-MDA-5 antibody-positive DM is unclear. This study was undertaken to investigate the HLA-DRB1 genotype in patients with anti-MDA-5 antibody-positive DM. METHODS We examined genetic differences among 17 patients with anti-MDA-5 antibody-positive DM, 33 patients with anti-aaRS antibody-positive PM/DM, 33 patients with PM/DM without anti-aaRS antibody or ILD, and 265 healthy controls. RESULTS The frequencies of HLA-DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti-MDA-5 antibody-positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti-MDA-5 antibody-positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti-MDA-5 antibody-positive DM than in patients with PM/DM without anti-aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9-370.2) (P = 1.1 × 10(-5)), or in patients with anti-aaRS antibody-positive PM/DM (OR 13.3 [95% CI 1.6-112.6], P = 4.5 × 10(-3)). CONCLUSION Our findings indicate that HLA-DRB1*0101/*0405 is associated with susceptibility to anti-MDA-5 antibody-positive DM in the Japanese population.