Hisae Ichida

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.

Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease

OBJECTIVE PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

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.

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.

Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease

OBJECTIVE To determine whether IL-18 is involved in the inflammation of DM and PM. METHODS Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission. RESULTS Serum IL-18 was significantly (P < 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042). CONCLUSION Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.

Semiquantitative measurement of aquaporin-4 antibodies as a possible surrogate marker of neuromyelitis optica spectrum disorders with systemic autoimmune diseases

ObjectivesTo assess the association between serum aquaporin-4 (AQP4) autoantibodies and neuromyelitis optica spectrum disorders (NMOSDs) associated with systemic autoimmune diseases.MethodsWe retrospectively studied 626 hospitalized patients with systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS). We collected serum samples from those patients with suspected NMOSDs (i.e., myelitis or optic neuritis) at the time of onset and thereafter. AQP4 antibodies were measured by a cell-based indirect immunofluorescence assay using AQP4-transfected HEK-293 cells in a semi-quantitative manner.ResultsSera from 6 patients with suspected NMOSDs and SLE (n = 3) or SS (n = 3) were evaluated. Among these, 2 patients’ sera samples, i.e., 1 with SLE and 1 with SS, were positive for AQP4 antibodies. There was an inverse relationship between disease amelioration and antibody titer in one NMOSD patient, whereas the antibody titer remained high in the other NMOSD patient, whose clinical manifestations of NMOSDs did not improve despite intensive immunosuppressive treatments.ConclusionsThese results indicate that serum AQP4 antibodies are present in some SLE/SS patients with myelitis/optic neuritis and might be associated with clinical outcomes. The semi-quantitative measurement of the AQP4 antibody might be a possible surrogate marker in patients with NMOSDs associated with systemic autoimmune diseases.

Urinary free light chain is a potential biomarker for ISN/RPS class III/IV lupus nephritis

OBJECTIVES To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN. METHODS Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of κ-LCs, λ-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled. RESULTS Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary λ-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19(-)/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary λ-FLCs could not be detected in any of the patients. CONCLUSION The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN.

Ghrelin attenuates collagen production in lesional fibroblasts from patients with systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by thickening of the skin and tissue fibrosis of the internal organs. Ghrelin is primarily described as a gut hormone, and many studies currently indicate that ghrelin has protective effects in different organs, including the heart, pancreas, lung and liver, resulting from its anti-fibrotic properties. We found decreased levels of ghrelin in the plasma from patients with SSc compared with those from healthy controls. In skin fibroblast cultures, recombinant ghrelin diminished the production of collagen type I. In addition, the mRNA levels of COL1A2 and TGFB genes were significantly decreased by the stimulation of ghrelin. We showed that ghrelin may exert anti-fibrotic effects in the skin fibroblasts from patients with SSc. Because the plasma levels of ghrelin are low in SSc, the administration of ghrelin could be a new strategy for the treatment of SSc.

Erythematosus plaques with macrophage infiltration as an initial manifestation of macrophage activation syndrome in a patient with systemic lupus erythematosus.

The diagnosis of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) may be challenging as it can mimic the clinical features of the underlying disease or be confused with an infectious complication. In this report, a Japanese woman in her forties had diverse clinical features of MAS at initial presentation of SLE, where erythematosus plaques with histiocytic infiltrates focally surrounding degenerated collagen might be the earliest indicator of MAS.

Clinical utility of computed tomographic scanning for the evaluation of lupus profundus in two patients with systemic lupus erythematosus

Lupus profundus is a rare lupus-specific skin lesion with skin biopsies exhibiting lobular lymphocytic infiltration and destruction of subcutaneous fat tissue. In this report, a CT scan was effective in demonstrating both the presence and the extent of inflammation of lupus profundus in two patients with systemic lupus erythematosus (SLE). Case 1 was a 30-year-old woman developing erythema with subcutaneous induration on the upper arms during the quiescent phase of SLE. A skin biopsy confirmed a diagnosis of lupus profundus. A CT scan of the right upper arm demonstrated a high density area (HDA) of the subcutis under the erythema: a finding consistent with lupus profundus. Case 2 was a 28-year-old woman recently diagnosed with SLE. She also developed a skin ulcer on the right hip. A CT scan of the hip revealed an HDA and lipoatrophy of the subcutis around the ulcer: these findings were compatible with lupus profundus. Treatment with high-dose prednisolone improved the illness in the both cases. A CT scan is a useful and convenient imaging modality for confirming the diagnosis of lupus profundus.