Haruka Tsuchiya

Mycophenolate mofetil therapy for rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis

Rapidly progressive interstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM) is often lethal despite corticosteroid therapy combined with cyclophosphamide and cyclosporine or tacrolimus. Several recent studies have described the treatment of ILD in patients with systemic sclerosis (SSc) or other connective tissue diseases with mycophenolate mofetil (MMF), a noncytotoxic immunosuppressant [1–9]. To our knowledge, this is the first report of MMF therapy as an alternative to intravenous pulses of cyclophosphamide (IVCY) for rapidly progressive ILD associated with CADM in combination with high-dose corticosteroids and oral tacrolimus. A 55-year-old female was admitted with a 1-week history of low-grade fever, muscle pain in the thigh, Gottron’s papules, and heliotrope rash. The white blood cell count was 3,230/ll with 75.9 % neutrophils, and C-reactive protein was 0.27 mg/dl (\ 0.3 mg/dl). The serum antinuclear antibody titre was not elevated and no anti-Jo-1 antibodies were detected. Anti-CADM 140 antibody was positive. She had no muscle weakness and her serum creatine kinase (156 IU/l; normal 45–163 IU/l) and aldolase (6.8 IU/l; normal 2.7–7.5 IU/l) levels were normal. Quadriceps magnetic resonance imaging and electromyography detected muscle inflammation. Slight fine crackles were audible bilaterally. Arterial blood gas analysis showed pH 7.472, PaO2 76.4 Torr, and PaCO2 34.5 Torr. The serum KL-6 was elevated at 695 U/ml (\ 499 U/ml). A chest X-ray revealed faint reticular shadows in both lower lung fields. Chest high-resolution computed tomography (HRCT) showed bilateral subpleural opacity with groundglass attenuation (GGA) (Fig. 1a). She was diagnosed with CADM and progressive ILD, and given intravenous pulse methylprednisolone therapy at 1 g/day for 3 days followed by oral prednisolone 1 mg/kg/day (50 mg/day). After 3 weeks, the muscle pain and skin manifestations had improved, while the chest images had deteriorated gradually with lung shrinkage on chest X-ray and increasing GGA with patchy consolidation on HRCT (Fig. 1b). Biweekly IVCY at 500 mg/body dose and oral tacrolimus were added immediately. The trough serum tacrolimus level was maintained at 8–10 ng/ml. Over the next 13 weeks, she received six sessions of IVCY therapy, the pulmonary lesion extended (Fig. 1c) and hypoxemia requiring oxygen therapy manifested. Intravenous pulse methylprednisolone therapy at 250 mg/day for 3 days was administrated followed by prednisolone 30 mg/day. Nevertheless, the chest images and her respiratory condition had not improved 4 weeks after these additional therapies. Furthermore, IVCY could not be continued because of sustained leukocytopaenia. We switched from IVCY to oral MMF, and gradual improvement of the hypoxemia and pulmonary lesions was obtained. Thirty-one weeks after starting MMF, when the prednisolone had been tapered to 10 mg/day, the lung GGA and exertional dyspnoea resolved (Fig. 1d) and the serum KL-6 level decreased from 4,837 to 563 U/ml (Fig. 2). During the combination therapy with MMF, she suffered from cytomegalovirus infection, which was successfully treated with ganciclovir. Her ILD and CADM have been well controlled without exacerbation for 2 years. H. Tsuchiya (&) H. Tsuno M. Inoue Y. Takahashi H. Yamashita H. Kaneko T. Kano A. Mimori Division of Rheumatic Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, shinjuku-ku, Tokyo 162-8655, Japan e-mail: elephantscale@yahoo.co.jp

A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-β cascades with restored caveolin-1 expression

ABSTRACT Introduction: Pulmonary hypertension (PH) is characterized by increased pressure in the pulmonary artery and right ventricular hypertrophy (RVH). Recently, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), was shown to inhibit experimental PH. Here we identified a novel ACE2 activator and investigated how the compound reduced monocrotaline (MCT)-induced PH. Methods: To induce PH, Sprague-Dawley rats were injected subcutaneously with MCT, followed by the continuous administration of NCP-2454, an ACE2 activator, using osmotic pumps. Pulmonary arterial compliance was monitored every week until 4 weeks post-injection (wpi). RVH and lung remodeling was evaluated using lung tissue at 4 wpi. Results: NCP-2454 upregulated the production of Ang-(1-7) when incubated with ACE2 and Ang II. Notably, a continuous infusion of NCP-2454 significantly improved pulmonary arterial compliance, right ventricular systolic pressure, and RVH in MCT-treated rats. Interestingly, NCP-2454 increased the relative expression of ACE2 and MAS mRNA in lung tissue, especially in MCT-treated rats. In addition, the compound inhibited the MCT-induced overexpression of transforming growth factor β, phosphorylation of signal transducer and activator of transcription-3 (STAT3), and interleukin-6 production. The compound also restored the expression of caveolin-1 (Cav-1), which negatively regulates the Janus kinase-STAT signaling cascade. Conclusions: NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression.

Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+ T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.

Successful tocilizumab therapy in seven patients with refractory adult-onset Still's disease

To evaluate the effects of tocilizumab (TCZ) on adult-onset Stills disease (AOSD), we reviewed medical records of seven patients with refractory AOSD treated with TCZ at our institution. TCZ therapy might allow rapid corticosteroid tapering and help maintain remission status, that is, resolution of clinical symptoms and normalization of biomarkers such as CRP and ferritin. Patients, however, should be monitored for the development of macrophage activation syndrome when TCZ is administered for active AOSD.

Identification of novel autoantibodies to GABAB receptors in patients with neuropsychiatric systemic lupus erythematosus

OBJECTIVE The gamma-aminobutyric acid type B receptors (GABAR(B)) are G-protein coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. We identified GABAR(B) subunits as candidate antigens in patients with SLE using a random peptide display library. The aim of this study was to investigate the possible link between anti-GABAR(B) antibodies and disease activity and NPSLE. METHODS ELISA was performed with recombinant proteins of GABAR(B1b) and GABAR(B2) on serum samples from patients with SLE (n = 88), scleroderma (n = 20), myositis (n = 20) or vasculitis (n = 20) as well as healthy subjects (n = 20). Cerebrospinal fluid (CSF) from 23 patients with SLE was also examined. RESULTS Autoantibodies to GABAR(Bs) were exclusive to patients with SLE (P < 0.001) and positively associated with SLEDAI (anti-GABAR(B1b), P = 0.001; anti-GABAR(B2), P < 0.001). Of note, autoantibodies were positively linked with NPSLE (anti-GABAR(B1b), P = 0.02; anti-GABAR(B2), P = 0.03). Moreover, anti-GABAR(Bs) was detected in 61.5% of CSF samples from patients with active NPSLE, a frequency that was significantly higher than that for patients with non-SLE syndromes. CONCLUSION Anti-GABAR(B) antibodies could represent novel candidate markers for disease activity and NPSLE.

Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4+ T cells, and disease activity

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.

TGF-β3 Inhibits Antibody Production by Human B Cells

TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-β3 on human B cells has not been reported, and we herein examined the effect of TGF-β3 on human B cells. TGF-β3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-β1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-β1 remains elusive; therefore, we examined the effect of TGF-β1 and β3 on pathways important in B cell activation and differentiation. TGF-β1 and TGF-β3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-β1 and β3 also inhibited B cell receptor signaling. Our results suggest that TGF-β3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.

Characteristics of 10 patients with paraneoplastic rheumatologic musculoskeletal manifestations

Abstract Objectives. To evaluate the possible correlation of malignant neoplasms and paraneoplastic rheumatologic syndromes. Methods. We studied a series of 10 patients with paraneoplastic rheumatological syndromes collected from our Division of Rheumatic Disease between 2006 and 2012. Results. Our series consisted of four males and six females, with a mean age of 65.5 years (range, 57–78 years). Of the 10 patients recruited, six had hematological malignancies and four had solid cancers. Malignancies were diagnosed after rheumatic symptoms were reported in all patients. Compared to solid tumors, hemopathy was diagnosed at a later time point (16.2 vs. 7.3 months). Extra-articular symptoms were associated with rheumatologic musculoskeletal manifestations in 100% of the patients. Polyarthritis was the main rheumatologic musculoskeletal manifestation (50% of the patients). The other manifestations were oligopolyarthritis and polymyalgia rheumatic-like symptoms (20% of the patients). Symmetric arthritis was present in 60% of the patients, and the remaining patients developed asymmetric arthritis. Musculoskeletal manifestations completely regressed in 66.7% of the patients after cancer therapy. When tumor relapse was observed, rheumatic symptoms did not recur in any of our patients (100%). Conclusions. Rheumatic disorders with atypical clinical presentation in older patients, poor response to usual treatment and systemic features such as weight loss and clinical findings compatible with well-recognized paraneoplastic syndromes should alert clinicians to the possible coexistence of an occult malignancy. Especially in cases of paraneoplastic rheumatic/musculoskeletal manifestations associated with hemopathy, the primary disease is unlikely to have manifested yet, making the diagnosis difficult. Thus, caution is required.

Two cases of adult-onset Still's disease with orbital inflammatory lesions originating from the lacrimal gland.

Orbital inflammation has been rarely associated with adult-onset Stills disease (AOSD). We herein describe two AOSD patients who developed lacrimal gland enlargement with inflammation spreading to the contiguous tissues in the orbit. Case 1 was a 26-year-old woman who developed bilateral eyelid swelling while taking prednisolone (22.5 mg/day) for AOSD. The swelling of the eyelid worsened after other symptoms emerged, such as a fever, a rash, and arthritis. The laboratory findings, including leukocytosis, liver dysfunction, and ferritin elevation, also suggested an AOSD flare-up. Case 2 was a 62-year-old woman who presented with left eyelid swelling. She was diagnosed with AOSD at 45 years of age but sustained remission. During admission, she subsequently developed a fever, a rash, arthritis, lymphadenopathy, and ocular hyperemia. AOSD was suspected from the clinical course. We speculate that dacryoadenitis and orbital inflammation are manifestations of AOSD.

Complete atrioventricular block and aseptic meningitis in a patient with adult-onset Still's disease and concurrent hemophagocytic syndrome

infection or reactivation, including blood cultures and serological tests or PCR examinations for hepatitis B, C, human immunodefi ciency virus, cytomegalovirus, Epstein – Barr virus, varicella virus, rubella virus and measles virus were negative. Urinalysis showed no abnormalities. Findings of a cerebral computed tomography (CT) scan were within normal limits. Cerebrospinal fl uid (CSF) analysis showed pleocytosis, 193/mm (predominantly lymphocytes), a high protein level of 60 mg/dl and a normal glucose level of 56 mg/dL. Gram staining, bacterial, fungal, and mycobacterial cultures and PCR testing for herpes simplex virus of the CSF were negative. Whole body CT scan, skin biopsies of the erythematous skin and cervical lymph node biopsy were negative for malignant lymphoma, and non-specifi c but severe infl ammatory cell infi ltration was observed. Bone marrow aspiration revealed macrophages actively phagocytizing blood cells. Electrocardiogram (Figure 1a) and chest radiography revealed no abnormalities. Therefore, aseptic meningitis accompanied by AOSD and concurrent HPS was diagnosed according to the Yamaguchi criteria [1]. Steroid pulse therapy (Dexamethasone 40 mg/day) and intravenous cyclosporine (200 mg/day) were initiated. On day 2, after admission, severe bradycardia developed and complete atrioventricular block was detected on an electrocardiogram (Figure 1b). Echocardiography revealed neither pericardial eff usion nor any wall motion abnormality and laboratory blood tests for myocarditis (i.e. creatinine kinase, troponin I) had not been elevated since admission. As there was no other cause of cardiac conduction disturbance (i.e. electrolyte abnormalities, myocardial ischemia), complete atrioventricular block due to AOSD and/or HPS was suspected. An external temporary pacemaker was implanted immediately and initial immunosuppressive therapy was continued. Subsequently, there was marked improvement in the patient ’ s symptoms and laboratory markers over the next 7 days, and on day 10 the electrocardiogram had normalized (Figure 1c) and so the pacemaker was removed. Thereafter, the steroid dose was slowly tapered and all clinical symptoms disappeared. Three months after admission, the patient was discharged on cyclosporine and 27.5 mg/day of prednisone. At a 2-year follow-up, the patient remained asymptomatic. Mod Rheumatol, 2014; Early Online: 1–2