Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC).

OBJECTIVE: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. METHODS: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. RESULTS: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p < .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. CONCLUSION: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.

Polymorphic lymphoproliferative disorders in patients with rheumatoid arthritis are associated with a better clinical outcome.

OBJECTIVES: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department. METHODS: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed. RESULTS: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively). CONCLUSION: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

Association of early physical activity time with pain, activities of daily living, and progression of vertebral body collapse in patients with vertebral compression fractures.

BACKGROUND: Physical activity can reduce pain and improve the ability to perform daily activities in patients with acute low back pain (LBP) due to various non-specific causes. The association between physical activity during the early phase of acute vertebral compression fractures (VCFs) and rehabilitation outcomes is unknown. AIM: The aim of this study was to investigate the effects of early physical activity time (EPAT) on pain following acute VCFs, recovery of the ability to perform activities of daily living (ADLs), and progression of fractured vertebral body collapse. DESIGN: Observational study. SETTING: Inpatient clinic. POPULATION: Sixty-nine patients with acute VCFs being treated conservatively at Nagasaki Memorial Hospital. METHODS: Physical activity was evaluated as the activity time corresponding to 1.8-8.3 metabolic equivalent activities measured by a motion-sensor during the first week after admission; it was defined as EPAT. The verbal rating scale (VRS) (0-4) at rest and during standing and walking and motor functional independence measure (mFIM) were assessed at weeks 0 (baseline), 2, and 4. Loss of vertebral height was measured in week 4. Mini-mental state examinations, trail making test part-A (TMT-A), and geriatric depression scale-15 were administered at baseline. Patients were divided into active (N.=35) and sedentary (N.=34) groups according to their median EPAT value during the first week. RESULTS: The completion times for TMT-A and mFIM scores at baseline as well as the relative functional gains of mFIM from baseline to week 2 or 4 were significantly associated with EPAT. VRS at rest and during standing and walking were not significantly different between the groups at week 2 and 4. Loss of vertebral height was not significantly different between the groups. CONCLUSIONS: EPAT in patients with acute VCF is associated with the recovery of the ability to perform ADLs. However, EPAT is associated with neither pain reduction nor progression of fractured vertebral body collapse. CLINICAL REHABILITATION IMPACT: This observational study indicates that physical activity in the early acute phase of VCF is associated with better recovery from acute VCF and would be an important factor for short-term recovery.

Thoracic intradural extramedullary lesions causing progressive myelopathy as an initial manifestation of granulomatosis with polyangiitis: a case report and review of literature.

CONTEXT: To our knowledge, only a few reports regarding the spinal involvement of granulomatosis with polyangiitis (GPA)-also termed as Wegener's granulomatosis-have been published. However, all these cases reportedly exhibited epidural tumor-like lesions or dural thickening. FINDINGS: We report the case of a 57-year-old woman with progressive myelopathy caused by multiple spinal lesions with GPA, which appeared to be protruding inwards, within the dura mater, on magnetic resonance imaging (MRI); these lesions were difficult to distinguish from intradural tumors. Moreover, these lesions exhibited low intensity on both T1- and T2-weighted MRI, and showed prominent enhancement on gadolinium-contrast imaging. Resection biopsy was effective for both diagnosis and the recovery of the neurological deficit. CONCLUSION: Based on these findings, we suggest that GPA lesions can exhibit variable patterns in the spine. Nevertheless, clinicians should consider the possibility of GPA in such cases, particularly when multiple, inwardly protruding tumor-like lesions are detected within the dura mater on MRI.

Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report.

A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogren's syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.

Tracheobronchitis with dyspnea in a patient with ulcerative colitis.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patient's respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

A new T-cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity.

Loss of tolerance for autoantigens is a common feature in autoimmune diseases. Bystander T-cell activation is the activation of T cells to produce functional changes through TCR-independent stimulation. Although bystander activation may be related to tolerance loss to multiple autoantigens, the activation mechanism of T cells directed to an autoantigen with limited amount is not clear. We investigated an activation mode of T cells (designated as "associator T cells") directed to a suboptimal dose of cognate antigen X in the presence of fully activated T cells (designated as "responder T cells") directed to an optimal dose of antigen Y. In in vitro coculture, the activation of associator T cells was dependent on the presentation of antigen X, and soluble factors from activated responder T cells were not sufficient. Therefore, we conclude this activation mode is different from bystander activation and named it "extended antigen priming (EAP)". T cells with EAP showed a different phenotype compared to conventionally primed cells, suggesting the unique nature of EAP. Intriguingly, EAP was dependent on the CD40-CD40L signaling pathway. Thus, the EAP model is a T-cell activation mode for suboptimal dose of antigen and presumably related to the immune response to autoantigens in autoimmune status.

Autoantigen BiP-Derived HLA-DR4 Epitopes Differentially Recognized by Effector and Regulatory T Cells in Rheumatoid Arthritis.

OBJECTIVE: The balance between effector and regulatory CD4+ T cells plays a key role in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine whether the RA autoantigen BiP has epitopes for both effector and regulatory immunities. METHODS: The proliferation and cytokine secretion of peripheral blood mononuclear cells (PBMCs) from HLA-DR4-positive RA patients in response to BiP-derived peptides were examined by (3)H-thymidine uptake and enzyme-linked immunosorbent assay. As a mouse therapeutic model, a BiP-derived peptide was administered orally to mice with collagen-induced arthritis (CIA). RESULTS: Among the peptides examined, BiP(336-355) induced the strongest proliferation of PBMCs from RA patients, but not from healthy donors. The proliferation of PBMCs in response to BiP(336-355) showed a correlation with clinical RA activity and serum anti-BiP/citrullinated BiP antibodies. In contrast, BiP(456-475) induced interleukin-10 (IL-10) secretion from CD25-positive PBMCs obtained from RA patients and healthy donors without inducing cell proliferation, and it actively suppressed the BiP(336-355)-induced proliferation and proinflammatory cytokine secretion by PBMCs. Oral administration of BiP(456-475) to mice with CIA reduced the severity of arthritis and T cell proliferation and increased the secretion of IL-10 from T cells as well as the number of CD4+CD25+FoxP3+ regulatory T cells. CONCLUSION: Effector and regulatory T cells recognized different BiP epitopes. The deviated balance toward BiP-specific effector T cells in RA may be associated with disease activity; therefore, BiP-specific effector or regulatory T cells could be a target of new RA therapies.

Characteristics of granulomatosis with polyangiitis patients in Japan.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a disease with significant ethnic differences. Reports on characteristics of Japanese granulomatosis with polyangiitis (GPA) patients are limited, and this study was undertaken to determine the characteristics of Japanese GPA patients. METHODS: This was a retrospective chart study of 24 Japanese GPA patients. GPA was defined according to the European Medicines Agency algorithm. RESULTS: The percentage of MPO-ANCA-positive patients was 33.3%, higher than the percentages reported in studies from Western countries. MPO-ANCA-positive GPA patients differed from PR3-ANCA-positive GPA patients in organs involved at diagnosis with MPO-ANCA-positive patients having nose and sinus involvement less frequently compared to PR3-ANCA-positive patients. Interstitial lung infiltrates were more common among MPO-ANCA-positive GPA patients compared to PR3-ANCA-positive GPA patients. CONCLUSION: Among Japanese GPA patients, the proportion of MPO-ANCA-positive patients is higher compared to reports from Western countries, and those patients are often different from the classical picture of GPA.

Transcription factor early growth response 3 is associated with the TGF-ß1 expression and the regulatory activity of CD4-positive T cells in vivo.

TGF-ß1 is an important anti-inflammatory cytokine, and several regulatory T cell (Treg) subsets including CD4(+)CD25(+)Foxp3(+) Tregs and Th3 cells have been reported to exert regulatory activity via the production of TGF-ß1. However, it has not yet been elucidated which transcription factor is involved in TGF-ß1 transcription. Early growth response 3 (Egr-3) is a zinc-finger transcription factor that creates and maintains T cell anergy. In this study, we found that Egr-3 induces the expression of TGF-ß1 in both murine and human CD4(+) T cells. Egr-3 overexpression in murine CD4(+) T cells induced the production of TGF-ß1 and enhanced the phosphorylation of STAT3, which is associated with TGF-ß1 transcription. Moreover, Egr-3 conferred Ag-specific regulatory activity on murine CD4(+) T cells. In collagen-induced arthritis and delayed-type hypersensitivity model mice, Egr-3-transduced CD4(+) T cells exhibited significant regulatory activity in vivo. In particular, the suppression of delayed-type hypersensitivity depended on TGF-ß1. In human tonsils, we found that CD4(+)CD25(-)CD45RO(-)lymphocyte activation gene 3 (LAG3)(-) T cells express membrane-bound TGF-ß1 in an EGR3-dependent manner. Gene-expression analysis revealed that CD4(+)CD25(-)CD45RO(-)LAG3(-) T cells are quite different from conventional CD4(+)CD25(+)Foxp3(+) Tregs. Intriguingly, the CD4(+)CD25(-)CD45RO(-)LAG3(-) T cells suppressed graft-versus-host disease in immunodeficient mice transplanted with human PBMCs. Our results suggest that Egr-3 is a transcription factor associated with TGF-ß1 expression and in vivo regulatory activity in both mice and humans.

Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis.

A 69-year-old man with sensorineural hearing loss and iritis was diagnosed with atypical Cogan's syndrome. He had several systematic manifestations: aortitis, meningitis, panniculitis and seronegative arthritis. Remission induced by treatment with high doses of prednisolone was followed by relapse within 1 year. Although his condition was resistant to various immunosuppressive drugs, including methotrexate, cyclosporine, azathioprine and adalimumab, his symptoms, inflammatory response and quality of life measures were successfully improved by tocilizumab, a humanized anti-interleukin-6 receptor antibody.

Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro-inflammatory role of citrullinated BiP in collagen-induced arthritis.

INTRODUCTION: Anti-citrullinated protein/peptide antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA) patients and are thought to have a close relationship with the pathogenesis of arthritis. Several proteins, including fibrinogen, vimentin, and alpha-enolase, were reported as ACPA-target antigens, and their importance in RA pathogenesis was widely proposed. We identified citrullinated immunoglobulin binding protein (citBiP) as another ACPA target in RA patients and examined its pro-inflammatory role in arthritis. METHODS: We measured the levels of anti-citBiP, anti-BiP, and anti-cyclic citrullinated peptide (CCP) antibodies in the serum of RA patients (n = 100), systemic lupus erythematosus (SLE) patients (n = 60), and healthy controls (n = 30) using ELISA and immunoblotting. Epitope mapping was performed using 27 citBiP-derived peptides. In the mouse study, after DBA/1J mice were immunized with BiP or citBiP, serum titers of ACPAs were measured by ELISA and immunohistochemistry. The development of collagen-induced arthritis (CIA) was observed in BiP- or citBiP-pre-immunized mice. RESULTS: The serum levels of anti-BiP and anti-citBiP antibodies were significantly increased in RA patients, although only anti-BiP antibodies were slightly increased in SLE patients. Interestingly, anti-citBiP antibody levels were higher than anti-BiP antibody levels in 72% of RA patients, whereas no significant increase in anti-citBiP antibody levels was detected in SLE patients and healthy controls. The serum levels of anti-CCP antibodies were correlated with those of anti-citBiP antibodies in RA patients (R2 = 0.41). Several citrulline residues of citBiP were determined to be major epitopes of anti-citBiP antibodies, one of which showed cross-reactivity with CCP. Immunization of DBA/1J mice with citBiP induced several kinds of ACPAs, including anti-CCP and anti-citrullinated fibrinogen antibodies. Pre-immunization with citBiP exacerbated CIA, and anti-CCP antibody levels were increased in citBiP-pre-immunized CIA mice. CONCLUSIONS: CitBiP is a newly described ACPA target that may play a pro-inflammatory role in arthritis.

CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2.

Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4(+)CD25(-)Foxp3(-) T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although approximately 2% of the CD4(+)CD25(-) T cell population consisted of CD4(+)CD25(-)LAG3(+) T cells in the spleen, CD4(+)CD25(-)LAG3(+) T cells are enriched to approximately 8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4(+)CD25(-)LAG3(+) Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4(+) T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4(+) T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3(+) natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4(+)CD25(-)LAG3(+) Tregs. In contrast, the number of CD4(+)CD25(-)LAG3(+) Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2(+)LAG3(+)CD4(+) Tregs can be exploited for the control of peripheral immunity.

The relationship between past traumatic experience and sickness absence.

BACKGROUND: Past traumatic experiences have been reported to lower stress tolerance, thereby increasing job strain. However, the relationship between past traumatic experiences and employee sickness absence is poorly understood. AIMS: This study explores the relationship between sickness absence and past traumatic experience with regard to the amount of time lapsed after the experience, job strain and other mental health states such as depression and anxiety. METHODS: A total of 3238 workers were assessed for levels of traumatic stress, depressive status, anxiety and job stress. RESULTS: Odds ratios of the presence of traumatic experiences to sickness absence, adjusted for sex, age and depressive and anxiety states, were presented according to the length of time that had passed since the traumatic events. The odds ratio in the 0-1 Years Group was 1.75 (p < 0.05), and the odds ratio for the 19+ Years Group was 1.46 (p < 0.1). CONCLUSIONS: Past traumatic events are related to sickness absence. Sickness absence resulting from a past traumatic experience is important with respect to industrial health.

Hepatocyte growth factor significantly suppresses collagen-induced arthritis in mice.

Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.