Idiopathic inflammatory myopathy（IIM）refers to heterogenous disorders that manifest mainly muscle weakness and myalgia due to inflammation of muscles. IIM is classified into largely three diseases; polymyositis（PM）, dermatomyositis（DM）and inclusion body myositis（IBM）. Previous studies revealed that autoantibodies directed against nuclear or cellular components are detected in patients with IIM. Most of these autoantibodies are found exclusively in patients with this condition and are called myositis-specific antibodies（MSAs）. Antibodies against aminoacyl tRNA synthetases（ARS）such as anti-Jo-1 antibody, signal recognition particle（SRP）or Mi-2 have been found at an early stage and are well-established PM/DM specific antibodies. Since 2000, additional autoantibodies specific for IIM have been discovered and reported by several investigators. These novel MSAs, with few exceptions, have proven useful for precise diagnosis, treatment selection, prognosis prediction, and classification of IIM patients into clinical entity. Especially, anti-TIF1-γ antibody and anti-MDA5 antibody are clinically important because the former is assosiated with cancer-associated myositis and the latter is detected in DM with rapidly progressive interstitial lung disease. This article reviews autoantibodies detected in patients with IIM as well as the association between these MSAs and clinical characteristics and immunological findings to classify IIM patients into distinct clinical subsets.

[Objective] Catastrophic thinking, which is believed to inflict patients with rheumatoid arthritis（RA）even if they are taking biological DMARDs（b-DMARDs）, is a factor leading to pessimism, passive behavior, and depression among patients. It is also assumed to affect the therapeutic effect of treatments. This study examined and compared the pain symptoms, functional impairment, and psychophysiological problems of RA patients taking biologic drugs, as well as the relationships among these factors.

[Patients] The subjects were 14 female patients with RA（59.71±4.61 years）.

[Methods] Items evaluated: Disease activity was measured using simplified disease activity index（SDAI）, pain intensity using as visual analogue scale（VAS）, and functional impairment using the pain disability assessement scale（PDAS）, health assessment questionnaire（HAQ）, and Locomo25. Psychophysiological state was evaluated using as pain catastrophizing scale（PCS）, hospital anxiety and depression scale（HADS）, tamper scale for kinesiophobia（TSK）, pain self-efficacy questionnaire（PSEQ）, and general self-efficacy scale（GSES）. As another evaluation, EuroQol 5 dimensions（EQ - 5D）was used.

[Results] Even among those who were taking b-DMARDs, some patients suffered from catastrophizing, feelings of powerlessness, anxiety, and kinesiophobia. Self-efficacy in confronting helplessness and pain was more strongly related with functional impairment than disease activity or pain intensity.

[Conclusion] When evaluating RA patients at home, it is important to adequately consider not only the disease activity and pain with functional impairment but also factor in the effects on psychosocial pain such as catastrophizing.

Conflict of interests: None.

  We developed a scale to assess core competencies of rheumatoid arthritis（RA）nurses, and verified its reliability and validity.

  We involved 22 RA nurses registered with the Certified Nurse by Japan Rheumatism Foundation（CNJRF）and discussed assessment items for expertise and practical capabilities. We then sent questionnaires to them by mail to check the 33 items identified for the original draft scale. From 1651 nurses listed on the Japan Rheumatism Foundation web site, we selected 600 nurses by stratified random sampling and mass-mailed them the questionnaire for the draft scale. Out of 227 who gave valid responses, 60 were resurveyed three weeks later for test-retest reliability and 47 responded. Exploratory factor analysis was conducted on 23 items to examine 5 factors, “knowledge and skills specialized in rheumatology（Cronbach's coefficient alpha=0.863）”, “listening attitude（α=0.919）”, “coordination for smooth rheumatology care provision（α=0.836）”, “practical techniques to support self-care（α=0.727）”, and “support for patients under treatment（α=0.900）”. Suitability was verified by confirmatory factor analysis, comparative fit index（CFI）＝0.926, standardized root mean square residual（SRMR）＝0.06, RMR＝0.049, root mean square error of approximation（RMSEA）＝0.06.

  The results demonstrate the scale has reliability（internal consistency and stability）, construct validity（validation by exploratory factor and confirmatory factor analyses）, and criterion-related validity（concurrent validity）, which indicates the scale’s merit and effectiveness.

  A man in his sixties with systemic lupus erythematosus（SLE）developed diffuse alveolar hemorrhage（DAH）during low-dose oral prednisolone maintenance therapy. Although typical manifestations of DAH, such as severe hypoxemia and hemoptysis, were not apparent on admission, the patient developed respiratory failure after 3 days of admission; a bronchoalveolar fluid analysis confirmed the diagnosis of DAH. The study results indicate that physicians should be cautious about the possibility of DAH occurring in SLE patients who develop new respiratory symptoms, and consider further examination, including bronchoscopy.

  Infliximab, an anti-TNF-α chimeric monoclonal antibody, has been marketed since July 2003 in Japan. Infliximab is given by intravenous infusions in a dosage of 3mg/kg（initially at weeks 0, 2 and 6; subsequently in intervals of 4-8 weeks）. Such a loading of infliximab brings about quick resolution of synovitis. The long persistence in this compartment（elimination half-life 7-12 days）enable to relative longer treatment intervals as every two months. RISING study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10mg/kg infliximab with those of 3mg/kg infliximab treatment in methotrexate-refractory RA patients. After the patients received 3mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10mg/kg infliximab every 8 weeks from week 14 to 46. Then, treatment with 10mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3mg/kg at week 10. The magnitudes of efficacies were correlated with the trough serum infliximab level. It can be assumed that trough concentrations above 1μg/mL could be used as a kind of therapeutic target. Now semi-quantitative measurement of serum infliximab is available and very helpful for the dose escalation. After attaining low disease activity（LDA）by infliximab, 56（55%）of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

  Humanized IL-6 receptor antibody, Tocilizumab（TCZ）is an inhibitor of IL-6, which plays an important role in the pathogenesis of rheumatoid arthritis（RA）. TCZ improves RA symptoms including joint destruction in MTX naïve, inadequate response（IR）to DMARDs, MTX and TNF inhibitors. The efficacy is comparable to other biologics. Especially, TCZ has a significant advantage in a monotherapy setting. However, the efficacy of TCZ to Ankylosing Spondylitis and Psoriatic Arthritis is unfavorable. Since TCZ hides CRP, CRP is useless for evaluation of disease activity or infection during TCZ therapy. Generation of neutralization antibody is rare and long-term retention of TCZ is favorable. However, trial of TCZ-free remission is an unfavorable outcome. So, beyond remission, tapering or extension of the interval of TCZ is a better choice than cessation. The most notable safety problem is infection. In particular, hidden or weakening symptoms of infection during TCZ therapy cause delayed treatment and critical illness. Finally, chooseable administration routes and economical advantages（in Japan）also make TCZ is an attractive alternative biologic to RA.

  With the introduction of conventional disease-modifying anti rheumatic drugs（csDMARDs）, especially methotrexate（MTX）and biological DMARDs（bDMARDs）, the disease activity of rheumatoid arthritis can be dramatically improved. However, the medical cost of bDMARDs is a big problem for both patients and the national medical system. A few studies have examined the effect of the discontinuation of anti-TNF antibodies, such as the BeST, RRR, and BuSHIDO studies for infliximab; the HONOR, HIT HARD, OPTIMA, and HOPEFUL-2, 3 studies for adalimumab（ADA）; and the CERTAIN and C-OPERA studies for certolizumab-pegol（CZP）. The PRESERVE and ENCOURAGE studies explored the effects of the tapering and discontinuation of the soluble TNF receptor, etanercept（ETN）. In order to achieve a so-called “Bio-free condition”, the early introduction of bDMARDs is desirable. We used ADA within 3 months of MTX introduction in 39 patients and obtained good results even though there was 1 anti-TNF non-responder who was rescued by tocilizumab. A Bio-free condition can still be achieved with the early introduction of bDMARDs, even those without cytotoxicity, such as ETN and CZP.

  Japan has become a super-aged society since 2007, and accordingly, patients with systemic rheumatic diseases such as rheumatoid arthritis are also increasing in age. Although immunosenescence was observed in elderly patients, the production of various inflammatory cytokines is rather upregulated; which results in a therapeutic dilemma. In addition, epithelial barrier dysfunction is a critical issue in elderly patients among the host-defense mechanisms.

  Infectious diseases and immune diseases are mutually related in a complex manner, and they often fall into a vicious cycle. Although it is common for immunosuppressive drugs to be discontinued during the time of infectious diseases, the treatment of infectious disease should be as short-term as possible taking account the risk for developing immune reactivation and subsequent serious complications.

Objective: The renal prognosis of active proliferative lupus nephritis（LN）（ISN/RPS Class III or IV）has been improved by introducing intravenous cyclophosphamide pulse therapy（IVCY）or mycophenolate mofetil（MMF）. However, there are still a certain number of refractory patients who progressed to end stage renal disease. We examined risk factors for poor renal prognosis and the current status of novel treatment strategies.

Results: Risk factors for poor renal prognosis have been reported from several institutions in Japan using their registries. We identified higher level of serum creatinine at renal biopsy, combination of proliferative lesions and membrane lesions（mixed type）, and combination of acute lesions and chronic lesions（A/C）, as independent risk factors for poor renal prognosis. In order to improve renal prognosis, it is important to induce remission using potent initial therapy. Various clinical trials of biologics, using MMF or IVCY as a standard therapy, have been conducted. However, no biologics have surpassed the standard therapy to date. On the other hand, an increasing number of reports demonstrated the efficacy of combination therapy with MMF and calcineurin inhibitors, named multi-target therapy. We also have used this regimen for severe LN and showed high remission rate and persistent remission.

Conclusion: Although the multi-target therapy seems to be effective, it is necessary to examine its long-term efficacy and safety. In addition, clinical trials of biologics targeted to B cells for active LN are still being conducted. We hope new treatment options will become available in the near future.

  Of the various neuropsychiatric manifestations in systemic lupus erythematosus（NPSLE）, acute confusional state（ACS）in diffuse psychiatric/neuropsychological syndromes（diffuse NPSLE）is the most serious. Recent studies have demonstrated that the elevation of neuron-reactive autoantibodies in cerebrospinal fluid（CSF）, especially anti-NMDA receptor NR2（anti-NR2）and anti-Sm antibodies, is associated with diffuse NP-SLE, most notably with ACS.

  Overall, there are 2 mechanisms for the elevation of CSF IgG, including transudation through the damaged blood-brain barrier and intrathecal synthesis. We have recently revealed that CSF anti-NR2 and anti-Sm levels and Q albumin were significantly higher in an acute confusional state（ACS）than in non-ACS diffuse NPSLE（anxiety disorder, cognitive dysfunction, mood disorder and psychosis）or focal NPSLE. However, there was no significant difference in CSF anti-NR2 or anti-Sm index and serum anti-NR2 and anti-Sm levels among the 3 groups. Both CSF anti-NR2 and anti-Sm levels were significantly correlated with Q albumin. These results demonstrate that the severity of blood-brain barrier damage plays a crucial role in the development of ACS, the most recalcitrant form of diffuse NPSLE.

  On the other hand, CSF IL-6 was elevated more markedly in diffuse NPSLE than in focal NPSLE. Moreover, CSF IL-6 was much higher in ACS than in non-ACS diffuse NPSLE. Therefore, it is suggested that CSF IL-6 as well as CSF anti-NR2 might be surrogate markers for severity of diffuse NPSLE.

OBJECTIVE: The chief cause of skin ulcers occurring in systemic scleroderma is ischemia, which is a refractory condition that occurs frequently. Treatment for such ulcers currently comprises vasodilators, anticoagulants, and antiplatelet agents. However, satisfactory results have not been obtained in many cases. This condition often severely affects the patient’s social life and the existing treatment is very expensive. Therefore, a new treatment method is urgently needed.

  When any novel therapy is introduced, its usefulness needs to be proved through a verification study. We are trying to establish low-energy shock wave therapy as a novel treatment for this condition.

METHOD: To conduct the verification study, it is necessary to gather basic information to determine the study design. Therefore, observational research to examine the natural history of cutaneous ulcers at the time of conventional treatment and clinical trial as a proof of concept（POC）study to search for efficacy/safety when performing low-energy shock wave therapy.

RESULTS : A new verification study was designed based on the results obtained from two clinical studies, observational studies of natural history when conventional treatment was performed, and a POC study using low-energy shock wave therapy.

  In fact, doctor-initiated clinical trials were implemented based on this and the analysis of the results is currently underway.

  Hemophagocytic syndrome（HPS）is a severe and life-threatening disease. Characteristic manifestations of HPS include fever, hepatosplenomegaly, pancytopenia, coagulopathy, and liver dysfunction. HPS is classified according to the underlying etiology into either primary（genetic）or secondary（reactive）HPS. Autoimmune-associated hemophagocytic syndrome（AAHS）is a secondary HPS, which is associated with underling autoimmune disease.

  There are currently no validated diagnostic criteria for AAHS, but several criteria have been proposed to date. These criteria pose particular problems for the diagnosis of AAHS, because some clinical and laboratory criteria, such as fever, may be presented in the underlying autoimmune disease itself. It is therefore necessary to establish validated diagnostic criteria.

  Corticosteroids were most commonly used for patients with AAHS, and 58% of patients were responded. Patients refractory to initial corticosteroids were usually treated by cyclosporine, intravenous cyclophosphamide（IVCY）or intravenous immunoglobulin G（IVIG）, and among these therapies IVCY was highly effective. Treatment with biologic agents resulted in favorable effects in the majority of patients. The development of a new approach using biologic agents, as well as small molecule inhibitors of intracellular signal transduction pathways, in the treatment of AAHS, seems to be challenging.