Neuropsychiatric manifestations are frequently observed in patients with systemic lupus erythematousus (SLE) and are sometimes refractory in clinical practice. Whereas the pathogenicity of neuropsychiatryic SLE (NPSLE) still remains unknown, previous reports indicate that some subsets of autoantibodies (auto Abs) and/or anti-nuclear antibodies (ANA) may be involved in the neuron damage. The majority of NPSLE studies strongly suggested that auto Abs and /or ANA in cerebrospinal fluid (CSF), but not in serum, were important. In anti-N-methyl-D-aspartate receptor 2 (NR2) Abs, which are clearly associated with diffuse NPSLE, an increased permeability of blood-brain barrier is critical for their neurotoxicity. On the other hand, CSF anti-U1 ribonucleoprotein (RNP) Abs, which are useful for NPSLE diagnosis in our study, might be independent of BBB breach and are not specific for diffuse NPSLE. As for other pathogenic auto Abs in for NPSLE, it is well known that anti-ribosomal P and anti-phospholipid Abs are closely associated with lupus psychosis/cognitive dysfunction and cerebrovascular diseases, respectively. Additionally, intrathecal inflammatory mediators (e.g., cytokines) are also important for NPSLE pathogenicity. There are some publications regarding the association between auto Abs and inflammatory mediators. Hopefully, these auto Abs will be recognized not only as a prognostic factor but also as a biomarker for treatment decisions for NPSLE patients in the near future.

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Objective: In patients with rheumatoid arthritis (RA) that maintained remission (REM) or low disease activity (LDA) at least for one year by methotrexate (MTX), the clinical course after decreasing MTX was evaluated respectively.
Methods: Twenty-six RA patients (3 males and 23 females) whose average age was 60 years and average disease duration was 9 years with REM or LDA maintained for at least one year were enrolled. Twelve RA patients (1 male and 11 females) whose average age was 60 years and average disease duration was 9 years who decreased or stopped MTX due to adverse events (AE) were evaluated for control. Rheumatoid activity (DAS28CRP) was observed for one year after MTX decreased in the REM or LDA group and the AE group.
Results: After MTX was decreased in the REM or LDA group, 11 cases (42%) were relapsed. On the other hand, in AE group (N=11cases), 7 cases (58%) were relapsed. The decreased MTX dose was significantly (p<0.05) lower in AE group compared with REM or LDA group. In REM or LDA group, the decrease in MTX was maintained in 9 cases out of 11 cases that relapsed after decreasing MTX. In 3 cases out of 7 cases with MTX decreased due to liver disorder, the same MTX dose was administered again because rheumatoid activity relapsed after increasing the folic acid dose.
Conclusion: In 26 RA patients who maintained REM or LDA at least for one year by MTX therapy, 15 cases (58%) continue REM or LDA after decreasing MTX. This study shows the possibility that decreasing the MTX dose is useful for RA patients after REM or LDA.

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    We reported the efficacy of dose escalation of infliximab (IFX) therapy in patients with rheumatoid arthritis (RA). However, the clinical course after escalation of IFX is unknown. This time, we report whether de-escalation of IFX is possible or not.
[Methods] Fifty patients (4 males and 46 females) treated with a high dose of IFX were examined. If the patients still remain in state of moderate disease activity, dose escalation of IFX is performed (3mg [8week [W]] -> 6mg [8W] -> 10mg [8W] or 6mg [4W]/kg). If the patients remain in remission, the dose de-escalation of IFX is performed (10mg [8W] or 6mg [4W] -> 6mg [8W] -> 3mg [8W]/kg). Moreover, when patients remain in remission for≧6 months at the dose of 3mg[8W]/kg of IFX and desired to discontinue IFX, IFX was discontinued.
[Results] The max dose of IFX was 6mg/kg in 12% and 10mg/kg in 88% of patients. At the time of the last observation, 20% of patients were given in dose of 10mg/kg [8W] or 6mg/kg [4W], 8% in 6mg/kg [8W] and 18% in 3mg/kg [8W] of IFX. Nine patients (18%) underwent discontinuation of IFX and 6 patients (12%) remained in remission over 1 year. Twenty-six percent of patients underwent discontinuation of IFX in mid-course, because of a number of some reasons (adverse effects; 8%, insufficiency; 16%, discontinuation of MTX; 8%, changing hospital; 2%, patient’s economical problem; 2%).
[Conclusion] The efficacy of dose escalation of IFX therapy in patients with RA is shown. Moreover, the doses of IFX could be de-escalated after escalation of IFX and cessation of IFX was successful in some cases.

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    In 2015, the Department of Orthopaedic Surgery, Kindai University Sakai Hospital conducted a survey on “Warai: smiling and laughing asking 396 outpatients who consent was obtained about 10 items. In this study, differences were studied based on gender, age, diseases (Rheumatoid arthritis: RA and chronic pain) and region (22 RA patients in Awaji island). The most common responses were as follows: 102 were joint disorder patients; 183 said they laughed the most when 20-50 years old; 181 said they laughed by opening their mouths a little; 138 recently laughed out loud within a few days: 234 laugh when something is funny; 123 laugh during conversation; 50 said that the celebrity who laughing suits the most is Sanma Akashiya; 124 said that smiling and laughing in medicine is most needed by family and society; 160 smiled if tickled by the doctor (13 referred to it as sexual harassment. No cases in RA but 5 cases in chronic pain patients); and 280 smiled when they saw questionnaire survey. RA patients expect for laughter for society and family, but this changed to nurses and/or receptionists for chronic pain patients, regardiess of gender and age. Incorporating laughter into therapy is important.

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    An 80-year-old woman presented with fever, cough and renal insufficiency in 2002. A diagnosis of microscopic polyangiitis was made based on the clinical findings of interstitial pneumonia, high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), and renal biopsy findings. She had received prednisolone (PSL) for 2 years. In 2008, she had low grade fever and general fatigue. C reactive protein levels (CRP) were elevated and abdominal computed tomography (CT) showed periaortic soft tissue mass. High-dose prednisolone was added and perivascular lesion of abdominal aorta was improved. In November 2013, she had low grade fever and general fatigue again. Laboratory studies showed increased levels of CRP and MPO-ANCA again, and intravenous cyclophosphamide was started. But periaortitis remained and positron emission tomography (PET)-CT revealed high accumulation there. She was treated with rituximab and the periaortic soft tissue disappeared. It is conceivable that ANCA associated large vessel disease is induced by vasculitis of the vasa vasorum in the aorta or main branches. Rituximab therapy would probably be effective these vasuculitis as well as usual ANCA-assosiated vasculitis. This is the first report on ANCA-associated large vessel disease treated with rituximab, and this drug could be a potentially useful treatment option.

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<Objective> To clarify the efficacy and safety of abatacept for secondary Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA).
<Patients and Methods> The primary endpoint of this open-labeled, prospective, observational multicenter study (ROSE trial) for secondary SS with RA was the remission rate of Simplified Disease Activity Index (SDAI) at 52 weeks after initiation of abatacept. The secondary endpoints included saliva volume by Saxon’s test and tear volume by Schirmer’s test. Adverse events (AEs) and adherence rate during the study period were also analyzed.
<Results> Thirty six patients (mean age was 54.9±14.0 years old, all females) were enrolled in this study. The mean SDAI decreased significantly from 20.6±11.2 at baseline to 10.0±10.5 at 52 weeks (P<0.05). Patients with SDAI remission increased from 0 (0 week) to 12 patients (33.3%) at 52 weeks. Saliva volume increased significantly from 2136±1809 (0 week) to 2397±1878 (24 weeks) mg/2min (n= 34, P<0.05). Saliva volume increased significantly from 2945±2090 (0 week) to 3419±2121 (24 weeks) mg/2min in 11 patients with Greenspan grade 1 or 2 of labial salivary glands biopsy (P<0.05), but no change was noted in 18 patients with Greenspan grade 3 or 4. Tear volume increased significantly from 4.2±4.8 (0 week) to 6.4±7.8 (24 weeks) mm/5min (n=30, P<0.05). The adherence rate to abatacept was 80.6% (29/36) over the 52-week period. Twelve AEs occurred in 10 of 36 patients, and 7 of these AEs were infections.
<Conclusion> Abatacept seems to be effective for both RA and SS related manifestations of secondary SS with RA.

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    The new therapeutic guideline just published from the Japanese government-funded study team recommends use of glucocorticoids (GC), small-molecule immune suppressants and immunoglobulins for treatment of polymyositis (PM) and dermatomyositis (DM). While some patients do not respond to these drugs, others suffer from relapses during tapering of GC. Anecdotal reports suggest benefits of biological agents that have been proven effective in treatment of rheumatoid arthritis. However, an open-label clinical trial to block tumor necrosis factor (TNF) alpha with infliximab did not improve the muscle power of the affected patients. Similarly, an open-label clinical trial to block interleukin (IL)-1 with anakinra did not improve the muscle pathology. In the United States, a clinical trial with IL-6 receptor antibody, tocilizumab will be carried out to confirm its efficacy shown in the anecdotal case. Rituximab is an antibody against CD20 on B cells and deplete B cells. Since many reports on the cases treated successfully with this agent had been accumulated, a double blind control study was carried out in the States. However, the results were negative, leaving the possibility that subsets of the patients responded. Abatacept is CTLA-4Ig that suppress CD28-mediated T cell activation. It was used in an open-label small scale clinical trial in Europe. Since the results were positive, larger double blind studies should be performed. We have to note that no biological agents were developed specifically for treatment of PM/DM. Hopefully, discerning the pathological processes involved in PM/DM will lead to development of more specific and effective agents.

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Purpose: To review adult Still’s disease (ASD), especially therapeutic strategies by biologics.
Methods: Literature about the use of biologics in ASD by the PubMed search were found.
Results: ASD is an inflammatory disorder of unknown cause, characterized by a spiking fever, joint pains and an evanescent rash. Proinflammatory cytokine and chemokines, such as IL-6, IL-18, TNF-α and CXCL10 (IP-10) are involved in the pathophysiology of ASD. Preliminary classification criteria for ASD by Yamaguchi et al. is used all over the world. There have been thirteen reports in the literature on several intractable patients at onset age 16 years or older with ASD treated with biologics including anakinra, tocilizumab, infliximab, or etanercept. These therapies were effective for most patients. Adverse events such as infection and injection-site reaction were reported. Most of studies were case series. A diverse definition of treatment-resistant cases was adopted.
Conclusions: A nation-wide registry or a prospective, double blind, randomized study would be desirable in future.

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    Before starting steroids, immunosuppressants including conventional synthetic disease modifying anti rheumatic drugs (csDMARDs) and biologic DMARDs, rheumatologists should pay attention to viral hepatitis. Especially, there were many case reports of hepatitis with anchor drug, methotrexate (MTX). Not only checking hepatitis B and C (HBs antigen and anti-HCV antibody), rheumatologists should check the past infection of hepatitis B (anti-HBs antibody and anti-HBc antibody). If the patient have a past infection of hepatitis B, HBV-DNA should be checked and monitored. If HBV-DNA exceeds more than 2.1logcopies/ml, entecavir should be started. Not only patients before the immunosuppressive therapy, but also patients under immunosuppressive therapy should be checked about the past infection of hepatitis B. Rheumatologists should consult hepatologists if patient have reactivation of HB virus.

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    Host defense mechanisms are composed of multiple security system including focal epithelial barrier, innate immunity and acquired immunity in order to prevent the invasion and growth of pathogenic microbes. Patients receiving the treatment with biological agents are at an elevated risk of opportunistic infections as well as community-acquired infections, because biological agents applied for the treatment of rheumatic diseases regulate the function and activation of immune cells. Profound understanding of clinical immunology, acknowledgement of the importance of focal factors in host defense, and proper screening, prophylaxis and monitoring of possible major infections are crucial for their management. The Japan College of Rheumatology conducted and published the postmarketing surveillance for every biological agent, and successfully boosted the Japan’s presence in the global field of rheumatology. Based upon those registry data, the Japan College of Rheumatology, as well as the American College of Rheumatology, has been published and revised the guidelines for the use of biological agents in rheumatoid arthritis, or the management of rheumatoid arthritis. The primary prophylaxis, or the treatment of latent infection, for tuberculosis and hepatitis B has been prevalent, although that for Pneumocystis pneumonia has not, because of its poor tolerability. However, salazosulfapyridine may be an alternative for primary and secondary prophylaxis for Pneumocystis pneumonia.

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