Methotrexate (MTX) is the anchor drug in the treatment for patients with rheumatoid arthritis (RA). The approved weekly dose and frequencies of some adverse reactions, however, are different between in Japan and American/European countries. The use of high doses of MTX (9-16 mg/week) was approved in 2011, and then the Japan College of Rheumatology published the clinical practice guideline of MTX for patients with rheumatoid arthritis. In the version updated in 2016, revisions included statements regarding new clinical evidences of high dose MTX use including rapid dose escalation, screening for the prevention of tuberculosis and hepatitis B virus reactivation, and MTX-associated lymphoproliferative disorders. Whereas RA treatment strategy is changing, MTX treatment is also critical and always updated. Japanese rheumatologists should be well informed about the current knowledge and endeavor to develop new evidence of MTX use in Japanese patients.

　This paper describes how to make an appropriate manuscript in English. Initially, the authors have to carefully read and properly understand the “instructions for authors,” especially the aims and scope in the targeted journal. Submitted manuscripts are subject to peer review by at least two referees and the editors, and to editorial revision of the language and contents. The quality of journals and manuscripts highly depends on the peer review processes. The editorial board is responsible for the acceptance, revision and rejection of the manuscripts. If authors are requested to make revisions, they can resubmit the manuscript after satisfactory revisions have been made. To ensure the review is conducted appropriately, it is strongly recommended that the manuscript is checked by scientists who are native English speakers before submission.

　Sjogren’s syndrome is a systemic autoimmune disease with elevated autoantibody titer, centered on exocrine glanditis in the lacrimal and salivary glands. At diagnosis, adult cases often show dry symptom of exorine glands. On the other hand, frequency of dryness of exorine glands in childhood with Sjogren’s syndrome is low. This is considered to be due to the short term of exocrine glanditis present in children compared with adults. Children with poor dryness often visit medical institutions with symptoms such as fever, repetitive parotitis, arthragia/arthritis, rash, general fatigue. It is estimated that many cases are not diagnosed with Sjogren’s syndrome, because typical dry symptoms are less frequent. For diagnosis, it is necessary for serologic evaluation and evaluation of exocrine glands. Secretion of tears and/or saliva is not likely to decrease, and labial small salivary gland biopsy (lip biopsy) is important for diagnosis. It seems necessary to conduct a long-term observation, such as whether we can prevent dryness by initiating immunosuppressive therapy before function decline of exocrine glands. Regarding treatment of extra-glandular symptoms, treat each case and organ dysfunction according to its degree. Steroids and/or Immunosuppressive agents may require aggressive treatment in some cases. Compare the comparative examples. Outlines the characteristics and treatment of childhood SS.

　SLE commonly affects women of childbearing age, but late-onset SLE is not uncommon. Disease onset after the age of 50 is defined as late-onset SLE and it is reported that 30% of all cases of SLE fall into this category. In late-onset SLE, the ratio between men to women is about 1: 2.5. Clinically, the occurrence of serositis and neuropathy are more frequent and dermatological features, such as malar rash and photosensitivity, are less common in late-onset SLE than younger onset. Because of lack of typical lupus symptoms and myriad differential diagnoses, including drug-induced lupus due to polypharmacy in elderly patients, correct diagnosis of late-onset SLE is often difficult and late. As for the treatment, there are several guidelines for lupus nephritis published abroad that recommend the use of steroid and immunosupppressive drugs in combination. However, because elderly patients have lower renal and immune functions, adjustment of medication is needed in order to avoid the adverse effects.

　Rheumatoid arthritis（RA）is autoimmune in nature and characterized by chronic inflammation of the synovial tissue in multiple joints, which leads to joint destruction, although the pathogenesis has not been elucidated completely. Arthritis models are extensively used in investigating the etiological and pathological features of RA, and studies using genetically modified models have been conducted to identify and validate potential targets for treatment. In particular, arthritis models have significantly contributed to the introduction of biologics that inhibit inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Although various animal models, with models of collagen-induced arthritis, are widely used in the development of novel drugs for the treatment of RA, the efficacy of drugs in arthritis models does not necessarily match the therapeutic effect in patients with RA. Whether or not the clinical drug efficacy can be predicted is significantly dependent on the choice of a model system and study protocol. Nevertheless, animal models are indispensable in elucidating the pathological mechanism of RA and in advancing the development of novel therapies. In this review, we will introduce arthritis models that are widely used at present as well as new animal models that have recently begun to be used to discover more innovative drugs for the treatment of RA.

[Objectives] To assess the effectiveness and safety of tocilizumab (TCZ) in patients with elderly rheumatoid arthritis who are aged 70 or over.
[Methods] Sixty-seven RA patients initiated TCZ in our institution from April 2008 to April 2015, and 58 of them continued TCZ for more than three months. We divided them into 2 groups; group A is under 70 years old (n=41), group B is 70 years old or higher (n=26). DAS28-ESR and CDAI were assessed at 0, 1, 2, 3, 6 and 12 months. We investigated about adverse events (AEs) during the 12 months.
[Results] DAS28-ESR / CDAI after initiation of TCZ decreased as follows; A:5.07±1.31→2.86± 1.31(p<0.001)/18.58±11.25→8.57±6.34(p<0.001), B:5.55±1.08→2.47±1.07(p<0.001)/21.71±8.11→7.50±6.33 (p<0.001). There were no significant changes between groups on remission rate at 12 months. The incidence rates of AEs and serious AEs were A:73%/10%, B:93%/7% and there were no fatalities caused by AEs. Persistence rate at 12months was A:70.7%, B:88.5%.
[Conclusion] These data indicate that TCZ therapy is safe and effective even for elderly RA patients.

　We describe a female diagnosed with MCTD at the age of 44 with Raynaud’s phenomenon, finger swelling, positive of anti-RNP antibody (but not anti-Sm or anti-DNA antibody), polyserositis, leukopenia and pulmonary fibrosis. She had a history of cutaneous vasculitis in the legs at the age of 50. She developed pulmonary hypertension at the age of 60 and the severity gradually worsened despite steroid therapy. However, pulmonary hypertension became comparatively stable after initiation of the endothelin receptor antagonist, bosentan. She developed general fatigue without fever, skin ulcer or other remarkable symptoms. On admission, slightly elevated anti-dsDNA antibody level, mild hypocomplementemia and image findings suspected of infection were observed. Diarrhea and cerebral hemorrhage successively occurred and lethal heart failure subsequently developed. Postmortem examination revealed widespread vasculitis involving the lungs, pancreas, digestive tracts, brain, uterus, ovaries, skeletal muscles and gall bladder (but not kidney). Careful follow-up of serum markers for SLE may be useful in selected MCTD cases for early detection of vasculitis because a marked predisposition to SLE might have been a contributory factor for onset of vasculitis in this case. In terms of the pathophysiology, prolonged morbidity of pulmonary hypertension might also have contributed to the onset of vasculitis. In the current situation where long-term survival is increasing in patients with MCTD complicated with pulmonary hypertension, careful observation is required when treating MCTD patients, especially those with a marked predisposition to SLE.

　Here, we report a case of transient hyperphosphatasemia (TH) in a 32-year-old man with Behçet’s disease receiving low-dose corticosteroid and infliximab therapy for six years. In November 2016, routine laboratory data revealed an extremely high serum alkaline phosphatase (ALP) level of 1212 U/L (normal 115 - 359 U/L). There were no evidences of hepatobiliary and bone diseases on various laboratory and imaging findings. ALP iso-enzyme analysis showed the appearance of two bands on both sides of the normal liver ALP (ALP type 2), and the abnormal band at the fast 𝛼2 position were identified. Finally, a diagnosis of TH was established according to these characteristic patterns of ALP isoenzyme analysis. His serum ALP level rose to a maximum of 2783 U/L, which is an approximately eight-fold increase relative to the upper normal limit, and returned spontaneously to the normal range nine weeks later. This clinical course also indicated TH. TH is characterized by the isolated elevation of serum ALP. When a patient with connective tissue disease develops these abnormality, we are liable to suspect first the exacerbation of the underlying disease or adverse effects of therapeutic agents as a cause. ALP iso-enzyme analysis is useful for a differential diagnosis of hyperphosphatasemia. This report emphasizes that the recognition of TH is crucial to avoid unnecessary investigation and change of treatment plan.