Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the drugs most frequently used for osteoarthritis and rheumatoid arthritis (RA). It has become a major problem that NSAIDs damage the mucosa of the upper gastrointestinal tract and eventually cause gastric and duodenal ulcer. Moreover, recent studies using video capsule endoscopy and balloon-assisted enteroscopy have clarified that NSAIDs frequently damage the mucosa of small intestine. Although selective COX-2 inhibitors prevent NSAID-induced small intestinal damage in short-term use, it has been shown that the preventive effect is eliminated in long-term use. The use of disease-modifying anti-rheumatic drugs with NSAIDs is considered to aggravate the small intestinal damage. On the other hand, it has been proven that RA patients who receive anti-TNF-α therapy have less severe NSAID-induced small intestinal damage than those who does not receive the therapy. It is clinically significant that proton pump inhibitors (PPIs) cannot protect the small intestine from NSAIDs as hydrochloric acid is not produced in the small intestine. Moreover, some studies have raised the possibility that PPIs might exacerbate the small intestinal damage. Although mucoprotective drug and prostaglandin analogue are expected to be effective for NSAID-induced small intestinal damage at the present, we consider that anti-TNF-α therapy, probiotics, and colchicine could be new candidates for therapeutic agents for the damage. Thus, therapeutic strategies for NSAID-induced gastrointestinal damage need to be established based on these new findings.

    There have been significant advances in the treatment of rheumatoid arthritis with methotrexate or biological disease-modifying antirheumatic drugs (bDMARDs). However, the number of rheumatologists is insufficient in Japan. Our rheumatic center is located in Niigata prefecture, which has heavy snow in winter. Many patients visit our rheumatic center from Yamagata prefecture or Fukushima prefecture as well as Niigata prefecture including Sado island. Since they cannot visit our rheumatic center in the event of an emergency in winter, we refer those patients to local general hospitals when we start bDMARDs. Patients who cannot use self-injectable subcutaneous bDMARDs by themselves, and patients with osteoporosis treated by weekly or monthly injectable drugs are also referred to local general practitioners (GPs) and receive injections there. We receive patients with fractures or with cerebrovascular diseases from Niigata Prefectural Shibata Hospital (a general hospital) and, provide rehabilitation at the convalescence rehabilitation ward. We have established a system for the referral of patients with proximal hip fractures to GPs for the prescription of bisphosphonate (BP). Since January 2015, we started to prescribe BP when discharging patients from our center and asked GPs to continue it. Since the osteoporosis outpatient ward was established in Shibata Hospital in April 2015, continuous checks have been performed for the progression of hip fractures and the adherence of BP is confirmed once a year.

    A 49-year-old woman presented to our hospital with 1-month history of acute onset pain of bilateral knees, hips and side of the chest. She was hospitalized in community hospital to investigate the cause of the pain and diagnosed with rheumatoid arthritis (RA) due to strongly positive anti-CCP antibody and findings of MRI. She was transferred to our hospital to receive treatment of RA.
    On admission, she presented arthritis of the bilateral wrist, elbow and shoulder joints. She also had pain in the knees and side chest without arthritis. Laboratory examination revealed high level of D-dimer so we suspected deep vein thrombosis and pulmonary infarction, which were confirmed by ultrasound sonography and chest CT. After edoxaban 30mg was started, the pain in the knee and side of the chest was immediately improved and emboli didn’t recur. Laboratory examination revealed that enzyme activity and antigen level of protein C (PC) was reduced and mutation of PC gene was confirmed by PCR afterward. Arthritis was gradually improved by methotrexate and low dose prednisolone.
    It is little reported that development of RA provoked thrombosis by PC deficiency, although both diseases are not so rare. We report this case and the relation between two diseases with a review of literature.

    Inflammatory abdominal aortic aneurysm (IAAA) accounts for 2-14 % of all cases of abdominal aortic aneurysm (AAA). IAAA is a subtype of AAA pathologically characterized by aortic wall thickening, fibrotic change around aneurysm and rigid adherence of the adjacent structures. Recently, IAAA has been a subset of chronic periaortitis, along with idiopathic retroperitoneal fibrosis because of the similarity of histological features between these disease entities. We report here a 50-year-old woman who was diagnosed with IAAA during therapy for rheumatoid arthritis. She was treated with prednisolone 4mg/day, methotrexate (MTX) 8mg/week and golimumab 50mg/month for rheumatoid arthritis. She was also treated with levothyroxine for hypothyroidism induced by radioiodine therapy for Graves’ disease. In 2015, she presented with low grade fever and lower abdominal pain. Computed tomography revealed an abdominal aortic aneurysm and [18F]fluorodeoxyglucose positron emission tomography /computed tomography (FDG-PET/CT) showed the uptake of FDG in thickening wall of aorta. She was diagnosed as having IAAA and the prednisolone was increased to a dose of 30 mg daily, which proved to be effective.

    A 75 year-old man was referred to our hospital for inflammatory disease with progressive anemia, thrombocytopenia, and renal insufficiency 9 months prior to admission. Positivity for ANCA and anti-dsDNA antibody made us suspect autoimmune diseases as the etiology, but detection of vegetation by echocardiogram led to diagnosis of infective endocarditis. Blood cultures were all negative, so we started treatment with gentamicin for 2 weeks and ceftriaxone for 6 weeks according to the protocol for culture-negative endocarditis. Decrease in CRP and size of vegetation were observed, but there was no complete recovery. Fortunately Bartonella henselae IgG and IgM antibody results turned out to be significant, led to an appropriate change in antibiotics, and finally complete remission of the inflammatory disease.　
    Patients with infective endocarditis may present rheumatic manifestations concurrent with autoantibodies. The incidence of infective endocarditis with negative culture was reported to be 2.5~31%, varying by country. Recognition of culture-negative infective endocarditis and its resemblance to autoimmune diseases is important since misdiagnosis may result in the initiation of immunosuppressive therapy, which could be detrimental to patients with infective endocarditis. Serological testing is one of the useful ways to determine the etiology of infective endocarditis.

    Cutaneous arteritis (CA) is a vasculitis involving small and medium-sized arteries localized at the dermal-pannicular junction; its pathogenesis is unknown. A 24-year-old woman was admitted to our hospital because of burning pain in her hands and feet and digital ischemia, Raynaud phenomenon, and livedo reticularis. Blood test results revealed elevated erythrocyte sedimentation rate and were negative for autoantibodies. Angiography of her left hand revealed a filling delay in the distal portion of the ulnar artery and palmar arch. Biopsy of plantar skin revealed leukocytoclastic vasculitis with fibrinoid necrosis at the dermal-pannicular junction. We made a diagnosis of CA. Treatment with multiple vasodilators and an antithrombotic worsened her skin lesion. Therefore, she was treated with 40 mg/day prednisolone. After initiating corticosteroid treatment, her skin lesion rapidly improved; she was discharged after 37 days. Typical clinical manifestations of CA include tender subcutaneous nodules, livedo reticularis, and cutaneous ulcerations on the lower extremities. Fever, arthralgia, myalgia, and peripheral neuropathy may also manifest. Although distal ischemia and Raynaud phenomenon are rare, CA should be considered as a differential diagnosis of these symptoms.

<Objective> To compare gene expression in IgG4-related disease (IgG4-RD) with Sjögren’s syndrome (SS) comprehensively, and to identify disease-related molecules.
<Methods> Gene expression was analyzed by DNA microarray in labial salivary gland (LSG) of IgG4-RD (n=5), SS (n=5), and healthy controls (HC) (n=3). Gene expression patterns were compared by principal component analysis (PCA), and differentially expressed genes (DEGs) between IgG4-RD and SS were identified in pairwise comparisons. Validation of the result was performed by quantitative PCR and immunofluorescence (IF) staining for highly expressed DEGs in IgG4-RD than in SS.
<Results> Gene expression patterns in IgG4-RD, SS, and HC were quite different with each other in PCA. In IgG4-RD, 1321 up-regulated and 1320 down-regulated genes compared with SS were identified as DEGs. Quantitative PCR validated significantly higher expression of chemokine (C-C motif) ligand 18 (CCL18) which has chemotactic activity on various lymphocytes and induces collagen production from fibroblasts, and lactotransferrin (LTF) which is an abundant iron-binding protein in milk and has the wide range of functions such as the maturation of dendritic cells (DCs), in LSG of IgG4-RD than in that of SS. IF staining clarified that CCL18 was specifically highly expressed in LSG of IgG4-RD, compared with those of SS and HC. Macrophages, DCs, B cells, and plasmacytes expressed CCL18 in LSG of IgG4-RD.
<Conclusion> These results clearly showed that the gene expression pattern in LSG of IgG4-RD is different from that of SS. CCL18 and LTF were identified as disease-related molecules of IgG4-RD.

“Objective” Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established.
“Patients and methods” Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6mg/kg body weight) with the dose reduced every 2 weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at 1 year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate and adverse events.
“Results” This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-related disease, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed.
“Conclusions” Glucocorticoid treatment is usually effective for patients with IgG4-related disease, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies. Strict classification criteria will be necessary for conducting clinical study.

Introduction: Only a few years have passed since the concept of IgG4 related diseases was formed. There are also many unclear points in daily clinical practice. We aim to clarify its clinical features by development of an IgG4 related disease case registration system (Sapporo Medical University and related institutes database for investigation and best treatments against IgG4-related disease: SMART) and analyzing the data obtained from it. In this article, I would like to outline the clinical features of IgG4-related dacryoadenitis and sialadenitis (IgG4-DS), the actuality of daily clinical practice, the problems and new possibilities in the treatment.
Clinical features: The sex ratio of the patients with IgG4-DS is almost same. The average age of the onset is over sixties. About 60% of the patients have other organ involvements. There are some cases that malignancies are found at the diagnosis of IgG4-DS. Although glucocorticoid can easily induce the clinical remission, almost patients require maintenance therapy. It is easy to relapse as the steroid gradually decreases. In patients presented with repeating relapse, biological agents may be useful.
Conclusion: It is important to perform systemic screening for the detection of other organ involvements and malignancies at the diagnosis of IgG4-DS. Further, it is necessary to carry out the histopathological examination to rule out malignant lymphoma. It is highly probable that immunosuppressants including biological agents are useful for the patients who need high dose of prednisolone or present with repeated relapse, but how to position them in the treatment algorithms is a future subject.