釜田 康行

OBJECTIVES: Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. METHODS: We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. RESULTS: The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. CONCLUSIONS: IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

A 53-year-old woman with a 6-year history of rheumatoid arthritis (RA) presented with pharyngeal pain, fever, and altered mental status. The patient had been treated with methotrexate (MTX) 12 mg/week, baricitinib 4 mg/day, and tacrolimus 2 mg/day. Magnetic resonance imaging of the brain revealed diffuse high-intensity lesions in the cerebral white matter, basal ganglia, brainstem, and right cerebellar hemisphere. She was diagnosed with Epstein-Barr virus (EBV) encephalitis due to elevated levels of EBV-DNA in the cerebrospinal fluid and serum. Although MTX-associated lymphoproliferative disorders are well-known complications in patients with RA, EBV encephalitis requires careful attention for such patients undergoing treatment with multiple potent immunosuppressants.

A 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum β-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.

A 72-year-old woman was admitted to our hospital with bilateral pleural effusions. She had a 31-year history of systemic lupus erythematosus and had been treated with prednisolone and azathioprine. Pleural fluid culture revealed Salmonella enterica subsp. arizonae infection. This pathogen rarely infects humans but is commonly found in the gut flora of reptiles, especially snakes. Our patient had not come in contact with reptiles. Despite antibiotic therapies and negative pleural cultures, the pleural effusion persisted. Colon cancer was detected concomitantly, and she finally died. The autopsy revealed that the pleuritis was due to underlying diffuse large B cell lymphoma.

UNLABELLED: For the first time ever, the details of osteoporotic treatment were unveiled through the big data published by the government of Japan. The number of patients being treated is low and treatment start is late, especially in men. Our data are useful for education to not only patients but also doctors. PURPOSE: To analyze the current status and trend of osteoporosis treatment in Japan by analyzing the data on main drugs for osteoporosis disclosed in the National Database open data. METHODS: We used the National Database open data released by the Ministry of Health, Labour and Welfare in September 2018. Data on bisphosphonates, denosumab, and teriparatide were extracted to calculate the number of patients treated with these drugs based on the number of prescriptions filed. Using these prescription numbers, the proportion of patients treated with bisphosphonates, denosumab, or teriparatide among osteoporosis patients was calculated. Further, the data on the incidence of hip fractures were employed to validate the appropriateness of the timing of treatment initiation to osteoporosis patients in Japan. RESULTS: The number of patients in men administered bisphosphonates, denosumab, or teriparatide was about one tenth of that in women. The proportion of osteoporosis patients in men treated with bisphosphonates, denosumab, or teriparatide was highest in age group over 80 years at 19.4%. The proportion of osteoporosis patients in women treated with bisphosphonates, denosumab, or teriparatide was highest in age group 70-79 years at 23.7%. The incidence of hip fractures increases sharply over 80 years of age in both genders. CONCLUSION: Our findings suggested that osteoporosis treatment should be initiated in younger age, especially in men, in order to avoid osteoporotic fractures in Japan.

To analyze the biologics usage and expenditure for the treatment of patients with rheumatoid arthritis (RA) in each prefecture throughout Japan using the national open database, the Ministry of Health, Labour and Welfare of Japan disclosed in Oct 2016, the data of the top 30 most-frequently prescribed drugs during a 1-year period from April 2014 to March 2015 in each prefecture in Japan, along with the patients’ age and sex. Seldom-used drugs were excluded. We picked up only biologics for the present study. The total expenditure on biologics used in each prefecture was correlated with the population thereof. However, there was a big difference, up to ~ twofold, in the average expenditure used for an RA patient: highest in Toyama and lowest in Wakayama. There was also a big difference, ~ 4.5-fold, in the number of rheumatologists/1000 RA patients, highest in Kyoto and lowest in Aomori. The average expenditure used for an RA patient was correlated with the number of rheumatologists in the western part of Japan. Etanercept seemed to be used most frequently to Japanese RA patients followed closely by infliximab. Abatacept was used more frequently to the elderly than other biologics. There was a big difference in the number of rheumatologists and expenditure on biologics for the treatment of an RA patient among prefectures in fiscal 2014. Factors that brought this unevenness need to be scrutinized for universal implementation of good RA care throughout Japan, where there are uniform health insurance system and free access to rheumatologists.

<p>  16歳男性．入院約1か月前に咽頭痛が出現し自然軽快したが，約2週前に両下腿の紫斑，両大腿・下腿の筋痛が出現した．他院でアレルギーを疑われ抗ヒスタミン薬を処方されたが改善なく，足関節痛も出現した．約1週前に再度他院を受診し，腹痛が出現し尿潜血も認めたことからIgA血管炎が疑われ，当科へ紹介され入院した．入院時は腹部全体に自発痛・圧痛を認め経口摂取困難で，両下肢全体に点状の紫斑が散在し，両手関節炎を認めた．絶食補液で経過をみたところ，関節炎は自然に軽快したが，紫斑，腹痛は残存した．下腿皮膚生検でIgA沈着を伴う白血球破砕性血管炎を認め，上下部消化管内視鏡検査では胃，十二指腸，回腸に発赤・びらんが散在したことからIgA血管炎と診断した．尿蛋白・潜血も認めたが軽度であり，紫斑，腹痛が遷延したことから，入院7日目にコルヒチン1 mg/日で治療を開始した．その後数日で紫斑は消失し，入院13日目に経口で摂食が可能となり，消化器症状の再燃もなく入院25日目に退院した．IgA血管炎では遷延する症状に対して副腎皮質ステロイドが使用されるが，症例によってはコルヒチンも有用な場合がある．</p>

Raynaud's phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 A degrees C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 A degrees C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs.

We examined change in the antibody titre against pandemic influenza A/H1N1/2009 before and after vaccination in Japanese patients with rheumatoid arthritis. This observational study was conducted with the participation of five hospitals in Japan. A total of 89 patients with rheumatoid arthritis were included in this study. The seroprotection and seroresponse rates to vaccination with the pandemic influenza A/H1N1/2009 vaccine were analysed. The seroprotection rates prior to the vaccination were 5.6% in the Japanese patients with rheumatoid arthritis. The seroprotection rates after subcutaneous vaccination were 55.1%. The seroresponse rate after subcutaneous vaccination was 50.6% in the patients with rheumatoid arthritis. Both the seroprotection and seroresponse rates obtained after the vaccination with the pandemic influenza A/H1N1/2009 vaccine were low in Japanese patients with rheumatoid arthritis. We should realise that a vaccination against this newly emerged influenza virus may protect only half of the Japanese patients with rheumatoid arthritis in a real world.

Prospective observational study was performed to elucidate the incidence and characteristics of healthcare-associated infections in a university hospital for rheumatology care. In this study, a total of 1,226 patients were prospectively enrolled between March 2004 and February 2006 and between April 2008 and December 2008. Healthcare-associated infection was defined as an infection developing after the third day of admission to the rheumatology ward. We detected the following 54 healthcare-associated infections in 49 patients: respiratory tract infection, 14 cases; Clostridium difficile infection, 2 cases; urinary tract infection, 4 cases; bloodstream infection, 9 cases; skin infection, 2 cases; reactivation of latent cytomegalovirus infection, 6 cases; herpes zoster infection, 5 cases; Candida infection, 7 cases; others, 4 cases. The incidence rate of respiratory tract infection was the highest. Methicillin-resistant Staphylococcus aureus was the causative bacterium in 21% of respiratory tract infections cases. Bloodstream infection due to the insertion of a catheter and opportunistic infection by a latent virus were also occurred commonly. Respiratory tract infection, bloodstream infection and opportunistic infection by a latent virus were the most common causes of healthcare-associated infection in rheumatology. It is important to pay more attention to healthcare-associated infection.

A 51-year-old Japanese woman developed systemic lupus erythematosus (SLE) in 1995. In August 2005, she had massive pericardial effusion due to lupus pericarditis, which was compromising her circulation. Methylprednisolone pulse, intravenous cyclophosphamide pulse and pericardiocentesis were all ineffective. The pericardium was cut surgically to create a passage to drain the liquid into the pleural cavity. The procedure was temporarily effective however, massive liquid accumulated in the pleural cavity within 1 year. Oral tacrolimus and topical betamethasone injection were ineffective. Since the interleukin-6 (IL-6) level in the effusion was markedly increased (1160 pg/ml), tocilizumab was administered intravenously at a dose of 8 mg/kg every 4 weeks. The effect was astonishing and only a residual amount of pericardial effusion remained. Prednisolone was tapered successfully from 15 to 5 mg daily. Tocilizumab is a treatment of choice when we confront an intractable serositis with massive effusion in SLE, if the IL-6 level is high. Copyright 2012 BMJ Publishing Group. All rights reserved.

Methods. Three patients with SSc, two with microscopic polyangiitis and one with MCTD were enrolled. All patients had severe RP, ulcers and/or necrosis in the extremities. MNCs were obtained from 400 to 1600 ml of peripheral blood and implanted into 20-80 different sites in the palms and/or soles. This procedure was repeated every 3 months up to 1 year. Humoral factors were measured by ELISAs. Results. Visual analogue scale scores for pain, coldness and subjective satisfaction were improved after implantation in all patients. Pre-treatment ulcers in five patients were cured after repeated implantations. Angiography showed increased vasculature compared with baseline. Serum levels of VEGF increased after implantation, whereas levels of IL-1 beta, fibroblast growth factor and endostatin had variable results. None of the patients had any adverse reactions during a follow-up period of up to 3 years. Conclusions. Repeated implantation of peripheral blood MNCs was effective and safe for the treatment of recalcitrant ulcers developing in ischaemic digits and toes in patients with CTD.

Objective. To determine levels of interleukin 33 (IL-33) in serum and synovial fluid (SF) and their clinical associations in patients with rheumatoid arthritis (RA). To evaluate the ability of activated peripheral blood mononuclear cells (PBMC) and fibroblast-like synoviocytes (FLS) from RA patients to release IL-33. Methods. Sera were obtained from 59 patients with RA, 10 patients with infectious diseases, and 42 healthy volunteers. SF samples were obtained from 15 patients with RA and 13 with osteoarthritis. IL-33 levels were measured using a sandwich ELISA after removal of rheumatoid factor with protein A-Sepharose beads. FLS were stimulated with IL-1 beta and tumor necrosis factor, and treated with or without chemical damage. PBMC were stimulated with anti-CD3/CD28 antibodies. The levels of IL-33 were measured in the culture supernatants and cell lysates by ELISA or immunoblotting. Results. Serum IL-33 levels were significantly higher in RA patients, especially in the high disease activity group compared to the moderate or low activity group. IL-33 levels in SF were elevated in all 15 RA patients measured. IL-33 levels were higher in SF samples than in sera in 7 RA patients measured simultaneously. The 30-kDa IL-33 precursor was detected in the culture supernatants of damaged FLS but was not detected in those of activated PBMC and non-damaged FLS. Conclusion. IL-33 levels were elevated in sera and SF samples from patients with RA, and correlated with disease activity. IL-33 was produced mainly in inflamed joints; IL-33/ST2L signaling might play an important role in joint inflammation of human RA. (First Release Nov 15 2009; J Rheumatol 2010;37;18-25; doi:10.3899/jrheum.090492)

The objective of this study is to investigate the clinical markers of life-threatening Pneumocystis pneumonia (PCP) in patients with collagen vascular diseases (CVD). The patients who contracted Pneumocystis jeroveccii were retrospectively selected from our medical charts and conditions related to the patients' death were reviewed. The findings indicated that lower levels of serum albumin and cholinesterase, increased alveolar-arterial oxygen gradient, intratracheal intubation, and necessity to treat in the intensive care unit were significantly related to deaths associated with PCP in CVD. A special attention should be paid to decreased serum albumin and cholinesterase as ominous predictors in PCP occurred in patients with CVD.

肺高血圧症は，稀な疾患ではあるが進行性かつ難治性で治療に難渋する．膠原病でもしばしば肺高血圧症の合併を認めるが，その予後は極めて不良である．しかし，近年プロスタサイクリンであるエポプロステノールをはじめ，エンドセリン受容体拮抗薬であるボセンタンや，ホスホジエステラーゼ-5阻害薬であるシルデナフィルなど，強力な血管拡張作用を有する薬剤が本邦でも使用できるようになった．これらの薬剤は運動耐容能をはじめ，循環動態，ADLの改善，さらには肺高血圧症の予後の改善が大いに期待できる薬剤である．本稿では肺高血圧症の治療薬のうち，最近本邦で認可されたエンドセリン受容体拮抗薬とホスホジエステラーゼ-5阻害薬について解説する．<br>

Systemic lupus erythematosus (SLE) is often complicated by pericarditis with effusion, which generally responds well to glucocorticoid. We report herein a Japanese patient with SLE who showed a sign of cardiac tamponade and severe chest and back pain because of massive intractable pericardial effusion. Pulse glucocorticoid and pulse cyclophosphamide gained marginal effects. Pericardial effusion accumulated again soon after ultrasound-guided pericardiocentesis and drainage. Pericardial fenestration performed Surgically as a last resort, for draining pericardial fluid into the pleural space, was very effective, and only a much smaller amount of fluid was observed in the space thereafter in comparison with the volume before the surgery. Pathological examination of the retrieved pericardium unfolded intense hyperplasia of small vessels and capillaries. Levels of IL-6 and TNF-alpha in pericardial effusion were extremely higher than those in serum. Pericardial effusion with extensive capillary hyperplasia in SLE would be resistant to medical treatment and require surgical fenestration. Lupus (2008) 17, 1033-1035.

Objective. CD34-positive bone marrow mononuclear cells (MNCs) have been successfully used for regeneration of small arteries in Buerger's disease. The objective of this study is to examine the angiogenetic potential of autologous MNCs from bone marrow and peripheral blood implanted into the ischaemic digits from patients with connective tissue diseases. Methods. Three patients with systemic sclerosis, two with mixed connective tissue disease, and one with CREST syndrome were enrolled who had painful ischaemic digits with necrosis refractory to several vasodilators including intravenous prostaglandins. MNCs obtained from 7 ml/kg bone marrow blood and 400 ml peripheral blood were implanted into 20 different sites in palms and/or soles. The study was performed open-labelled. Results. Pain in the numeric rating scale improved remarkably up to 1 month after implantation of bone marrow or peripheral MNCs to the same extent, although no significant differences were found in transcutaneous oxygen pressure and thermogram before and after the implantation. Bone marrow MNCs increased blood flow of the hand determined by intra-arterial digital subtraction angiography, while peripheral MNCs did not. Conclusions. Implantation of autologous MNCs from peripheral and bone marrow into the ischaemic digits was so effective in pain-relief and more clinical trials would be warranted to see whether this could be a new treatment modality for angiogenesis in connective tissue diseases as in Buerger's disease.

Sildenafil and bosentan were added recently to the treatment with great expectations, effectiveness for the acute exacerbation of pulmonary arterial hypertension (PAH) is not fully examined. Two cases of acutely exacerbated PAH associated with collagen vascular diseases were treated first with sildenafil for six months followed by bosentan for another six months and the characteristics of this treatment modality were examined. Sildenafil showed an immediate effect which started in as early as similar to 30 min and was maximized in 60-90 min after oral ingestion. Continuous use of sildenafil for six months lowered pulmonary arterial pressure, pulmonary vascular resistance and the levels of brain natriuretic peptides along with an increased distance in 6-minute-walk, and replacement of it to with bosentan kept these effects. We think it as a treatment choice to use sildenafil first as a reliever and replace it with a controller bosentan, considering the immediate effects of sildenafil.

2005年1月から6月までにアレルギーリウマチ科に入院した100症例を対象とし,入院時と入院1週間後に血中Dダイマー値を測定した。Dダイマーレベルが高値またはその変化が大きかった症例と,下肢深部静脈血栓症(DVT)を疑わせる症状を有する症例について下肢静脈超音波検査を行い,DVTの有無を検査した。その結果,100例中5例にDVTを認めた。うち3例は入院前からDVTを発症しており,2例は入院中に新たにDVTを発症した。DVTがみつかった5症例は全例臨床症状を伴っていたが,臨床症状を伴っていてもDダイマーレベルが上昇していない症例は,下肢静脈超音波検査にてDVTは見られなかった。Dダイマーレベルの変化と臨床症状が見られた症例に対して下肢静脈超音波検査を行うことにより,効率的にDVTを診断できるものと考えられた。

A 70-year-old man presenting with a chief complaint of tongue swelling had been diagnosed with prostate cancer 1 year earlier. He had been on an oral angiotensin-converting enzyme inhibitor (ACE) inhibitor for hypertension for 20 years. Two months before the first of 4 episodes of tongue swelling within a period of 40 days, he had been prescribed oral estramustine phosphate (EMP) for the prostate cancer. He was admitted to our hospital for the evaluation after massive swelling of the tongue and epiglottis which necessitated tracheotomy. Food allergies, allergic reactions to environmental factors, and hereditary angioneurotic edema were excluded. Massive swelling of the tongue and epiglottis disappeared completely after EMP was discontinued. We concluded that angioedema was induced by EMP used concurrently with the ACE inhibitor.