痛風の最新治療 シンポジウム「痛風研究に関する最近の話題」 第44回日本痛風・核酸代謝学会総会 長瀬クリニック 長瀬満夫 京王プラザホテル 2011年2月17日 痛風関節炎の治療 痛風関節炎は尿酸塩結晶により誘発さ れる炎症である。したがって非ステロイド 抗炎症薬（NSAIDs）、副腎皮質ステロイ ド、コルヒチンが使用されている。2010年 米国から痛風発作初期にコルヒチンを低 用量投与での有効性が報告された。 【コルヒチン １】 コルヒチンはコルチカム（秋咲きイヌサフラン）などの 球茎や球根から抽出されるアルカロイドであり、痛風治 療法としてエジプトでパピルスに記載され、その抗炎症 作用については紀元前５世紀から認識されている。コル ヒチンは、微小管を特異的に脱重合させ、好中球の炎症 部への移動や尿酸塩結晶の貪食などを阻害する、また尿 酸塩結晶によるNALP3インフラマソームを介するカス パーゼ-1活性化を抑制する。 【コルヒチン ２】 治療安全域が狭く、コルヒチンの毎時投与法 によって、治療を受けたすべての患者に副作 用が現れた。痛風発作後、できるだけ早期に 投与したほうがより有効性が高い。コルヒチ ンは痛風発作の前兆期に一錠（0.5mg）のみ 用い、発作を頓挫させる。予兆のある例では 効果的であり、コルヒチンを携行することを 勧める。痛風発作が頻発する場合には、コル ヒチン一日1錠を連日内服させるコルヒチ ン・カバーが有効である。 【コルヒチン ２】 治療安全域が狭く、コルヒチンの毎時投与法 によって、治療を受けたすべての患者に副作 用が現れた。痛風発作後、できるだけ早期に 投与したほうがより有効性が高い。コルヒチ ンは痛風発作の前兆期に一錠（0.5mg）のみ 用い、発作を頓挫させる。予兆のある例では 効果的であり、コルヒチンを携行することを 勧める。痛風発作が頻発する場合には、コル ヒチン一日1錠を連日内服させるコルヒチ ン・カバーが有効である。 生物学製剤の関節リウマチ以外への 適応についての文献紹介と 当院での関節リウマチに対する エタネルセプト使用症例 長瀬クリニック 長瀬満夫 第6回城北関節炎・RA ・ OA・AS談話会 2005年11月10日 要旨 生物学製剤の関節リウマチ以外への適応についての文献紹介（痛風） TNF阻害薬の承認状況 痛風での エタネルセプト vs rasburicase （ヒト組み換え型ウリカーゼ） 当院での関節リウマチに対するエタネルセプト使用症例 文献紹介 Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Tausche AK, Richter K, Grassler A, Hansel S, Roch B, Schroder HE. Ann Rheum Dis. 2004 Oct;63(10):1351-2. We report the case of a 53 year old man with a history of gouty arthritis extending over several years. He had had an acute kidney failure（急性腎不全） 2 years previously because of nephrolithiasis（腎結石症） with urate calculi（尿酸塩結石）. CASE REPORT (1) At the first consultation the patient had severe painful gouty arthritis (three to four attacks a week) of the joints of the big toes, the ankle joints, and different finger joints as well as in joints of the hands, shoulders, and knees. In addition to the polyarticular joint manifestation, multiple gouty tophi were present in the subcutaneous tissue (fig 1). CASE REPORT (2) The medical history of the patient showed he had arterial hypertension and hypertriglyceridaemia. He consumed 20-25 units of alcohol weekly. Standard treatment was impractical because the patient had developed incompatibility with allopurinol and benzbromarone, which manifested as diarrhoea and a generalized exanthema. Laboratory tests showed a raised white blood cell count (WBC) of 9.4 x 10 to 9/l (9400/μl); an erythrocyte sedimentation rate (ESR) 55 mm/1st h, C reactive protein (CRP) 61.0 mg/l (6.1 mg/dl), serum uric acid 580 μmol/l (9.7 mg/dl). Transaminases were normal apart from a γ-glutamyltransferase of 282 U/l. CASE REPORT (3) Clinical examination, including cardiovascular and respiratory systems, an electrocardiogram, and a chest radiograph were normal. Abdominal ultrasound was also normal apart from showing hepatomegaly. The radiographs of all symptomatic joints showed impressive signs of destructive gouty arthritis (fig 2). CASE REPORT (4) Despite exhaustive treatment with colchicine, diclofenac, methylprednisolone, and opioids, the arthritis attacks did not improve considerably (table 1 ). After obtaining the latest detailed information about the patient and his informed consent, treatment with etanercept (Enbrel) 25 mg subcutaneously twice weekly was started. As table 1 shows the frequency (gouty attacks per week) and the intensity (number of painful joints) of the gouty arthritis decreased considerably after four injections of etanercept. Laboratory tests showed a noticeable decrease of the inflammation, with WBC of 7.4 x 10 to 9/l (7400/μl); ESR 6 mm/1st h, CRP 6.1 mg/l (0.61 mg/dl). During the anti-inflammatory treatment, antihyperuricaemic treatment with probenecid and urine akalisers was maintained; the level of serum uric acid remained roughly the same. Thus, treatment with the tumour necrosis factor a (TNFα) inhibitor etanercept in a patient with a complex gouty arthritis impressively reduced the clinical manifestations of gout, and uric acid depots were depleted generally. serum uric acid 580 μmol/l (9.7 mg/dl) serum uric acid 560 μmol/l (9.4 mg/dl) DISCUSSION 1 Effective treatment exists to prevent the complications of symptomatic hyperuricaemia. However, severe gouty arthritis together with tophaceous manifestations are rarely Seen. In most cases standard treatment with colchicine, non-steroidal antiinflammatory drugs, and moderate doses of glucocorticosteroids is sufficient to control the inflammation of gouty attacks. In our patient the conservative treatment of the gout, including opioids for analgesia, did not control the attacks. The use of etanercept produced a noticeable decrease in all the pathological clinical and laboratory findings (table 1). DISCUSSION 2 TNFα plays an important part in different inflammatory diseases. Today, anti-TNFα is widely used in the treatment of different kinds of arthritis and primary vasculitis. Acute and chronic gouty arthritis is an inflammatory disease, in which activation of certain white blood cells occurs owing to the presence of a foreign substance-namely, urate crystals. The activation of monocytes and macrophages releases TNFα into the synovial fluid. Increased concentrations of TNFα are detectable in joints of gouty arthritis．In certain cases，gout can mimic rheumatoid arthritis. We describe the first published case of severe，recurrent tophaceous gouty arthritis refractory to anti-inflammatory treatment in a patient who was subsequently treated successfully with a TNFα inhibitor．Of particular interest is the possibility of maintaining antihyperuricaemic treatment during the antiphlogistic protection of etanercept, especially as there is a massive excavation of uric acid from the depots owing to the antihyperuricaemic treatment． TNF阻害薬の承認状況 針谷正祥：RA治療のnew standard-生物学的製剤の使い方Medical Practice 22:465-471,2005 etanercept or rasburicase Tausche el al described a case of severe tophaceous gouty arthritis, which was treated with etanercept. They showed that anti-tumour necrosis factor α (TNFα) treatment can reduce the incidence of gouty attacks, which corresponds with the observation that TNFα is activated in patients with gouty arthritis. Clearly, this is a costly symptomatic approach that is only in addition to the main treatment, which is lowering the serum uric acid (SUA) level in order to deplete urate depots and prevent gouty attacks and joint damage in the long term. In the case presented, uricosuric treatment could only lower SUA levels from 0.58 mmol/l to 0.56 mmol/l despite high doses of 2-3 g probenecid a day. This is in contrast with our experience. In our population of 95% undersecretors (defined as uric acid excretion in urine <6.0 mmol/day during normal diet) monotherapy with probenecid 500 mg twice daily lowers SUA levels by 35% (mean (SD) 0.l7 (0.05) mmoU1), whereas probenecid 500 mg twice daily in combination with allopurinol 200 mg daily lowers SUA levels by 48% (0.27 (0.08) mmol^) in patients with an adequate renal function (endogenous creatinine clearance >50 ml/min). In the case presented by Tausche el al we would like to suggest another option for treating patients with severe tophaceous gout-that is, treatment with rasburicase. This recombinant form of urate oxidase very effectively metabolises uric acid in allantoin, which dissolves readily and is excreted by urine. So far one patient has been treated by applying rasburicase and urate depots were readily depleted (Moolenburgh JD el al, submitted paper) In our opinion, for a case of severe tophaceous gout, When an expensive treatment is indicated, rasburicase should be considered as a potentially very effective treatment before using anti-TNFα. Authors' reply Like Reinders et al, we have found that in the defined “normal" population of undersecretors, conventional treatment effectively lowers serum uric acid (SUA) levels to the norm. In those critical cases of severe tophaceous gout, as presented by us, the multiple tophi in the tissue and joints contain around 50 g or more uric acid. Despite the escalation of antihyperuricaemic (uricosuric and uricostatic) drugs, the SUA levels cannot be lowered significantly because of uric acid mobilisation from these depots and secondary shift to the serum. Therefore, measurement Of SUA levels alone does not verify the efficiency of treatment: In view of our own experience (unpublished data), we agree with Reinders et al that the recombinant urate oxidase rasburicase should be introduced into the treatment of severe tophaceous gout if conventional uric acid lowering treatment is not effective or contraindicated. These cases are extremely rare and occur in under 0.01% of the population of undersecretors. There are two principles in the treatment of gout: firstly, uric acid lowering treatment with uricostatic and uricolytic agents and, secondly, anti-inflammatory treatment Of gouty quacks. Both of these treatment regimens should follow a ''step scheme". In the uric acid lowering treatment rasburicase might rank as the last step in treatment of patients with tophaceous gout. When gouty arthritis is refractory to treatment (with non-steroidal anti-inflammatory drugs, steroids, opioids) it is useful to introduce tumour necrosis factor α (TNFα) blockades, as we showed in the published case. Because two different principles of action can be followed there seems to be no need to answer the question of priority of one of these treatments. Rasburicase should not be considered before TNFα blockade but, rather, the two should be combined if conventional treatment is not sufficient. The main dilemma of both treatments in the first instance is not the high cost but the missing approval by the FDA in severe tophaceous gout. Unfortunately, valid data are lacking, for instance, about the best way of application (dosage, application interval) owing to the absence of clinical studies. Shortly after infusion of rasburicase instant uric acid metabolisation with abrupt decrease of SUA is observed. The resultant shift of uric acid from tissues to blood may cause a higher intensity of gouty attacks, and as we observed in one patient with urate nephropathy the worsening of renal function. We are very interested to learn of the article proposed by Moolenburgh el al. Tausche AK, Schroder HE. Reinders MK, van Roon EN, Brouwers JR, Jansen TL. A costly therapeutic dilemma in tophaceous gout: is etanercept or rasburicase preferable? Ann Rheum Dis. 2005 Mar;64(3):516 rasburicase ヒト組み換え型ウリカーゼ Abstract We recently encountered a destructive case of tophaceous gout in a 57-year-old patient. Despite perfect therapy compliance, the patient failed in the conventional urate-lowering treatment, accounting for the ongoing urate retention and accumulation with progressive tophaceous bulky disease. Application of an experimental scheme of uricolytical therapy on this patient was able to reduce bulky disease significantly. In modern medicine, potent urate-debulking medication with urate oxidase (uricase) derivatives is at our disposal, and it is a challenge for rheumatologists to install the right strategy including innovative approaches with potent uricolytic therapy on the right patient at the right time. J. D. Moolenburgh, M. K. Reinders and T. L. Th. A. Jansen Rasburicase treatment in severe tophaceous gout: a novel therapeutic option Clin Rheumatol. 2005 Oct 25;:1-4 Mechanism on HLA-DRa expression J. D. Moolenburgh, M. K. Reinders and T. L. Th. A. Jansen Rasburicase treatment in severe tophaceous gout: a novel therapeutic option Clin Rheumatol. 2005 Oct 25;:1-4 mechanism Mechanism IFN-g Stat1 on HLA-DRa expr IFN-g receptor Jak2 Jak2 Jak1 Jak1 Stat1 P Nucleus P Stat1 GAS CIITA gene HLA-DRa expression mechanism Mechanism IFN-g Stat1 on HLA-DRa expr IFN-g receptor Jak2 Jak2 Jak1 Jak1 Stat1 P Nucleus P Stat1 GAS CIITA gene HLA-DRa expression Pathways of urate Alexander So, Bernard Thorens J Clin Invest. 2010;120(6):1791-1799 Cytokine and chemokines that play a role in gouty inflammation IL-1β Endothelial adhesion Endogenous pyrogen TNFα Cellular activation Endothelial adhesion Phagocytosis IL-6 ? Granulocyte colony-stimulating factor CXCL1 (KC, Groa) CXCL8 (IL-8) CCL2 (monocyte chemoattractant protein-1) CCL3 (macrophage inflammatory protein-1) Monocyte, dendritic cells inflammatory macrophage Monocyte, macrophage, lining cell Monocyte, macrophage Neutrophil survival and proliferation Endothelium, macrophage Neutrophil chemotaxis Macrophage, neutrophil Neutrophil chemotaxis Macrophage, endothelium Monocyte and dendritic cell chemotaxis Mast cell degranulation Neutrophil chemotaxis Monocyte, macrophage Busso and So Arthritis Research & Therapy 2010 12:206 Enzymatic activity of uricase (uric acid oxidase) Robert Terkeltaub Gout. Novel therapies for treatment of gout and hyperuricemia Arthritis Research & Therapy 200: 236, 2009. Molecular models of the uricase tetramer and of the PEGylated uricase pegloticase containing strands of 10 kDa polyethylene glycol (PEG) linked to each uricase tetramer. Robert Terkeltaub Gout. Novel therapies for treatment of gout and hyperuricemia Arthritis Research & Therapy 200: 236, 2009. The NLRP3 inflammasome and IL-1β processing and secretion in crystal-induced inflammation. Robert Terkeltaub Gout. Novel therapies for treatment of gout and hyperuricemia Arthritis Research & Therapy 200: 236, 2009. Composition of the NALP3 inflammasome and its activation by monosodium urate Busso and So Arthritis Research & Therapy 2010 12:206 Cytokine and chemokines that play a role in gouty infl ammation Cytokine Actions contributing to gouty Cytokine inflammation Produced by References IL-1β Endothelial adhesion Monocyte, dendritic cells inflammatory [11,12,20,25] macrophage Endogenous pyrogen TNFα Cellular activation Monocyte, macrophage, lining cell [11,12] Endothelial adhesion Phagocytosis IL-6 ? Monocyte, macrophage [11,17] Granulocyte colony-stimulating factor Neutrophil survival and proliferation Endothelium, macrophage [11,17] CXCL1 (KC, Groα) Neutrophil chemotaxis Macrophage, neutrophil [11] CXCL8 (IL-8) Neutrophil chemotaxis Macrophage, endothelium [36,37] CCL2 (monocyte chemoattractant protein-1) Monocyte and dendritic cell chemotaxis [11] Mast cell degranulation CCL3 (macrophage infl ammatory protein-1) Neutrophil chemotaxis Monocyte, macrophage [11] Busso and So Arthritis Research & Therapy 2010 12:206 Multiple steps are needed to trigger inflammation in gout Busso and So Arthritis Research & Therapy 2010 12:206 要旨 生物学製剤の関節リウマチ以外への適応についての文献紹介（痛風） TNF阻害薬の承認状況 痛風での エタネルセプト vs rasburicase （ヒト組み換え型ウリカーゼ） 当院での関節リウマチに対するエタネルセプト使用症例 各種化合物による一重項 酸素の消去作用 遠藤仁 綜合臨床 2010;59(2):178-183 各種霊長類での血中尿酸 値と寿命との関連性 遠藤仁 綜合臨床 2010;59(2):178-183 痛風診断項目の陽性尤度比 津谷寛、稲井邦博： 痛風の診断・鑑別診 断。綜合臨床 2010; 59: 231-236 本邦男性における痛風診断項 目陽性時の痛風診断確率 津谷寛、稲井邦博： 痛風の診断・鑑別診 断。綜合臨床 2010; 59: 231-236
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