sarcoidosis

Japanese: サルコイドーシス

Sarcoidosis is a systemic disease characterized by the formation of epithelioid cell granulomas without necrosis. It often begins with bilateral hilar lymphadenopathy (BHL), pulmonary infiltration, and eye and skin lesions. Lesions can form in almost any organ in the body, but the organs affected and the severity of the disease vary from person to person. The clinical course is also characterized by diversity, ranging from spontaneous improvement to persistent and refractory cases. Common immunological findings include a weakening of delayed-type hypersensitivity in the skin and an increase in Th1-type immune response at the site of the lesion. Furthermore, immune complexes may be observed in the blood in association with the activation of B cell function (Hunninghake, 1999).
ClassificationThose that develop with acute symptoms are called acute onset types, and include Löfgren's syndrome (presenting BHL, arthralgia, and erythema nodosum) and alveolar sarcoidosis (presenting pneumonia-like infiltrative shadows), and are considered to have a good prognosis.Those that become refractory or persistent are called refractory or persistent sarcoidosis.
Cause and Etiology Until now, the cause of this disease has been considered "unknown." However, research reports from Japan have revealed that by using quantitative PCR and specific antibodies for the normal bacteria Propionibacterium acnes, bacterial components of this bacterium are almost certainly present within the lesions of this disease, but are almost never present in lymph nodes of patients with other diseases. Many theories on the etiology have been put forward to date, but the propionibacterial etiology theory is currently attracting the most attention.
Epidemiology : This disease is found worldwide, with the incidence rate being higher in women than in men. There are large regional and racial differences in the condition, and in Japan, compared to Europe and the United States, there are more patients with mild symptoms, more eye and cardiac involvement, and more cardiac deaths and less deaths from respiratory failure. In a 1991 questionnaire survey, the estimated incidence rate in Japan was 12.3 per 100,000 population, but a 2004 epidemiological report using individual clinical survey forms for intractable diseases showed that it had dropped to one-tenth of this rate. This is thought to be because individual clinical survey forms are not always submitted, especially for mild cases or cases of spontaneous improvement.
The age at onset of the disease is bimodal in both men and women, with the peak incidence rate in men between the ages of 20 and 34 and in women between the ages of 60 and 64 (Figure 7-4-5). Recently, the incidence rate in young people has decreased in both men and women, while the number of elderly people has increased, resulting in an increase in difficult-to-treat cases.
In Japan, the majority of cases are discovered during health checkups, but the number of cases where symptoms are detected is increasing. In particular, there has been an increase in cases presenting with eye and skin findings.
Pathology: The pathological features of this disease are characterized by the formation of epithelioid cell granulomas without necrosis. Granulomas are distributed along lymphatic vessels, and in the lungs, they are distributed in the broad interstitium, such as around the bronchi and vascular bundles, the pleura, and the interlobular septa. Over the chronic course, fibrosis derived from granulomas is seen mainly in the broad interstitium, causing lobar collapse along with alveolar collapse around the airways, but the lesions are more severe in the upper lobes. Granulomas invade blood vessels, causing granulomatous vasculitis, and in the lungs, they invade both arteries and veins, causing fibrotic stenosis of blood vessels during the healing scarring process, which can cause pulmonary hypertension. On the other hand, it is known that microvascular lesions (MAP) are formed by various factors released from epithelioid cells and macrophages, even in areas without granulomas. MAP is characterized by endothelial cell degeneration in capillaries and small blood vessels, and multilayering of the basement membrane, and is said to be related to the formation of lesions in various systemic organs.
Pathophysiology : In this disease, based on genetic predisposition, a type I helper T cell (Th1) immune response is triggered by the causative antigen, promoting granulomatous inflammation. While most cases regress naturally, persistent chronic granulomatous inflammation can lead to fibrosis. Sex hormones and mental and physical stress have been reported to be involved in the onset and exacerbation of symptoms. Furthermore, not only fibrosis but also the aforementioned granulomatous vasculitis and MAP are involved in the worsening and prolongation of the disease.
Small fiber neuropathy (SFN), which is an accompaniment to this disease and has recently attracted attention, is believed to be the cause of organ-nonspecific systemic symptoms such as pain, numbness, and shortness of breath. One theory that SFN is caused by blood flow disorder due to MAP is
Clinical symptoms The clinical symptoms of typical organ lesions are shown in Table 7-4-12 and Figure 7-4-6.
Test Results and Diagnosis: The basis for diagnosing this disease is a tissue diagnosis, but as tissue diagnosis cannot be obtained in all cases, a "clinical diagnosis group" has been established. The Ministry of Health, Labor and Welfare's certification criteria (diagnostic criteria) for sarcoidosis, a specified disease, stipulate that the clinical diagnosis group requires three or more of the following to be positive, including a) or b) above: a) negative tuberculin reaction, b) high serum ACE levels, c) high gamma globulin levels, d) high serum lysozyme levels, e) increased accumulation on gallium scintigram, f) increased total cell count or lymphocyte CD4/CD8 on bronchoalveolar lavage. On a gallium scintigram, if accumulation is found in the parotid gland, the panda sign (Figure 7-4-7), which is characteristic of this disease, will be observed. Furthermore, the diagnostic criteria established by the Society in 2006, "Diagnostic Criteria and Diagnostic Guide for Sarcoidosis 2006" (edited by the Japanese Society of Sarcoidosis/Granulomatous Disorders et al., 2007), state that test findings indicative of a systemic reaction to this disease are: 1) swelling of bilateral hilar lymph nodes, 2) high serum ACE activity, 3) negative tuberculin reaction, 4) significant accumulation on gallium scintigram, 5) increased lymphocytes (25% or more) or high CD4/CD8 ratio (3.5 or more) on bronchoalveolar lavage test, and 6) high serum or urinary calcium levels. It should be noted that there are currently two diagnostic criteria.
When epithelioid cell granuloma is found as a tissue diagnosis , other infectious granulomatous diseases must be excluded. It is difficult to differentiate from chronic beryllium lung disease both clinically and pathologically, so an occupational history is important. In addition, when sarcoidosis shows shadows predominantly in the lower lung fields or when images show other interstitial pneumonia, it is difficult to distinguish whether the disease is caused by sarcoidosis or a complication. In addition, sarcoidosis generally has few subjective symptoms, but when symptoms are severe, it is necessary to differentiate it from malignant lymphoma, other lymphoproliferative diseases, metastatic lung tumors, hypersensitivity pneumonitis, etc. In addition, IgG4-related disease, which has recently attracted attention, may be accompanied by uveitis and swelling of bilateral glandular tissues, and therefore requires differentiation.
Sarcoidosis is a pathological abnormality involving lymphocytes, and is often accompanied by similar conditions such as Sjögren's syndrome, thyroid dysfunction, and hypersensitivity pneumonitis. Sarcoidosis is also often accompanied by malignant tumors, especially malignant lymphoma, in daily clinical practice, but it is difficult to prove that the incidence is high epidemiologically. Other common complications include shingles and urinary stones.
Treatment Oral steroid hormone drugs are the basis of treatment for sarcoidosis. If cardiac involvement is confirmed, steroid therapy should be started even if there are no symptoms. In the case of pulmonary involvement, subjective symptoms are few compared to the amount of shadows, and treatment is started if the shadows increase or the lung field shrinks. Treatment of ocular involvement requires detailed observation of the eye findings and a diagnosis by an ophthalmologist is required. For other organs, steroid drugs can be increased or decreased depending on subjective and objective symptoms. Usually, the dose of prednisolone is gradually decreased from about 30 mg/day, but there are cases where even a small amount is effective. In some cases, it may be necessary to continue treatment at 10 to 5 mg/day. Details are given in "Opinions on Sarcoidosis Treatment-2003" (edited by the Japanese Society of Sarcoidosis/Granulomatous Diseases et al., 2003). The treatment procedure for pulmonary sarcoidosis is shown in Figure 7-4-8. Methotrexate (MTX) is commonly used in Europe and the United States because it has a steroid-sparing effect.
Course and prognosisThe clinical course of sarcoidosis is diverse and varies widely from case to case. That is, it varies from case to case where the disease improves naturally in a short period of time to case where the disease persists for a long period of time, and from case to case where the disease responds well to steroids. It is generally said that most cases improve naturally, but cases where the disease develops at an advanced age or where there is involvement of multiple organs tend to have a prolonged course of the disease. Also, even if organ involvement improves, there are cases where the systemic symptoms such as pain, shortness of breath, and fatigue, which will be described later, persist. In cases where the disease persists, it may not be possible to discontinue steroids or immunosuppressants.
Prevention and rehabilitation: In many cases, stress is thought to be involved in the onset or worsening of the disease, so in order to prevent the disease from worsening, patients are advised to avoid stress, lead a regular life, and especially to eat well and get enough sleep.
Contraindications: In sarcoidosis, an increase in endogenous vitamin D is thought to cause an increase in calcium levels and promote granuloma formation. When taking steroids, bisphosphonates are recommended as osteoporosis prevention drugs rather than active vitamin D preparations. [Yamaguchi Tetsuo]
■ References
Hunninghake GW, et al: Statement on sarcoidosis. Sarcoidosis Vasuculitis and Diffuse Lung Diseases,16: 149-173,1999.
Japanese Society of Sarcoidosis and Granulomatous Diseases, et al.: Viewpoints on the treatment of sarcoidosis 2003. Journal of the Japanese Society of Sarcoidosis and Granulomatous Diseases, 23: 105-114, 2003.
Japanese Society of Sarcoidosis and Granulomatous Disorders, et al.: Diagnostic criteria and diagnostic guide for sarcoidosis 2006. Journal of the Japanese Society of Sarcoidosis and Granulomatous Disorders, 27: 89-102, 2007.

Table 7-4-12
Representative organ lesions of sarcoidosis ">

Table 7-4-12

Figure 7-4-5
Age at onset and gender differences in sarcoidosis in Japan ">

Figure 7-4-5

Fig. 7-4-8
Treatment Procedures for Pulmonary Sarcoidosis

Fig. 7-4-8

Sarcoidosis (rheumatic disease)

[⇨ 7-4-5)] [Tatsuya Atsumi]
■ References
Atsumi T, Amengual O, et al: Antiphospholipid syndrome: pathogenesis. In: Systemic Lupus Erythematosus 5th ed (Lahita RG, ed), pp945-966, Academic Press, San Diego, 2010.
Otomo K, Atsumi T, et al: The efficacy of antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum, 64: 504-512, 2012.
Sakai Y, Atsumi T, et al: The effects of phosphatidylserine dependent antiprothrombin antibody on thrombin generation. Arthritis Rheum, 60: 2457-2467, 2009.

Sarcoidosis (nervous system disorder associated with collagen disease and inflammatory disease)

(4) Sarcoidosis A systemic disease characterized by non-caseating epithelioid cell granulomas (sarcoid nodules) of unknown cause. When sarcoid nodules are found in the central nervous system, peripheral nerves, and muscles, it is called neuromuscular sarcoidosis. Many cases are asymptomatic, but meningoencephalopathy and myelopathy can become severe. In addition, in cases of myopathy in middle-aged or older women, the cause should be searched for with this disease in mind. In progressive and refractory cases, large doses of steroids are required. [⇨7-4-5)] [Ikeda Shuichi]
■ References <br /> Neuromuscular disorders associated with collagen diseases. Journal of the Japanese Society of Internal Medicine, 99(8), 2010.
Collagen diseases and neurological disorders: from basic to clinical applications. Clinical Neuroscience, 28(2), 2010.

Sarcoidosis (liver damage associated with other diseases)

(8) Sarcoidosis
Sarcoidosis is a non-caseating granulomatous disease of unknown cause that affects multiple organs. Granulomas frequently form in the liver, but liver damage rarely becomes a clinical problem. Serum angiotensin converting enzyme (ACE), lysozyme, and adenosine deaminase (ADA) activities are high, and tuberculin reactions are negative, which helps differentiate sarcoidosis from hepatic tuberculosis. [Nishiguchi Shuhei]

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　サルコイドーシスは壊死を伴わない類上皮細胞肉芽腫形成を特徴とする全身性疾患である．しばしば両側肺門リンパ節腫脹（BHL），肺浸潤，眼病変，皮膚病変で発症する．全身のほぼすべての臓器で病巣を形成しうるが，個々人によって侵される臓器も重症度も異なる「多彩性」があり，臨床経過も自然改善例から遷延・難治化例までの「多様性」があることが特徴である．しばしばみられる免疫学的所見は，皮膚の遅延型過敏反応の減弱と，病変部位におけるTh1型免疫反応の亢進である．また，B細胞機能の活性化に伴って血中免疫複合体を認めることもある（Hunninghake，1999）．
分類
　急性の症状を伴って発症するものを急性発症型といい，Löfgren症候群（BHL，関節痛，結節性紅斑を呈する）やalveolar sarcoidosis（肺炎様の浸潤陰影を呈する）などがあり，予後良好とされる．難治化，遷延化するものは難治性・遷延性サルコイドーシスとされる．
原因・病因
　本症はこれまで「原因不明」とされてきた．しかし，わが国からの研究報告の発信で，常在菌である Propionibacterium acnesの定量的PCR法や特異的抗体を用いることによって，本菌の菌体成分は本症の病巣内にはほぼ確実に存在し，かつ，ほかの疾患のリンパ節などにはほぼ存在しないことが明らかにされた．これまでも多くの病因説があげられたが，プロピオニバクテリア病因説は現在最も注目されている．
疫学
　本症は世界中でみられる疾患であり，罹患率は男性より女性に高い．地域や人種間での病態の差が大きく，わが国では欧米に比べて，軽症者が多い，眼と心臓の罹患が多い，心臓死が多く呼吸不全死が少ないという特徴がある．わが国の推定罹患率は，1991年のアンケート調査では人口10万人あたり12.3人であったが，2004年の難病の臨床調査個人票を用いた疫学報告ではこの1/10に低下していた．これは，特に軽症例や自然改善例では臨床調査個人票が必ずしも提出されていないためと思われる．
　発症年齢は男女ともに二峰性に分布し，男性の罹患率のピークが20～34歳，女性は60～64歳代である（図7-4-5）．また最近は男女ともに若年者の発症が減少し，高齢者が増加して難治例が増えてきているといわれている．
　発見動機では健診発見が多いのがなおわが国の特徴であるが，自覚症状発見例が増加している．特に，眼と皮膚所見を呈するものが増えている．
病理
　本症の病理像は壊死を伴わない類上皮細胞肉芽腫の形成を特徴とする．肉芽腫はリンパ管に沿って分布し，肺では気管支・血管束周囲，胸膜，小葉間隔壁などの広義間質に分布する．慢性の経過で肉芽腫に由来する線維化は広義間質を中心としてみられ，気道周囲の肺胞虚脱とともに肺葉虚脱の原因となるが，上葉に病変が強い．肉芽腫は血管を侵襲して肉芽腫性血管炎をきたし，肺では動脈・静脈のいずれをも侵してその治癒瘢痕過程で血管の線維性狭窄をきたし肺高血圧症の原因となりうる．一方，肉芽腫の存在しないところにも，類上皮細胞やマクロファージなどから放出されるさまざまな因子によって微小血管病変（microangiopathy：MAP）が形成されることが知られている．MAPは毛細血管や細小血管の内皮細胞変性，基底膜の多層化などを特徴としており，さまざまな全身臓器病変の形成に関連しているとされている．
病態生理
　本症では，遺伝的素因を基礎にして，原因抗原物質により惹起されたI型ヘルパーT細胞（Th1）型免疫応答がおこり，肉芽腫性炎症が促進される．多くは自然退縮する一方で，慢性的な肉芽腫性炎症が持続すると線維化をきたす．発症や症状増悪においては，性ホルモンや精神的肉体的ストレスの関与があることが報告されている．また，病態の悪化・遷延化には，線維化だけでなく，上述の肉芽腫性血管炎やMAPなども関与している．
　最近注目されている本症に合併する小径線維神経障害（small fiber neuropathy：SFN）は，痛み，しびれ，息切れなどの臓器非特異的全身症状の原因となっているとされているが，このSFNの原因としてMAPによる血流障害説があげられている．
臨床症状
　代表的な臓器病変の臨床症状を表7-4-12，図7-4-6に示す．
検査成績・診断
　本症の診断の基本は組織診断であるが，すべての例で組織診断が得られるわけではなく，「臨床診断群」を設けている．厚生労働省の特定疾患であるサルコイドーシスの認定基準（診断基準）では，「a）ツベルクリン反応陰性　b）血清ACE高値　c）ガンマグロブリン高値　d）血清リゾチーム高値　e）ガリウムシンチグラムで集積増加　f）気管支肺胞洗浄で総細胞数またはリンパ球CD4/CD8の増加」のうち，a）またはb）を含む3項目以上の陽性が臨床診断群では必要とされている．ガリウムシンチグラムでは，耳下腺に集積があると，本症に特徴的なパンダサイン（図7-4-7）を呈する．また，2006年に学会が定めた診断基準である「サルコイドーシスの診断基準と診断の手引き－2006」（日本サルコイドーシス/肉芽腫性疾患学会ら編，2007）では，本症の全身反応を示す検査所見として，①両側肺門リンパ節腫脹，②血清ACE活性高値，③ツベルクリン反応陰性，④ガリウムシンチグラムで著明な集積所見，⑤気管支肺胞洗浄検査でリンパ球増加（25％以上）またはCD4/CD8比高値（3.5以上），⑥血清あるいは尿中カルシウム高値，としている．現在は診断基準が2本立てになっていることに注意を要する．
鑑別診断
　組織診断として類上皮細胞肉芽腫が得られた場合にもほかの感染性肉芽腫性疾患を除外する必要がある．慢性ベリリウム肺とは臨床的にも病理学的にも鑑別は難しく職業歴聴取が重要になる．また，下肺野優位の陰影を呈するサルコイドーシスや画像上その他の間質性肺炎像を呈する場合には，サルコイドーシスによるものなのか合併症なのか鑑別が難しい．また，サルコイドーシスは一般に自覚症状が乏しいものが多いが，症状が強い場合には悪性リンパ腫やほかのリンパ増殖性疾患，転移性肺腫瘍，過敏性肺炎などの鑑別が必要になる．また，最近注目されているIgG4関連疾患でMikulicz病を合併している場合にはブドウ膜炎や両側腺組織の腫脹などを伴うことがあり鑑別を要する．
合併症
　サルコイドーシスはリンパ球のかかわる病態異常であり，似た病態であるSjögren症候群，甲状腺機能異常，過敏性肺炎などの合併は多い．また，悪性腫瘍とくに悪性リンパ腫の合併も日常臨床では多いと感じられるが疫学的に合併率が高いことを証明することは難しい．その他，帯状疱疹，尿路結石などの合併も多い．
治療
　サルコイドーシスの治療の基本は経口ステロイドホルモン薬である．心臓病変が確認された場合には無症状でもステロイド治療を行ったほうがよいとされている．また肺病変の場合は陰影の量に比べて自覚症状が少なく，陰影の増強，肺野の収縮傾向があれば治療を行う．眼病変の治療には詳細な眼所見の観察が必要であり眼科医の診断が求められる．そのほかの臓器では，自他覚症状に応じてステロイド薬を増減すると考えてよい．普通はプレドニゾロン30 mg/日程度から漸減するが少量でも有効な例がある．10～5 mg/日で治療を継続することが必要な場合もある．「サルコイドーシス治療の見解-2003」（日本サルコイドーシス/肉芽腫性疾患学会ら編，2003）にその詳細がある．肺サルコイドーシスの治療手順を図7-4-8に示す．メトトレキサート（MTX）は，ステロイド節約効果（sparing effect）があるとされ欧米ではよく使用されている．
経過・予後
　サルコイドーシスの臨床経過は多様性があり個々の例で幅が大きい．すなわち，短期間で自然改善するものから長期間にわたって遷延化するもの，ステロイド薬に反応のよいもの悪いものなどさまざまである．多くは自然改善すると一般にはいわれているが，高齢発症の例，多臓器病変を有する例などは遷延化する傾向にある．また，臓器病変が改善しても，後述する痛み・息切れ・疲れなどの全身症状だけが長引く例もある．遷延化例ではステロイド薬や免疫抑制薬を中止にできない場合もある．
予防・リハビリテーション
　発病や悪化にストレスが関与していると思われる例が多く，疾患を悪化させないためには，ストレスをかけないこと，規則正しい生活をすること，とくに十分に摂食してよく眠ることを指導する．
禁忌
　サルコイドーシスでは内因性ビタミンDの増加によって，カルシウム値の上昇や肉芽腫形成の促進などが起こるとされている．ステロイド薬を服用する場合には，骨粗鬆症予防薬として，活性型ビタミンD製剤よりもビスホスホネート系薬剤が推奨される．［山口哲生］
■文献
Hunninghake GW, et al: Statement on sarcoidosis. Sarcoidosis Vasuculitis and Diffuse Lung Diseases,16: 149-173,1999.
日本サルコイドーシス/肉芽腫性疾患学会，他編:サルコイドーシス治療に関する見解-2003．日サ会誌，23: 105-114,2003.
日本サルコイドーシス/肉芽腫性疾患学会，他編:サルコイドーシスの診断基準と診断の手引き　2006．日サ会誌，27: 89-102, 2007．

表7-4-12
サルコイドーシスの代表的な臓器病変">

表7-4-12

図7-4-5
わが国におけるサルコイドーシスの発症年齢と性差">

図7-4-5

図7-4-8
肺サルコイドーシスの治療手順">

図7-4-8

サルコイドーシス(リウマチ性疾患)

　【⇨ 7-4-5）】［渥美達也］
■文献
Atsumi T, Amengual O, et al: Antiphospholipid syndrome: pathogenesis. In: Systemic Lupus Erythematosus 5th ed (Lahita RG, ed), pp945-966, Academic Press, San Diego, 2010.
Otomo K, Atsumi T, et al: The efficacy of antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum, 64: 504-512, 2012.
Sakai Y, Atsumi T, et al: The effects of phosphatidylserine dependent antiprothrombin antibody on thrombin generation. Arthritis Rheum, 60: 2457-2467, 2009.

サルコイドーシス(膠原病・炎症性疾患に伴う神経系障害)

（4）サルコイドーシス
　原因不明の非乾酪性類上皮細胞性肉芽腫（サルコイド結節）を特徴とする全身性疾患である．サルコイド結節を中枢神経，末梢神経，筋に認めるものを神経筋サルコイドーシスという．無症候例も多いが，髄膜脳症，脊髄症は重篤になりやすい．また中年期以降の女性のミオパチーでは本疾患を念頭において原因検索を行う．進行性・難治性例ではステロイド薬の大量投与を必要とする．【⇨7-4-5）】［池田修一］
■文献
膠原病に伴う神経・筋障害．日本内科学会雑誌，99(8), 2010.
膠原病と神経疾患—基礎から臨床まで．Clinical Neuroscience, 28(2), 2010.

サルコイドーシス(ほかの疾患に伴う肝障害)

（8）サルコイドーシス（sarcoidosis）
　サルコイドーシスは，原因不明の多臓器を侵す非乾酪性の肉芽腫性疾患である．肝にも高頻度に肉芽腫を形成するが，臨床的に肝障害が問題になることは少ない．血清アンジオテンシン変換酵素（angiotensin converting enzyme：ACE），リゾチーム，アデノシンデアミナーゼ（adenosine deaminase：ADA）活性が高値で，ツベルクリン反応は陰性であり，肝結核との鑑別に役立つ．［西口修平］

出典　内科学第10版内科学第10版について　情報

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