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Cryoglobulinemia

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Cryoglobulinemia

  1. 1. Cryoglobulinemia Cryofibrinogenemia クリオグロブリン血症 クリオフィブリノーゲン血症 UpToDate 16.3 他
  2. 2. Cryoglobulin, Cryofibrinogen • <37度で凝集することを寒冷凝集と言う – Cryoglobulin – Cryofibrinoge 血漿, 血清から検出: Cryoglobulinemia 血漿のみから検出: Cryofibrinogenemia (後述) • Cryoglobulinは免疫グロブリン and/or 補体を含む – Cryoglobulinemiaは比較的高頻度で認めるが (HIV感染の2-15%, 膠原病の15-25%, HCVの40-50%) – 症候性のCryoglobulinemiaは1/100 000の頻度と稀 2-50%が症候性となる. 症候性の3徴; 紫斑, 関節痛, 脱力 は80%で認める. >> Cryoglobulinemic disease, vasculitisと呼ぶ.
  3. 3. Cryoglobulinの生成 Lancet 2012; 379: 348–60 • B cellのクローナルな増殖により生成される. – リンパ増殖性疾患, 慢性炎症を来す感染症, 自己免疫疾患が原因となる. – 後に説明するtype I cryoglobulinはmonoclonalな増加であり, リンパ性疾患, MM, MGUS, smoulderingが原因となり, type IIはpolyclonalな増加であり, 炎症性疾患が原因となる. – type IIIではB cell増生はpolyclonalであることが多い. 3
  4. 4. Bone marrow Skin HCV Core protein TLR SR-B1 CD-81 C-type lectins GAG Dendritic cell C1qR BCR Liver BAFF VH1-69+ B cell CXCL13 BAFF receptor Peripheral compartments Clonal expansion Genetic aberrations Plasma cells Mutator phenotype IgM with RF activity Oncogenic signals Blood vessel Cold-precipitable immune complexes B-cell non-Hodgkin’s lymphoma Neutrophil Endothelial activation C4 Skin C4 C4d Proteolytic cleavage C4d Chemotactic peptides Inflammatory response 4 Leukocytoclastic vasculitis
  5. 5. Brouetの分類 Type I (5-25%) Type III (40-50%) Essential (72%) 30% 70% 57% Secondary (28%) 70% 30% 43% 関連疾患 LPD >> Essential > CTD, CLD LPD > CLD > CTD CLD >> CTD >> LPD Immunoglobulin Monoclonal Mono/poly + RF Polyclonal 紫斑 + +++ +++ 壊死 +++ +~++ +/- 関節痛>>関節炎 + ++ +++ 腎障害 + ++ + 神経障害 + ++ ++ 肝障害 *実際oligoclonal,  biclonalなど,  II-IIIの境界もあり、  判断は困難 Type II (40-60%) +/- ++ +++ 症状 LPD; Lympho proliferative Disorder, CLD; chronic liver disease, CTD; Connective tissue disorder
  6. 6. Type I Type III Monoclonal lg • Type II Monoclonal lgM+polyclonal lgG Polyclonal lgM+polyclonal lgG typeFigure 1: Classification of cryoglobulinaemia主にIgMとIgG. Iはmonoclonal Ig. 5 Most frequent Infrequent type IIはmonoclonalLess frequentpolyclonal IgGと, IgM複合体の混合. IgM, causes causes causes Infections Hepatitis C HIV; Hepatitis B virus Streptococcus spp; Brucella spp;  IgM複合体はリウマチ因子活性を示す. spp; Coxiella spp; Klebsiella spp; Leishmania spp; ChlamydiaB-19; virus Mycobacterium tuberculosis; leprosy; hepatitis A virus; cytomegalovirus; parvovirus chikungunya virus; Epstein-Barr virus; hantavirus; plasmodium; amoebaiasis; toxoplasmosis type IIIはpolyclonal Systemic lupus IgM, IgGの混合. antiphospholipid syndrome; inflammatory myopathies; adult-onset Still’s Systemic sclerosis; Autoimmune Sjögren’s diseases syndrome erythematosus; Rheumatoid arthritis disease; polyarteritis nodosa; giant-cell arteritis; Takayasu’s arteritis; ANCA-associated vasculitis; 6 autoimmune hepatitis Cancer B-cell lymphoma Multiple myeloma Hodgkin’s lymphoma; chronic lymphocytic leukaemia; chronic myeloid leukaemia; myelodysplasia; Lancet 2012; 379: 348–60 hepatocellular carcinoma; papillary thyroid cancer; lung adenocarcinoma; renal cell carcinoma;  type IIIはtype IIの亜型とされることが多い.
  7. 7. Cryoglobulinemiaの原因 • 感染症; 主にHCV, HIV, HBV – HCV-RNAはmixed cryoglobulinemiaの90%で検出される.  type IIとの関連性が特に高い. – HIV感染では7-17%でcryoglobulinemiaを認めるが, HCVとの混合感染では35-64%に上昇. • 自己免疫疾患 – Primary Sjogren’s syndromeでの合併例があり, B cell lymphomaや死亡リスク因子となる. さらにHCVが混合感染している場合は合併リスク5倍となる. – 他にはSLE, RAの10%程度でCryoglobulinが検出されるが, 量は少ない. 7
  8. 8. Most frequent causes Less frequent causes Infrequent causes Infections Hepatitis C virus HIV; Hepatitis B virus Streptococcus spp; Brucella spp; Coxiella spp; Klebsiella spp; Leishmania spp; Chlamydia spp; Mycobacterium tuberculosis; leprosy; hepatitis A virus; cytomegalovirus; parvovirus B-19; chikungunya virus; Epstein-Barr virus; hantavirus; plasmodium; amoebaiasis; toxoplasmosis Autoimmune diseases Sjögren’s syndrome Systemic lupus erythematosus; Rheumatoid arthritis Systemic sclerosis; antiphospholipid syndrome; inflammatory myopathies; adult-onset Still’s disease; polyarteritis nodosa; giant-cell arteritis; Takayasu’s arteritis; ANCA-associated vasculitis; autoimmune hepatitis Cancer B-cell lymphoma Multiple myeloma Hodgkin’s lymphoma; chronic lymphocytic leukaemia; chronic myeloid leukaemia; myelodysplasia; hepatocellular carcinoma; papillary thyroid cancer; lung adenocarcinoma; renal cell carcinoma; nasopharyngeal carcinoma Other causes ·· Alcoholic cirrhosis Co-trimoxazole;* interferon alfa;* cocaine;* intravenous radiographic contrast;* influenza vaccination; hepatitis B vaccination; intravesical BCG; moyamoya disease; endocarditis; chilblains ANCA=antineutrophil cytoplasmic antibodies. *Associated with cryoglobulinaemic exacerbation. Table: Main causes associated with cryoglobulinaemia since 199023 • 悪性腫瘍 In primary Sjögren’s syndrome, cryoglobulinaemia is Malignancy associated with extraglandular involvement, an B-cell lymphoproliferative diseases are the major cause – B cell lymphomaでの合併例が多く, cryoglobulinaemia associated with enhanced risk of B-cell lymphoma, and poor survival.24–26 of その場合はMixed typeとなる. malignancy. The prevalence of cryoglobulinaemia is five times higher Type I cryoglobulinaemia is reported predominantly in in patients – Waldenstrom’ssyndrome and HCV patients with Waldenström’s macroglobulinaemia, with both Sjögren’s macroglobulinemia, Multiple myeloma, CLLでは 27 infection compared withCryoglobulinemiaが多い. multiple myeloma, or chronic lymphocytic leukaemia.30 Type I those not infected with HCV. Cryoglobulins are detected in nearly 10% of patients Mixed cryoglobulinaemias occur mainly in B-cell with systemic lupus erythematosus and rheumatoid lymphomas.31 Cryoglobulins can be detected in patients • 他; idiopathicは10%程度 arthritis, but cryocrit values are generally lower with solid cancers.32 compared with those in patients with Sjögren’s syndrome, – MGUSでもあり得る. and the clinical manifestations of cryo- Essential cryoglobulinaemia 8 globulinaemic vasculitis are much less common.23,28,29 Nearly 10% of cases of mixed cryoglobulinaemia are Cryoglobulins can be detected in a wide range of other regarded as idiopathic or essential,7 a percentage that
  9. 9. 19% USA 44% • 慢性HCV患者での 0% Sweden Cryoglobulinemia頻度 China 32% 37% Japan India 51% 地中海沿岸地域では高頻度. HCV長期感染患者ほど高リスク. Lithuania 15% 19% Ireland 55% UK (OR 2倍) 28% Germany Poland 56% また, 肝硬変患者ではOR 4.87 France 37% 43% 55% Spain Italy Bulgaria 17% 46% Turkey Greece 12% 29% Israel Egypt 9 Lancet 2012; 379: 348–60 16% Iran 30% Kuwait
  10. 10. 950例の慢性C型肝炎患者 Medicine 2013;92: 245-256 • 1990-2010年に診断された慢性C型肝炎患者のうち, 246例(25.8%)でMixed cryoglobulinemia(+). – その内184例がCryoglobulinemic syndromeを認めた. – Type IIが88.6%, Type IIIが11.4%. – 症状はPalpable purpura 90%, 脱力 86.5%,  関節痛, 関節炎 63.1%, 皮膚潰瘍 29%であった. – 肝硬変例は8%と, MC(-)と比較して同等の頻度. – MC, CSの有無はC型肝炎の生命予後には関連しない. むしろMC(+)群では肝硬変進展率が低い. ただし, MC(+)群では腎不全や末梢神経障害が多くなる. 10
  11. 11. TABLE 2. Chronic Active Hepatitis to Cirrhosis Progression in Chronically HCV-Infected Patients With or Without Cryoglobulins Characteristic CAH to cirrhosis progression, n (%) Diagnosis of cirrhosis Histology, n (%) *Clinical grounds, n (%) Time to progression, yr, meanTSD Age, yr, meanTSD (range) Baseline Parameters Female, n (%) HCV genotype, n (%) GT-1 GT-2 GT-3 Liver histology (METAVIR), n (%) 0 1 2 3 Necro-inflammatory score Steatosis score ALT, (IU/L, 30Y65) GGT, (IU/L, 5Y55) ALP, (IU/L, 20Y136) PT INR (G1.20) Albumin (g/dL, 3.4Y5) Cryoglobulinemic Syndrome Positive (n = 130) Mixed Cryoglobulinemia Negative (n = 562) P 20 (15.4) 150 (26.7) 0.005 7 (35) 13 (65) 8.0 T 3.7 70 T 7 (55Y82) 56 (37.3) 94 (62.7) 7.2 T 3.4 68 T 5 (42Y83) NS NS NS NS 11 (55) 70 (47) NS 11 (55) 9 (45) 0 83 (55.3) 63 (42) 4 (2.7) NS NS NS 5 (25) 5 (25) 6 (30) 4 (20) 1.6 T 0.6 0.9 T 1 59.9 T 20.8 76.4 T 17.6 138.7 T 50 1.26 T 0.24 2.7 T 0.37 17 (11.3) 20 (13.4) 21 (14.0) 92 (61.3) 2.2 T 0.4 1.3 T 1.1 63.5 T 28.6 84.3 T 33.1 147.7 T 65.2 1.27 T 0.24 2.6 T 0.24 NS NS NS 0.006 NS NS NS NS NS NS NS NS = not significant, CAH = chronic active hepatitis, ALT = alanine aminotransferase, GGT = gammaglutamyl-transpeptidase, ALP = alkaline phosphatase, PT INR = prothrombin time international normalized ratio. *Ultrasonography/computed axial tomography showing surface nodularity, portal vein diameter 915 mm, transient elastography 914 KPa, splenomegaly, esophageal varices. CS(+)群はMC(-)と比較して肝硬変への進行頻度が少ない. subsequent liver biopsies. Twenty-five of the 30 CS(+) patients and 60 of the 85 MC(j) patients who refused IFN-> T ribavirin shown in Table 2, the only independent predictor was METAVIR Medicine 2013;92: stage 3 at baseline (p = 0.006). 245-256
  12. 12. TABLE 3. Clinical Outcome According to the Presence or Absence of Cryoglobulins Cryoglobulins Positive (n = 141) Outcome/Comorbidity Admission End Admission End 0 46 (32.6)*** 7.4 T 2.5 (5Y12) 38 (27) 4.2 T 2.5 (1Y8) 23 (16.3) 4.9 T 3.9 (1Y15) 17 (12)**** 4.5 T 3.7 (1Y12) 1 (0.7) 2 44 (31.2)*** 10 (7) 4.4 T 2.7 (1Y12) 5 (3.5) 3 T 1.7 (2Y5) 2 (1.4) 2 T 1.4 (1Y3) 2 (1.4) 3.7 T 2.9 (2Y8) 1 (0.7) 2 0 2 (0.3) 4 T 1.4 (3Y5) 20 (3.3) 7.5 T 7.9 (1Y20) 18 (3) 7 T 5.3 (3Y20) 0 18 (3) 4.7 T 1.6 (3Y8) 91 (15.1) 5.3 T 4.2 (3Y15) 47 (7.8) 6.2 T 3.4 (1Y14) 5 (0.8) 10 T 8.5 (4Y16) 16 (2.7) 5.4 T 4.8 (1Y15) 29 (4.8) 93 (15.5)*** 6 T 3.1 (1Y14) 12 (2) 3.3 T 2.6 (1Y8) 14 (2.3) 6.2 T 4.5 (1Y16) 9 (1.5) 4.6 T 2.9 (1Y8) 22 (3.7)* 5.4 T 2.7 (1Y10) 27 (4.5) 7.3 T 3.9 (2Y14) 5 (0.8) 9.6 T 4.5 (5Y14) 4 (0.7) 5.5 T 2.1 (4Y7) 5 (0.8) 9 T 6.5 (3Y16) 7 (1.2) 3.2 T 2.6 (1Y6) 4 (0.6) Nephropathy, n (%) yr, mean T SD (range) Thyropathy, n (%) yr, mean T SD (range) Diabetes mellitus, n (%) yr, mean T SD (range) MGUS IgM, n (%) yr, mean T SD (range) MGUS non-IgM, n (%) yr, mean T SD (range) Peripheral neuropathy, n (%) Arterial hypertension, n (%) yr, mean T SD (range) Autoimmune diseases, n (%) yr, mean T SD (range) 7 (5) 11 (7.8) 3.2 T 1.5 (2Y5) 0 1 (0.7) 5 0 4 (2.8) 3.7 T 1.7 (2Y6) 0 Solid tumor, n (%) yr, mean T SD (range) Ischemic heart disease, n (%) yr, mean T SD (range) Multiple myeloma, n (%) yr, mean T SD (range) Pneumopathy, n (%) yr, mean T SD (range) Waldenstrom disease, n (%) yr, mean T SD (range) ¨ Negative (n = 601) 0 1 (0.7) 3 0 4 (2.8) 3.7 T 1.5 (2Y5) 0 11 (1.8) 5.7 T 3.6 (3Y11) 0 50 (8.3)*** 4.8 T 3 (1Y13) 5 (0.8) 9 T 1.4 (8Y10) 4 (0.7) 4.7 T 3.8 (1Y10) 7 (1.2) 3.5 T 1.3 (2Y5) 0 0 20 (3.3) 6.8 T 4.7 (3Y15) 0 Chronic lymphocytic leukemia, n (%) yr, mean T SD (range) 0 0 0 Hodgkin lymphoma, n (%) yr, mean T SD (range) 0 0 Amyloidosis AL, n (%) yr, mean T SD (range) 0 0 2 (0.3) 4.5 T 0.7 (4Y5) 0 Gastrointestinal involvement, n (%) 0 3 (2.1) 0 *p G 0.05, **p G 0.009, ***p G 0.0009. MC(+)群は経過と伴に腎不全, 末梢神経障害発症例が有意に多い. MC(j) evident during follow-up in 38 CS(+) (27%) and 91 frequency in CS(+) patients. Its mean time to appearance was 4.5 T 3.7 years in 17 CS(+) patients (12%) and 10 T 8.5 years in (15.1%) patients (p = 0.002). Similarly, the distribution of au-
  13. 13. 臨床症状; Type I • Type I CGは無症候性が多い – 多発性骨髄腫に由来するMonoclonal Ig Hyperviscosity, Thrombosisが主な症候となる. – type Iでは血管閉塞が主. type IIでは反対に免疫複合体沈着による血管炎を来す – Raynaud現象, 指先虚血, Livedo reticularis, 紫斑など 網膜血管の過粘稠性変化も要チェック. – 脳神経障害, 認知症, 意識障害, Strokeなど様々 – 予後はCGによるものよりは原疾患で決まる – Type 1 CGでは皮膚, 腎, 骨髄, 中枢神経 Mixed CGでは皮膚, 末梢神経, 腎臓を主に侵す
  14. 14. • 血液の粘稠度評価も有用な検査. • 4.0 centipoiseを超えるあたりから症候性となる. • 過粘稠性の症状が出現した場合, 早期の治療が重要 – 治療としては血漿交換など. 14
  15. 15. Whitney test to compare continuous variables. The Kaplan-Meier curve was plotted to describe the survival rate according to the type of CryoVas, and the log-rank test compared both curves. Differences were considered significant when the p values were G 0.05. showing type I membranoproliferative glomerulonephritis in 17 cases and glomerulonephritis with isolated C3 deposits in 1 case. The patient without kidney biopsy had a urine protein excretion of 1.12 g/d with hematuria. None of the patients had central nervous system, pulmonary, gastrointestinal, or cardiac involvement. Fifty patients (78%) had severe manifestations of vasculitis, defined as the presence of extensive cutaneous ulcers and/or necrosis, sensorymotor multiple mononeuropathy, and/or glomerulonephritis. The Medicine 2013;92: 61-68 median cryoglobulin level at diagnosis was 1.55 g/L (range, 0.1Y10.4 g/L), and the median C3 and C4 complement levels were Type I Cryoglobulinemia vasculitis 64例の解析 RESULTS Patient Characteristics Sixty-four patients met the • MGUSが28例, inclusion criteria (Table 1). The 血液腫瘍が36例. mean age at diagnosis was 65.4 T 11.4 years (range, 38Y89 yr), TABLE 1. Main Characteristics of the 64 Patients at Diagnosis of CryoVas Characteristic 障害臓器は  皮膚  末梢神経  関節  腎臓 Epidemiologic features Mean age, yr Female sex, no. (%) Cause of CryoVas MGUS, no. (%) Hematologic malignancy, no. (%) WM, no. MM, no. MZL, no. CLL, no. Other B-NHL, no. Vasculitis involvement Skin, no. (%) Purpura, no. (%) Acrocyanosis, no. (%) Necrosis, no. (%) Ulcers, no. (%) Peripheral nerve, no. (%) Sensory, no. (%) Sensory-motor, no. (%) Joints, no. (%) Arthralgia, no. (%) Arthritis, no. (%) Kidney, no. (%) Laboratory features Cryoglobulin level, median g/L C3 level, median g/L C4 level, median g/L Creatinine level, median Hmol/L GFR*, mL/min GFR G60 mL/min*, no. (%) All (n=64) MGUS (n=28) Hematologic Malignancy (n=36) P 65.4 T 11.4 36 (56) 65.5 T 10.9 17 (61) 65.2 T 11.9 18 (50) 0.93 0.45 28 (44) 36 (56) 13 12 6 2 3 V V V V V V 55 (86) 44 (69) 19 (30) 18 (28) 17 (27) 28 (44) 15 (23) 13 (20) 18 (28) 13 (20) 5 (8) 19 (30) 26 (93) 22 (79) 11 (39) 9 (32) 10 (36) 11 (39) 5 (18) 6 (21) 11 (39) 7 (25) 4 (14) 8 (29) 29 (81) 22 (61) 8 (22) 9 (25) 7 (19) 17 (47) 10 (28) 7 (19) 7 (19) 6 (17) 1 (3) 11 (31) 1.55 (0.1Y10.4) 0.89 (0.30Y1.93) 0.09 (0.01Y0.34) 80 (59Y800) 68 T 26 21 (33) 1.60 (0.18Y8.0) 1.09 (0.39Y1.93) 0.09 (0.01Y0.34) 80 (59Y329) 69 T 25 7 (25) 0.96 (0.1Y10.4) 0.76 (0.30Y1.33) 0.06 (0.01Y0.20) 83 (60Y800) 67 T 28 14 (39) 0.28 0.61 0.10 0.99 0.52 0.02 0.23 0.48 0.76 0.29
  16. 16. plasmapheresis in 6 (18%); alkylating agents in 11 (37%; including chloraminophene in 4, cyclophosphamide in 4, melphalan • Type I CryoVas 64例; 初期治療 Medicine 2013;92: 61-68 TABLE 2. First-Line Treatments in Patients With Type I CryoVas According to the Underlying B-Cell Disorder 初期治療の大半がPSL 1mg/kg. 一部で血漿交換等. 反応性は良好だが, 再発率が高い. 基礎疾患の治療が重要. Therapeutic Management First-line therapy Prednisone Median dosage, mg/d Plasmapheresis Alkylating agents Polychemotherapy Rituximab Azathioprine/MMF Bortezomib-based regimen Fludarabine MGUS (n=28) Hematologic Malignancy (n=36) 23 20 (87) 60 (20Y120) 3 (13) 5 (22) 0 (0) 2 (9) 1 (4) 0 (0) 0 (0) 33 29 (88) 60 (40Y120) 6 (18) 11 (37) 9 (27) 5 (17) 2 (7) 2 (6) 1 (3) 8 (35) 6 (26) 9 (39) 13 (3Y144) 0 (0) 7 (21) 7 (21) 16 (48) 12 (4Y59) 3 (10) Response to first-line treatment Sustained remission Nonresponder Responder-relapser Median time to relapse, mo Not assessable 64 www.md-journal.com 16
  17. 17. 臨床症状; Mixed CG(Type II, III) • Type II, III CG – 慢性炎症が原因となることが多いが, リンパ系疾患も原因となる (膠原病, SLE, Sjogren’s, HCV, HIV) • HCVは>90%で陽性となる • HBVは<5%でMixed CGの原因となり得る (J Clin Pathol 2002;55:4-13) • HCV患者の36-55%にMixed cryoglobulinemiaを認めるが, 実際血管炎を呈するのは2-3%のみ (Am J Med 2010;123:400-8) – CGを産生するB cellの増殖が関与するとも言われるが, 実際は不明 – 非特異的症状が多い; 関節痛, 怠感, 筋肉痛, 紫斑, 皮膚血管炎, 末梢神経障害 – Melzer’s triadは25-30%でのみ陽性(関節痛, 脱力, 紫斑) – 症状は間欠的で, 1-2wk持続, 月に1-2回程度
  18. 18. Mixed CG(Type II, III) Lab Test 特徴 年齢(SD;Range) 51yr(11;29-73) Cryocrit (SD) 3.7% (7.0) 女性/男性 2.8 Type II / Type III 2/1 罹患期間(SD;Range) 11.9(6.4;1-34) CH50 (SD) 83 U (58) 症状 頻度 C3 (SD) 770mg/L (280) 紫斑 91% C4 (SD) 100mg/L(150) 脱力 89% 関節痛 83% ANA 24% 関節炎 10% 抗ミトコンドリア抗体 10% Raynaud現象 34% 抗平滑筋抗体 23% Sicca Syndrome 36% Ant-extractable ANA 7% 末梢神経障害 36% 腎障害 31% 抗HCV抗体 90% 肝障害 70% HCV RNA 86% B cell non-Hodgkin’s Lymphoma 7.5% 抗HBV抗体 40% 肝細胞癌 2.4% HBsAg 3.5% Mixed CG 170名の解析 (J Clin Pathol 2002;55:4-13)
  19. 19. • 皮膚所見 – 直径3-10mmのPalpable purpuraが主な所見 – 下肢で多い.(静脈のうっ滞により, 免疫複合体沈着が亢進) – 腹部まで生じることはあるが, 胸部や上肢は少ない • 腎障害 – HCV関連のCGの1/3に腎障害を合併する 血尿, 蛋白尿, RBC円柱, 様々な程度の腎障害を認める. – ネフローゼ症候群を21%, それに近いものが14% 透析を必要とするのは10%程度. • 末梢神経障害 – 17-60%で合併する. 最も多いのは多発単神経炎. 初発症状として出現することもある. – Pure motor neuropathyは稀であり, 感覚障害を伴うことが多い 19 Am J Med 2010;123:400-8 Lancet 2012; 379: 348–60
  20. 20. • Rheumatologic manifestations  – 関節痛が最も多い症状であり, 両側対称性に認める – 中∼大関節の場合も, RAに類似した小関節痛もあり得る – 口腔内乾燥も30%で認められ, Sjogrenとの鑑別が必要となる • 他の症状 – 致死的となるのは冠動脈の炎症. 少ないが報告例はある. – 腸間膜動脈を侵すと消化管出血の原因となり得る. 消化管障害は2-6%で認める. 他には膵炎や胆嚢炎を併発することもあり. – 肺病変は5%. 呼吸器症状や肺線維化, 肺胞出血の報告例がある. – 中枢神経系ではStrokeが多い. Am J Med 2010;123:400-8 Lancet 2012; 379: 348–60 20
  21. 21. A B C D Figure 3: Cutaneous involvement in cryoglobulinaemia (A) Purpura in legs, (B) atypical purpura, (C) cutaneous ulcers, (D) digital necrosis. measure serum viscosity. Patients usually become symptomatic at viscosity measurements that exceed 4·0 centipoise,56 but some patients are symptomatic with lower viscosities.57 Symptomatic hyperviscosity requires urgent treatment (eg, plasma exchange). Cryoglobulinaemic vasculitis Flares of cryoglobulinaemic vasculitis 348–60 but not Lancet 2012; 379: are often, always, accompanied by general symptoms such as fever, 21
  22. 22. HCV(+), IgM 1000台, RF 3000台の高齢女性. 食道静脈瘤破裂にて入院.  末梢血像にて破砕赤血球を認めるが,  RBCは蛋白凝集に隣接しているもののみ破砕されており, 他部位は問題無い.
  23. 23. CGによるNeuropathy • 71名のCG + Neuropathyの解析 (J Neurol Neurosurg Psychiatry 2005;76:1410-4) Neuropathy 頻度 症状 頻度 感覚神経障害 73% 刺痛 55%  非対称性 21% 感覚性運動失調 38%  SFSN 25% 温度感覚障害 42%  LFSN 41% 感覚運動神経障害 18% 多発単神経炎 8% 痛 Restless leg syndrome 42% 45% SFSN; Small fiber sensory neuropathy, LFSN; Large fiber sensory neuropathy
  24. 24. 症状まとめ 症状 皮膚症状 頻度 Erythematous macule Purpuric papule 塞, 出血, 潰瘍 90-95% 10-25% Raynaud現象, Livedo, 全体的にType I CGに多い 下肢で多いが, 頭部, 頚部, 粘膜でもある Post-inflammatory Hypergipmentation 30-50% 寒冷暴露による増悪 10-30% 末端チアノーゼ 筋, 骨格 関節痛, 筋肉痛 70% Mixed CGで多い所見, 関節炎, 筋炎は稀 Type I CGではあまり認められない 神経症状 末梢神経障害 70-80% Mixed CGで多く, Type Iでは稀 呼吸器 Small Airway Disease 40-50% Mixed CGで認める. 咳嗽, 低酸素など. BOOP, 肺胞出血, 肺血管炎も稀だが報告あり 腎障害 膜性増殖性糸球体腎炎 5-60% 主に免疫複合体沈着による障害 血管閉塞によるものはType Iで多いが稀 Mixed CG 所見, 症状 頻度 Sjogren’s Syndrome 4-20% Raynaud phenomenon 50% 肝腫大, 肝酵素異常, 肝生検にて異常あり 90% リンパ節腫大 20% 脾腫 30% 腹痛 20% 生検にて診断された糸球体腎炎の2%を占める
  25. 25. 検査所見 Lancet 2012; 379: 348–60 • Cryoglobulinの血液検査 – 採血したら37-40度に維持し, 決して<37度の状態にはしない. (採決後、スピッツをお湯につける) – その後4度で保存し, 数時間で凝集を認める場合はtype I, 凝集までに数日かかる場合はmixed typeである可能性が高い.  (特にtype IIIは数日かかる.) – 健常人でもCryoglobulin <0.06g/L程度は検出される. type Iでは5g/L以上となることが多いが, type II, IIIはそれよりも少ない. ただし, 陰性ならば否定できる, という訳でもなく, 偽陰性も多く注意が必要(検査方法, 採血タイミングなど) 26
  26. 26. ere are no standardised or validated diagnostic or ssification criteria for cryoglobulinaemic vasculitis.83 Regard cryoglobulinaemia as highly probable when at least agnosis is based on clinical, laboratory, and histo• most patients, cryoglobulinaemic two features of different subsets are present 他の検査所見 thological data. For Clinical findings sease is diagnosed by the presence of typical organ – 肝障害, 腎障害のチェック.• Skin purpura in adults volvement (mainly skin, kidney or peripheral nerve) Seminar • Cutaneous necrotic ulcers d circulating cryoglobulins. – type IIでは補体は通常C4が低下する. また, RFも陽性となる. • Glomerulonephritis The diagnosis of cryoglobulinaemia requires demon• Peripheral ation of the presence Cryoglobulinemiaを疑った場合は, neuropathy – of cryoglobulins in serum • Non-erosive arthritis anel 1). Appropriate sample collection and handling is • HCV-RNA, HBV, HIVの検査, Acral ischaemia ucial.84 Blood should be collected in prewarmed syringes • Cold-induced acrocyanosis d tubes, transported, clotted, and centrifuged at ANA, 抗DNA, anti-Ro/La, anti-citrullinated antibodyをチェック. • Raynaud’s phenomenon –40°C, ensuring that the temperature never falls low 37°C. The serum should then be stored at 4°C for Laboratory abnormalities Panel Precipitation of type I cryoglobulins usually to 7 days. 1: Clinical, laboratory, and histopathological red • Monoclonal gammopathy, particularly of IgM isotype or flags advising cryoglobulin testing r curs within hours. By contrast, mixed cryoglobulins, with hyperviscosity 3 rticularly type III, can need days to precipitate.85 at least • Unexplained low concentrations of complement Regard cryoglobulinaemia as highly probable when Experttwo features of different subsets are present laboratory interpretation that considers the (especially C4) c tient in the appropriate clinical context is essential. • Unexplained high titres of rheumatoid factor Clinical nme healthy findings individuals have low concentrations of • Pseudothrombocytosis • Skin purpura in adults 86,87 ) yoglobulins (<0·06 g/L), and mixed polyclonal • Formation of erythrocyte rouleaux • Cutaneous necrotic ulcers yoglobulins often occur transiently during infection.49 • Glomerulonephritis Histopathological findings n the other hand, a negative test for cryoglobulins does • Peripheral neuropathy • Leukocytoclastic vasculitis in adults mt exclude cryoglobulinaemia because of the possibility • Non-erosive arthritis • Membranoproliferative glomerulonephritis s false-negative results caused by improper sample • Acral ischaemia slection or inconsistent laboratory techniques.49 • Hyaline thrombi in capillaries in context of • Cold-induced acrocyanosis t glomerulonephritis or small-vessel vasculitis oreover, Raynaud’s phenomenon cryoglobulin concentrations can fluctuate, • s • Endoneural vasculitis pending on their in-vivo precipitation in target vessels. 27 r • Unclassified systemic necrotising vasculitis involving Laboratory abnormalities Lancet 2012; 379: 348–60 yoglobulin should be assayed serially when there is a y degree of suspicion of disease.49,85 small–medium-sized vessels gh • Monoclonal gammopathy, particularly of IgM isotype or
  27. 27. • 組織所見; 障害臓器の生検が有用 – 凝集したcryoglobulinをヒアリン血栓として小血管内に認める. 特にType I, IIのmonoclonal componentがある場合に多い. – Mixed typeでは小血管の血管炎所見を認める. 少ないが, 中血管の炎症もあり得る. 皮膚の紫斑部の皮膚生検ではLeukocytoclastic vasculitisを認める – 腎生検ではtype I membranoproliferative glomerulonephritisが70% Glomerular crescent 10-20%, Renal necrotising vasculitis 5-30%,  Interstitial inflammationが稀だが認められる. 28 Lancet 2012; 379: 348–60
  28. 28. 鑑別診断 • Cryoglobulinemic Vasculitis  – Small ~ Medium-sized Vesselを侵す血管炎 – Hypersensitivity vasculitis,   Henoch-Schonlein purpura  ANCA関連血管炎 (Wegener’s,Microscopic polyangiitis, Churg strauss) 感染性血管炎 (心内膜炎, 溶連菌感染後血管炎, 腎炎) 膠原病関連 (SLE, RA, Sjogren’s) 血栓性疾患 (抗リン脂質抗体症候群, TTP, HUS, Atrial myxoma) • Cryoglobulinemic hyperviscosity  – 血流障害 (Leukostasis, Polycythemia) 閉塞 (鎌状RBC, RBC寄生; マラリア, Babesiosis) 血液粘性の上昇 (Waldenstrom’s Hyperglobulinemic purpura, macroglobulinemia)
  29. 29. 致死的Cryoglobulinemia Medicine 2013;92: 273-284 • HCVに伴う致命的Cryoglobulinemic vasculitis 279例の解析. – 単一施設より30例, 論文より249例の報告を解析. – 致命的CVとは, 糸球体腎炎, 消化管血管炎, 肺胞出血, CNS障害, 心筋障害を認める血管炎で定義. – 糸球体腎炎; Cre上昇 >1.5mg/dL, 腎生検にてMPG, MPGN, FPG – 消化管血管炎; 食道, 胃, 小腸, 大腸, 他腹腔臓器を含む.  消化管出血, 腸管虚血, 膵炎, 急性胆管炎. – CNS障害; 脳虚血, 出血, 脊髄, 脳神経障害 – 心筋障害; 冠動脈障害を含む. 30
  30. 30. Cardiac involvement 3 (1) 3Y120 mo) from the Other cryoglobulinemic manifestations patients developed c TABLE 1. Epidemiologic Features, Associated Processes, at diagnosis TABLE 1. (Continued) Mean Cryocrit, and Causes of Death in 279 HCV Patients With to end-stage renal d Cutaneous purpura 185 (66.3) Life-Threatening Cryoglobulinemia ciated with survival Articular involvement 151 (54.1) who died had higher HCV Patients Peripheral neuropathy 125 (44.8) HCV Patients 0.76 mg/dL vs. 2.40 With Life-Threatening Fever 56 (20) With Life-Threatening filtration rate (GFR) Cryoglobulinemia Cryoglobulinemia Treatment Renal Disease (MDR Feature (n=279) No. Feature (n=279) No. (%) Corticosteroids 167 (59.8) (%) p G 0.001). We also Plasma exchanges 148 (53) Outcomes the main outcomes Sex (female) 146 (52) Interferon-> 8338 (13.6) (29.7) creatinine 9 2 mg/dL Chronic renal failure Mean age at diagnosis of 54 (25Y87) respect to renal outc cryoglobulinemia (range), yr Immunosuppressive agents 8333 (11.8) (29.7) Relapse were treated less freq Mean age at life-threatening involvement 55 (25Y87) Interferon-> + ribavirin 7410 (3.5) (26.5) Neoplasia (range), yr Patients who died ha Rituximab 2463 (22.5) (8.6) Death ( p = 0.001), immun First clinical manifestation of 232 (83) Retamozo et al Medicine Infliximab death & Volume 92, Number 5, September 2013 2 (0.71) Causes of cryoglobulinemia changes ( p = 0.043) Mean follow-up of life-threatening 1426 (41.2) (3Y120) Infectious process may have been relate Associated conditions cryoglobulinemia, mo Cryoglobulinemia vasculitis 24 (38) contrast, patients wh Chronic viral infection Neoplasia 6 (9.5) viral therapies ( p G 0 TABLE 1. coinfection HIV Epidemiologic Features, Associated Processes, 25 (8.9) TABLE 1. (Continued) Liver-related process 4 (6.3) MeanHBV coinfection Cryocrit, and Causes of Death in 279 HCV Patients With 7 (2.5) Cardiovascular events 2 (3.1) Life-Threatening Cryoglobulinemia Gastrointestinal V Autoimmune diseases 15 (5.3) Other causes 1 (1.5) Gastrointestinal Sjogren syndrome ¨ 6 (40) HCV Patients HCV Patients Abbreviations: ANCA = antineutrophil cytoplasmic antibodies, SLE = quently reported lifeSLE 4 (26.6) With Life-Threatening With Life-Threatening systemic lupus erythematosus. Cryoglobulinemia Polyarteritis nodosa 2 (13.3) Cryoglobulinemia Feature (n=279) No. (%) 276 www.md-journal.com Mixed connective tissue disease (6.6) Feature (n=279)1No. (%) Rheumatoid arthritis 1 (6.6) Outcomes Sex (female) 146 (52) 1 (6.6) Chronic renalCopyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction failure 38 (13.6) Mean Vasculitis ANCA of age at diagnosis (+) 54 (25Y87) syndrome in 96 (47%) patients and nephritic syndrome Neoplasia 8 (2.8) cryoglobulinemia (range), yr Relapse 33 (11.8) (proteinuria, hypertension, general edema) in 19 (9%), while Immunologic features Mean age at life-threatening involvement 55 (25Y87) Neoplasia 10 (3.5) the remaining 90 (44%) patients had an indolent presentation Mean cryocrit, % (n=66) 6.8 (0.5Y80) (range), yr Deathasymptomatic raised creatinine levels. Renal biopsy dis63 (22.5) with Mean manifestation (n=50) 102.1 (0.36Y1113) First clinicalcryocrit, mg/dLof 232 (83) Causes ofmembranoproliferative glomerulonephritis in 175 (85%) closed death cryoglobulinemia (G0.82 g/L) Low C3 levels 112/156 (71.8) cases, mesangial Infectious process proliferative glomerulonephritis in 15 (7%), 26 (41.2) AssociatedC4 levels (G0.11 g/L) Low conditions 96/125 (76.8) focal proliferative glomerulonephritis in 1024 (38) and other (5%), Cryoglobulinemia vasculitis Chronic viral infection Clinical presentations histopathologic lesions in 5 (2%) patients. 6 (9.5) Neoplasia HIV coinfection due to 25 (8.9) Renal failure 205 (73.4) Specific treatment for cryoglobulinemia consisted of comLiver-related process 4 (6.3) glomerulonephritis HBV coinfection 7 (2.5) bined therapy including antiviral agents in 121 cases (59%), plasma Cardiovascular events 2 (3.1) Gastrointestinal exchange in 110 (54%), corticosteroids in 95 (47%), immunoAutoimmune diseases 15 45 (16.1) (5.3) Other causes suppressive agents in 50 (24%), hemodialysis 1 (1.5) in 26 (13%), and Sjogren syndrome ¨ CNS involvement 6 38 (13.6) (40) Abbreviations: ANCA antineutrophil cytoplasmic antibodies, and inbiological agents in=13 cases (6%) (rituximab in 12 SLE = Pulmonary involvement SLE 4 18 (6.4) (26.6) systemic lupus erythematosus. fliximab in 1). After a mean follow-up of 13.2 months (range, Cardiac involvement 3 (1) Polyarteritis nodosa 2 (13.3)
  31. 31. TABLE 3. Epidemiologic Features, Associated Processes, Mean Cryocrit, and Causes of Death in 45 HCV Patients With Cryoglobulinemic Gastrointestinal Involvement Feature HCV Patients With Gastrointestinal Involvement (n=45) No. (%) Sex (female) 25 (55.5) Mean age at diagnosis of cryoglobulinemia 54.4 (28Y81) (range), yr Mean age at life-threatening involvement 57 (28Y81) (range), yr Mean time between cryoglobulinemia and 35 (0Y132) life-threatening involvement (range), mo Associated conditions Chronic viral infection HBV coinfection 1 (2.2) HIV coinfection 1 (2.2) o et al Autoimmune diseases 4 (8.8) Sjogren syndrome ¨ 2 (50) Polyarteritis nodosa 2 (50) Immunologic features 3. Epidemiologic Features, Associated Processes, Mean cryocrit, % (n= 2) 7 (1Y25) Cryocrit, and Causes of Death in 45 HCV Patients With Mean cryocrit, mg/dL (n=7) obulinemic Gastrointestinal Involvement 396 (0.18Y1113) Low C3 levels (G0.82 g/L) 11/17 (64.7) Low C4 levels (G0.11 g/L) 12/17 (70.1) HCV Patients With Clinical presentation Gastrointestinal Abdominal pain 39 (86.6) Involvement Bloody stool 9 (20) (n=45) No. (%) Intestinal perforation 3 (6.6) male) 25 (55.5) Hematemesis 2 (4.4) ge at diagnosis of cryoglobulinemia 54.4 (28Y81) Hypermenorrhagia 1 (2.2) e), yr Gastrointestinal involvement ge at life-threatening involvement 57 (28Y81) Intestinal ischemia 38 (84.4) e), yr Cholecystitis 3 (6.6) me between cryoglobulinemia and 35 (0Y132) Pancreatitis 3 (6.6) reatening involvement (range), mo Adnexa and greater omentum 1 (2.2) Pancreatitis 3 (6.6) TABLE 3. (Continued) omentum Adnexa and greater 1 (2.2) Other cryoglobulinemic manifestations at diagnosis HCV Patients With Cutaneous purpura 29 (64.4) Gastrointestinal Articular involvement 16 (35.5) Involvement Peripheral neuropathy Feature (n=45)12 (28.5) No. (%) Fever 5 (11.1) Causes of death Raynaud phenomenon 4 (8.8) Cryoglobulinemia vasculitis 9 (60) Treatment intestinal) (ischemia Corticosteroids 36 Infectious processes 5 (33.3)(80) Liver disease 1 (6.6) (37.7) Immunosuppressive agents 17 Interferon-> 15 (33.3) Surgery 12 (28.5) EMRI^ in exchanges and postmortem studies in 4),10 (22.2) transverse Plasma all patients myelitis in 4 (10%), and cerebral hemorrhage in 2 (5%) patients. Rituximab 9 (20) Treatment included corticosteroids (n = 33), immunosuppresInterferon-> + ribavirin 5 (11.1) sive agents Medicine plasma exchange (n = 17), antiviral agents 2013 (n = 20), & Volume 92, Number 5, September Mean follow-up of life-threatening2). After a mean follow-up 11.2 (6Y24) (n = 13), and biological therapies (n = cryoglobulinemia, mo of 16 months (range, 6Y84 mo) from the diagnosis of CNS inOutcomes 5 patients had established neurologic impairment volvement, (pyramidal syndrome and paraplegia in 2; pyramidal synRelapse 2 TABLE 3. (Continued) dysarthria, and spasticity in (4.4) drome in 1; dysbasia, 1; and Neoplasia 2 (4.4) sensory alteration in 1). Death 15 (33.3) HCV Patients With Gastrointestinal Eighteen patients presented with pulmonary hemorrhage 3,38,43,47,69,71,77,84,85,92,93 (Table 278 www.md-journal.com 5). There were 11 Involvement female paFeature 7 male, with a mean age of 56 years at (n=45) No. (%) tients and diagnosis of Pulmonary Hemorrhage lonephrit (n = 18) (n = 8), a Cardia Thr been rep diagnosi nosis of ischemic had asso emic ma joint inv Treatmen per d) an Activity At d mean BV a mean o life-threa died. Th cryoglob renal fail cryoglobulinemic and 58 years at diagnosis of Causes of death vasculitis© 2013 Lippincott Williams &pulCopyright Wilkins. Unauthorized monary hemorrhage. The clinical features included respiratory Cryoglobulinemia vasculitis 9and dys(60) failure in 11 (61.1%) patients, hemoptysis in 9 (50%), (ischemia intestinal) pnea in 6 (33.3%) patients. All patients showed pulmonary inInfectious processes 5 (33.3) filtrates in the chest X-ray and required admission to the intensive care unit. Thirteen (72%) patients concomitantly had1glomeruLiver disease (6.6) lonephritis. Treatment included intravenous methylprednisolone (n = 18), immunosuppressive agents (n = 9), plasma exchanges
  32. 32. TABLE 4. Epidemiologic Features, Associated Processes, Mean Cryocrit, and Causes of Death in 38 HCV Patients With Cryoglobulinemic CNS Involvement Feature HCV Patients With CNS Involvement (n=38) No. (%) Sex (female) 21 (55.2) Mean age at diagnosis of cryoglobulinemia 52.4 (33Y74) (range), yr Mean age at life-threatening involvement 53.7 (34Y76) (range), yr Mean time between cryoglobulinemia to 12 (0Y60) life-threatening involvement (range), mo Medicine & Volume 92, Number 5, September 2013 Associated conditions HBV coinfection 2 (5.2) HIV coinfection 1 (2.6) Autoimmune diseases Features, Associated Processes, Mean 5 (13.1) TABLE 4. Epidemiologic Cryocrit, and Causes of Death in 38 HCV Patients With SLE 2 (40) Cryoglobulinemic CNS Involvement Sjogren syndrome ¨ 1 (20) Rheumatoid arthritis 1 (20) With HCV Patients Vasculitis ANCA (+) 1 (20) CNS Involvement Neoplasia (2.6) Feature (n=38)1No. (%) Immunologic features Sex (female) 21 (55.2) Mean cryocrit, % (n=14) 3.2 (1Y13) Mean age at diagnosis of cryoglobulinemia 52.4 (33Y74) Mean cryocrit, mg/dL (n=7) 6.5 (0.3Y13) (range), yr Low at levels (G0.82 g/L) 11/15 (73.3) Mean ageC3 life-threatening involvement 53.7 (34Y76) Low C4 levels (G0.11 g/L) 13/18 (72.2) (range), yr Neurologic presentations Mean time between cryoglobulinemia to 12 (0Y60) life-threatening involvement (range), mo Hemiplegic 18 (47.3) Associated conditions Coma 8 (21) HBV coinfection 2 (5.2) Visual impairment 6 (15.7) HIV coinfection 1 (2.6) Encephalopathy 5 (13.1) Autoimmune diseases 5 (13.1) Seizures 4 (10.5) SLE 2 (40) Paraplegia 3 (7.8) Sjogren syndrome the bladder ¨ 1 (20) Disturbances of 3 (7.8) Rheumatoid arthritis 1 (20) Generalized pyramidal syndrome 3 (7.8) Disturbances of the bladder 3 (7.8) Generalized pyramidal 3 (7.8) TABLE 4. (Continued)syndrome CNS involvement Cerebral ischemia 18 (47.3) CNS vasculitis 15 Patients HCV (39.4) With CNS (10.5) Transverse myelitis 4 Involvement Feature hemorrhage (n=38) No. (%) Cerebral 2 (5.2) Other cryoglobulinemic manifestations Mean follow-up of life-threatening 16 (6-84) at cryoglobulinemia, mo diagnosis Cutaneous 22 (57.8) Outcomes purpura Peripheral neuropathy 18 (47.3) Relapse 9 (23.6) Articular involvement 11 (28.9) Neurologic damage 5 (13.1) Treatment Neoplasia 1 (2.6) Corticosteroids 33 (86.8) Death 13 (34.2) Life-Threatening HCV Cryoglobulinemia Immunosuppressive agents 20 (52.6) Causes of death Plasma exchange 17 (44.7) Cryoglobulinemia vasculitis 8 (61.5) Interferon-> 11 (28.9) Infectious processes 1 (7.6) Interferon-> + ribavirin 2 (5.2) TABLE 4. (Continued) Neoplasia 2 (15.3) Infliximab (anti-TNF) 1 (2.6) Other 2 (15.3) Rituximab 1 (2.6) Abbreviations: TNF = tumor necrosis factor. HCV Patients With CNS Involvement Feature (n=38) No. (%) the organ invo CNS, and mult in Figure 3. Th presenting wit nary involvem therapy was us IFN-> and 74 virin); life-thre administration tivariate Cox r CI, 1.007Y1.06 0.296; 95% CI tors at diagno KaplanYMeier the use of antiv The prev patients ranges valence found 12% and 56% globulins, with patients.78 How globulinemia a severity of th in 4, CNS vasculitis in 2, and cerebral hemorrhage(6-84)patient) nearly half the Mean follow-up of life-threatening 16 in 1 in 24 (38%), neoplasia in 6 (10%), chronic liver disease in 4 (6%), cryoglobulinemia, mo cardiovascular disease in 2 (3%), and post-renal biopsy bleedOutcomes * ing complication in 1 (1%) patient. The main cause of death 2013 Lippincott Williams & Wilkins Relapse 9 (23.6) was sepsis (42%) in patients with glomerulonephritis, and cryoNeurologic damage 5 (13.1) globulinemic Copyright © 2013in patients Williams(2.6) vasculitis itself Lippincott with 1 & Wilkins. Unauthorized repro gastrointestinal, Neoplasia pulmonary, and CNS involvement (60%, 57%, and 62%, respecDeath 13 (34.2) tively). No patient with myocardial involvement died. SurviCauseshad death baseline FFS score (1.57 T 0.03 vs. 1.62 T 0.07; vors of a lower Cryoglobulinemia vasculitis 8 (61.5) p = 0.548) and a lower BVAS score (14.63 T 0.30 vs. 16.27 T Infectious processes 1 (7.6) 0.84; p = 0.025) in comparison with patients who died. Neoplasia 2 shows the survival rate of the entire cohort (77%). 2 (15.3) Figure KaplanYMeier survival plots of patients classified(15.3) Other 2 according to the organ involved = tumor gastrointestinal, pulmonary, cardiac, (renal, necrosis factor. Abbreviations: TNF CNS, and multiple organ life-threatening involvement) are shown
  33. 33. Mean cryocrit, % (n=10) 11.7 (1Y60) 8/9 (88.8) TABLE 5. Epidemiologic Features, Associated Processes, Mean Low C3 levels (G0.82 g/L) Low C4 levels (G0.11 g/L) 8/9 (88.8) Cryocrit, and Causes of Death in 18 HCV Patients With Cryoglobulinemic Pulmonary Hemorrhage Pulmonary presentations Respiratory failure 11 (61.1) HCV Patients With 9 (50) Pulmonary Involvement Hemoptysis Dyspnea 6 (33.3) Feature (n=18) No. (%) Pulmonary involvement Sex (female) 11 (61.1) Pulmonary hemorrhage 18 (100) Mean age at diagnosis of 56 (36Y75) Other cryoglobulinemic cryoglobulinemia (range), yr manifestations at diagnosis Mean age at life-threatening 58 (36Y75) Cutaneous purpura 10 (55.5) involvement (range), yr Fever 5 (27.7) Mean time between cryoglobulinemia 21.3 (0Y108) and life-threatening involvement Articular involvement 3 (16.6) (range), mo Peripheral neuropathy 2 (11.1) Associated conditions Treatment Chronic viral infection Corticosteroids 18 (100) HBV coinfection 2 (11.1) Immunosuppressive agents 9 (50) CMV coinfection 1 (5.5) Plasma exchange 8 (44.4) Autoimmune diseases 2 (11.1) FIGURE 2. Interferon-> Kaplan-Meier survival curve in 2794patients with (22.2) Sjogren syndrome ¨ 1 (50) HCV-related ribavirin life-threatening cryoglobulinemia. (11.1) Interferon-> + 2 Mixed connective tissue disease 1 (50) Rituximab 2 (11.1) Immunologic features cryoglobulinemic glomerulonephritis, with 20% of patients Mean follow-up of life-threatening 9.5 (4Y12) Mean cryocrit, % (n=10) 11.7 (1Y60) developing chronic renal failure and 5% progressing to endcryoglobulinemia, mo Low C3 levels (G0.82 g/L) 8/9 (88.8) stage renal disease. Studies have suggested that cryoglobOutcomes Low C4 levels (G0.11 g/L) 8/9 (88.8) ulinemic glomerulonephritis significantly affects the prognosis Relapsesurvival and is a major cause of death,6either directly or (33.3) and Pulmonary presentations Death 14 (77.7) secondary to infection or cardiovascular disease, with series Respiratory failure 11 (61.1) Causes of the 1990s showing 10-year survival rates ranging between from death Hemoptysis 9 (50) 33% and 49%.31,94 However, authors of a 82007 multicenter Cryoglobulinemia vasculitis (57.1) Dyspnea 6 (33.3) Italian study83 including 146 patients with 6 (42.8) cryoglobulinemic Infectious processes Pulmonary involvement Pulmonary hemorrhage 18 (100) Abbreviations: CMV = cytomegalovirus. Other cryoglobulinemic
  34. 34. TABLE 2. Epidemiologic Features, Associated Processes, Mean Cryocrit, and Causes of Death in 205 HCV Patients With Renal Failure Caused by Biopsy-Proven Cryoglobulinemic Glomerulonephritis Feature HCV Patients With Renal Failure (n=205) No. (%) Sex (female) 99 (48.2) Mean age at diagnosis of cryoglobulinemia 50 (25Y81) (range), yr edicine & age at life-threatening 5, September 2013 (25Y81) Mean Volume 92, Number involvement 52 (range), yr Mean time between cryoglobulinemia and 18.6 (0Y168) life-threatening involvement (range), mo Associated conditions ABLE 2. Epidemiologic Features, Associated Processes, Chronic viral infection Mean Cryocrit, and Causes of Death in 205 HCV Patients With enal Failure Caused by Biopsy-Proven Cryoglobulinemic HIV coinfection 21 (10.2) lomerulonephritis HBV coinfection 4 (1.9) Autoimmune diseases 6 (2.9) HCV Patients Sjogren syndrome ¨ 2 (33.3) With Renal Failure SLE 1(16.6) eature (n=205) No. (%) Polyarteritis nodosa 1(16.6) ex (female) 99 (48.2) Rheumatoid arthritis 1(16.6) ean age at diagnosis of cryoglobulinemia 50 (25Y81) Vasculitis ANCA (+) 1(16.6) (range), yr Neoplasia 7 (3.4) eanImmunologic features age at life-threatening involvement 52 (25Y81) (range), yr cryocrit, % (n=43) Mean 7 (0.5Y80) ean time between cryoglobulinemia and 18.6 (0Y168) Mean cryocrit, mg/dL (n=10) 16.7 (0.36Y50) life-threatening involvement (range), mo Low C3 levels (G0.82 g/L) 97/132 (73.5) ssociated conditions Low C4 levels (G0.11 g/L) 90/102 (88.2) hronic viral infection Renal presentations HIV coinfection 21 (10.2) Renal failure 205 (100) HBVNephrotic syndrome coinfection 496 (46.8) (1.9) Nephritic syndrome utoimmune diseases 619 (9.2) (2.9) SjoRenalsyndrome ¨ gren involvement 2 (33.3) 175 (85.3) SLE Membranoproliferative 1(16.6) glomerulonephritis Polyarteritis nodosa 1(16.6) Mesangial proliferative 15 (7.3) Rheumatoid arthritis 1(16.6) glomerulonephritis Vasculitis ANCA (+) glomerulonephritis 1(16.6) Focal proliferative 10 (4.8) eoplasia 7 5 (2.4) (3.4) Other Focal proliferative glomerulonephritis 10 (4.8) TABLE 2. (Continued) Other 5 (2.4) Other cryoglobulinemic manifestations at diagnosis Cutaneous purpura 136 (66.3) HCV Patients Articular involvement 116 (56.5) With Renal Failure Peripheral neuropathy 78 (38) Feature (n=205) No. (%) Fever 6 (2.9) Mean follow-up of life-threatening 13.2 (3Y120) Treatment cryoglobulinemia, mo Plasma exchanges 110 (53.6) Outcomes Corticosteroids 95 (47.5) Life-Threatening HCV Cryoglobulinemia Chronic renal failure 39 (19) Interferon-> + ribavirin Relapse 12 65 (31.7) (5.8) Interferon-> Hemodialysis 10 56 (27.3) (4.8) Immunosuppressive agents Neoplasia 750 (24.3) (3.4) TABLE 2. (Continued) Hemodialysis Death 4326 (12.6) (20.9) Rituximab 12 (5.8) Causes of death Infectious 18 (41.8) Infliximab processes 1 (0.5) Cryoglobulinemia vasculitis Multiorgan failure Liver-related processes Neoplasia Feature Cardiovascular events Mean follow-up of life-threatening Iatrogenic * 2013 Lippincott Williams & Wilkins cryoglobulinemia, mo 10 (23.2) 6 (13.9) HCV Patients 3 (6.9) With Renal Failure 3 (6.9) (n=205) No. (%) 2 (4.6) 13.2 (3Y120) 1 (2.3) cally in 23 patients; i was confirmed by en cholangiopancreatog the diagnosis was bas Treatment included c sive agents (n = 17), plasma exchanges (n CNS Involvement Thirty-eight pati ment2,3,6,8,9,15,17,27,32, There were 21 femal of 52 years at diagn 54 years at diagnosis The clinical presenta patients, coma in 8 ( cephalopathy in 5 (1 3 (8%), disturbances pyramidal syndrome consisted of cerebral litis in 15 (40%) (dem Abbreviations: See previous table. Outcomes Chronic renal Copyright © 2013 Lippincott Williams (19) failure 39 & Wilkins. Unauthorized reproduction Relapse 11,19,24,33,42,43,48,49,51,59,69,73,77,81,83,89,93,98 12 (5.8) 3). (45 cases) (Table Hemodialysis There were 25 female patients and 20 male, with a10 (4.8) mean age 7 (3.4) ofNeoplasia at diagnosis of cryoglobulinemic vasculitis and 54 years 57 years at diagnosis of gastrointestinal vasculitis. 43 (20.9) The mean Death time between diagnosis of cryoglobulinemia and life-threatening Causes of death involvement was 35 months. The clinical presentation included Infectious processes 18 (41.8) intestinal ischemia in 38 (84%) patients, abdominal pain in the Cryoglobulinemia vasculitis of cholecystitis in 3 (7%), cryo10 (23.2) upper right quadrant suggestive Multiorgan pancreatitis in 3 (7%), and cryoglobulinemic 6 (13.9) globulinemic failure Liver-related adnexa and 3 patient. vasculitis of theprocesses greater omentum in 1 (2%) (6.9) Clinical symptoms included severe abdominal pain 3 (6.9) and genNeoplasia eral malaise in 39 patients, bloody stool in 9, intestinal perCardiovascular events 2 (4.6) foration in 3, hematemesis in 2, and hypermenorrhagia in Iatrogenic 1 (2.3) 1 patient. Intestinal vasculitis was confirmed histopathologiAbbreviations: See previous table. cally in 23 patients; in 6 patients, gastrointestinal involvement was confirmed by endoscopy, in 2 by endoscopic retrograde
  35. 35. Skin Kidney Palpable Purpura Arterial Hypertension Leg Hyperpigmentation Glomerulonephritis Raynaud’s Phenomenon Nephrotic Syndrome 0 Leg Ulcers 10 20 30 40 50 60 70 80 90 100 Percent Livedo Reticularis Nervous System Cold Urticaria Motor-sensory Axonopathy Digital Gangrene 0 10 20 30 40 50 60 70 80 90 100 Percent Neurocognitive Impairment Mononeuritis Multiplex 0 Rare Manifestations 10 20 30 40 50 60 70 80 90 100 Percent Hemorrhagic Alveolitis, Interstitial Lung Fibrosis Musculoskeletal System Gastrointestinal Vasculitis Arthralgia Heart Failure, Dilated Cardiomyopathy Asthenia Painful Osteosclerosis Myalgia–Fibromyalgia Hyperviscosity Syndrome Nonerosive Arthritis 0 1 2 3 4 5 6 Percent 7 8 9 10 0 N Engl J Med 2013:369:1035-45. 10 20 30 40 50 60 70 80 90 100 Percent Figure 2. Spectrum of Clinical Features in Patients with HCV-Related Cryoglobulinemic Vasculitis. The percentages reflect our experience in treating 246 patients with chronic HCV infection and cryoglobulinemic vasculitis. The pathogenesis of rare manifestations is unclear. Hemorrhagic alveolitis may be due to vasculitis that involves small arteries, capillaries, and venules, resulting in interstitial lung fibrosis.11 Small- and medium-vessel vasculitis accounts for gastrointestinal involvement.12 Cryoglobulinemic vasculitis–induced cardiomyopathy probably reflects myocardial vessel disease; an association with B-cell non-Hodgkin’s lymphoma and severe clinical manifestations has been recognized.13 HCV-associated osteosclerosis may be caused by an imbalance of the osteoprotegerin–receptor activator of the nuclear factor κB ligand system.14 Finally, a hyperviscosity syndrome, which is most frequent in type I cryoglobulinemia, develops as a product of the formation of macromolecular cryoprecipitating complexes.15
  36. 36. CGの治療 Am J Med 2010;123:400-8 治療 目的 Option 生活療法 Riskの軽減 長時間の立位, 座位保持を避ける 寒冷を避ける Stockingの使用 対症療法 症状の軽減 Low-dose steroid 降圧薬(ACE-I, ARB) 神経 痛に対する抗うつ薬など 重度の血管炎に対するIloprost 原因治療 HCVの治療 Peg-IFN + Ribavirin 病態の治療 B-cell clonal expansion suppression Circulation immune complex reduction Inflammation suppression 免疫抑制療法(cyclophosphamide 2mg/kg/d) Plasma exchange Low-antigen content diet High-dose steroids: Prednisone 0.5-1.5mg/kg/d 3d  → 1.0mg/kg/d 2-4wk 37 Methylprednisolone 0.5-1.0g/d 3d
  37. 37. Stratified treatment of HCV-related cryoglobulinaemic syndrome according to disease severity Mild/moderate disease Severe disease Induction phase Antiviral therapy +/– Corticosteroids Maintenance phase • Purpura, articular, general features • Mild neuropathy • GN without renal failure Antiviral therapy • Cutaneous ulcers, ischaemia • Severe neuropathy • GN with renal failure/ nephrotic syndrome • GI involvement Refractory Rituximab + Corticosteroids Antiviral therapy Life-threatening • Rapidly progressive GN • CNS involvement • Intestinal ischaemia • Alveolar haemorrhage Plasma exchanges + Corticosteroids pulses Refractory + Cyclophosphamide or Rituximab Antiviral therapy 38 Figure 5: Proposed therapeutic algorithm for patients with HCV-related cryoglobulinaemic syndrome according to disease severity Cryo vascu variou ation. comm capill erythr might identi type a skin, Outc The widel with n have failur life-th aemic comp Risk more or pu type I
  38. 38. HCV B-Cell Expansion Microenvironment Dual-antiviral combinations First-generation B-cell–depleting monoclonal antibodies Antiinflammatory agents Rituximab (complement-mediated cell lysis through C1q binding) Glucocorticoids (inhibition of proinflammatory cytokines) Alkylating agent Recombinant interleukin-2 Cyclophosphamide (DNA toxicity) Aldesleukin (inducer of regulatory T-cell activity) Peginterferon alfa-2a or alfa-2b plus ribavirin Multiple-antiviral combinations Peginterferon alfa-2a or alfa-2b plus ribavirin plus first-generation NS3/4A protease inhibitor (boceprevir or telaprevir) Peginterferon alfa-2a or alfa-2b plus ribavirin plus NS5B polymerase inhibitor (sofosbuvir) Peginterferon lambda-1a plus ribavirin plus daclatasvir Interferon-free regimens NS5B polymerase inhibitor sofosbuvir plus ribavirin NS5B inhibitor (BI-207127) Protease inhibitor (ABT-450) Second-generation B-cell–depleting monoclonal antibodies Ofatumumab (C1q activation in rituximab-resistant cells) Veltuzumab (complement-dependent cytotoxicity) Third-generation B-cell–depleting monoclonal antibodies HCV関連の Cryoglobulinemic vasculitisの 治療 N Engl J Med 2013:369:1035-45. Obinutuzumab (GA101) (direct killing of rituximab-resistant cell lines) Ocaratuzumab (antibody-dependent, cell-mediated cytotoxicity) PRO131921 monoclonal antibody (antibody- or complement-dependent cytotoxicity) Figure 3. Drugs for the Treatment of HCV-Related Cryoglobulinemic Vasculitis, According to the Therapeutic Target. Established drugs are shown in white.16-21 Drugs for which phase 3 clinical studies or uncontrolled observational data are available are shown in yellow.22-27 Promising therapeutic agents, the clinical application of which has so far been limited to exploratory studies or must await the results of phase 1–2 studies or of randomized, controlled trials, are shown in pink.28-34 39
  39. 39. (Fig. 4). sults of HCV RNA analyses in eight patients with Clinically asymptomatic Wait and watch with or without antiviral therapy Plasmapheresis, glucocorticoids, and a B-cell–depleting monoclonal antibody, with or without cyclophosphamide, followed by antiviral therapy 25–30% Rapidly progressive or lifethreatening CV CV associated with B-cell non-Hodgkin’s lymphoma 2–5% 40–45% Cutaneous CV without organ damage 7–12% 20–30% Antiviral therapy with or without glucocorticoids Antiviral therapy and rituximab, with or without chemotherapy CV with organ damage Antiviral therapy, a B-cell–depleting monoclonal antibody, and glucocorticoids Figure 4. Proposed Therapeutic Algorithm for HCV-Related Cryoglobulinemic Vasculitis (CV), According to Arbitrarily 40 Assessed Disease Activity. N cryoglobulins are detected, unA “wait and watch” strategy is suggested for asymptomatic patients in whom serum Engl J Med 2013:369:1035-45.
  40. 40. rituximab, with or without chemotherapy N Engl J Med 2013:369:1035-45. CV with organ damage Antiviral therapy, a B-cell–depleting monoclonal antibody, and glucocorticoids Figure 4. Proposed Therapeutic Algorithm for HCV-Related Cryoglobulinemic Vasculitis (CV), According to Arbitrarily Assessed Disease Activity. A “wait and watch” strategy is suggested for asymptomatic patients in whom serum cryoglobulins are detected, unless the goal is viral eradication. Antiviral therapy combining peginterferon alfa and ribavirin is advised for patients with clinically symptomatic, mild-to-moderate CV mostly involving the skin. The addition of low-to-medium doses of glucocorticoids may help relieve symptoms. If severe organ damage is present (including nephropathy, peripheral neuropathy, or both), antiviral therapy should be integrated with a B-cell–depleting monoclonal antibody (rituximab or ofatumumab) and glucocorticoids. CV associated with B-cell non-Hodgkin’s lymphoma may be treated with a rituximab-containing regimen as first-line therapy, with antiviral agents administered to prevent or reduce the risk of hepatic toxic effects and hepatitis flares.77 For recurrent or resistant non-Hodgkin’s lymphoma, a chemotherapeutic regimen such as fludarabine, rituximab, and cyclophosphamide may be required.78 Rapidly worsening and life-threatening CV requires prompt therapeutic intervention, initially including a combination of glucocorticoids, plasmapheresis, and a B-cell–depleting monoclonal antibody. If necessary, the short-term administration of an immunosuppressive drug such as cyclophosphamide can be considered, but the risk of infectious complications should be taken into account. Once the emergency phase is over, combination antiviral treatment should be initiated. By analogy with the approach to the treatment of patients with chronic hepatitis C who do not have cryoglobulinemia, a triple-antiviral combination (peginterferon alfa, ribavirin, and either boceprevir or telaprevir) can be adopted to treat patients with HCV genotype 1 infection and patients with refractory or relapsing disease. n engl j med 369;11 nejm.org september 12, 2013 41 The New England Journal of Medicine aded from nejm.org by UNSPECIFIED * on September 11, 2013. For personal use only. No other uses without permission.
  41. 41. • 最重症例ではmPSLパルス + PSL 1mg/kg/d, 免疫抑制療法が適応となる. – 免疫抑制療法では • Panel 3: Recommended treatment regimen for 114 combination interferon* and ribavirin† Cyclophosphamide 2mg/kg/d, もしくは750mg/m2/mo therapy Azathioprine 2mg/kg/d, Therapeutic regimens Mycophenolate mofetil 1g bidなど. Pegylated interferon alfa-2a 180 µg subcutaneously per week + – 血中の抗体除去目的の血漿交換, Apheresisも適応となる. Ribavirin 1000 mg orally per day (bodyweight HCV由来のCGならば抗ウイルス薬が適応. <75 kg) 1200 mg orally per day (bodyweight >75 kg) Panel 3: Recommended treatment regimen for combination interferon* and ribavirin† therapy114 Therapeutic regimens Pegylated interferon alfa-2a 180 µg subcutaneously per week + Ribavirin 1000 mg orally per day (bodyweight <75 kg) 1200 mg orally per day (bodyweight >75 kg) or Pegylated interferon alfa-2b 1–5 µg/kg subcutaneously per week Lancet 2012; 379: 348–60 + Ribavirin cryoglobulins. This idea needs further testing in or mechanistic studies linked to clinical trials, but the Pegylated interferon alfa-2b 1–5 µg/kg subcutaneously per results of small series are promising.121–126 These studies suggest that disease relapses are associated with the week +absence of virological control and the recovery of peripheral B cells. In patients receiving conventional Ribavirin therapy, a per day (bodyweight ≤65 vasculitis despite 800 mg orallythird had a relapse of kg) sustained virological response.127 This finding suggests 1000 mg orally per day (bodyweight 65–85 kg) that B-cell proliferation can become independent of HCV 1200 mg orally per day (bodyweight 85–105 kg) combined over time and that a targeted B-cell approach 1400 mg orally per day (bodyweight >105 kg) with pegylated interferon alfa and ribavirin might be successful in Recommended deleting both virus-dependent and virusduration of antiviral courses‡ independent clones. 42 • Genotypes 1 and 4: 48 weeks Substantial clinical experience in the off-label use of • rituximab in patients with HCV-related cryoglobulinaemia Genotypes 2 and 3: 24 weeks
  42. 42. • Biological therapies  – RituximabによるB cellの抑制.  >> B cell由来のClonal Ig産生低下を狙う – 未だStudyは少ないが, 小規模Studyでは期待できる結果. HCVの治療に関係なく, cryoglobulinを低下させることが可能. – HCV由来のCG患者において, Rituximab 375mg/m2/wk or 1000mg/2wk 1mo継続 vs HCV治療群 で比較した結果, 腎障害改善率(81% vs 40%), Cryoglobulinクリアランス改善(68% vs 44%)は有意に Rituximab群で良好であったとの結果. – 今後の期待できるとともに, 試しても良い治療. 43 Lancet 2012; 379: 348–60
  43. 43. Cryoglobulinaemic diseaseの予後 • 約半数が慢性化, 1/3が中等度∼重度の障害を認める – 慢性腎不全や肝硬変へ進展する例もある. また, 15%は致命的な病態へ進展する. – 予後不良因子は男性, >60yr, 糸球体腎炎, 消化管障害, 肺障害の合併, HCV感染の合併, type II cryoglobulinemia. • 致命的なCryoglobulinemiaとは – 糸球体腎炎では10%が急性腎不全, もしくは慢性進行性の腎不全となる – 糸球体腎炎例の10年生存率は33-49%だが, 近年の報告では80%と良好の報告もある. 44 Lancet 2012; 379: 348–60
  44. 44. Cryofibrinogenemia • 血漿成分のみで寒冷凝集素が存在する病態 – 血清成分にも含まれるのをCryoglobulinemiaと言う – CGは免疫グロブリン, 補体を含むが, CFは免疫グロブリン, Fibrinogen, Fibrin, Fibronectinを含む – 頻度は, 135名のレジデントの3%でCF陽性 (J Lab Clin Med 1963;61:203-10) – 36000名の入院患者では3.4% (4度, 24hr) (Am J Clin Pathol 1972;58:524-30) 665名の入院患者では13% (4度, 48hr) (J Lab Clin Med 1963;61:203-10) – 無症候性のCFは多く認められるが, 症候性CFは少なく, 寒冷凝集を認める患者の殆どがCyroglobulinemiaである • 335名の寒冷凝集(+)患者中, 1名がCF, 265名がCGであった (Electrophoresis 1999;20:606-13)
  45. 45. CFの基礎疾患 • 悪性腫瘍, 感染症, 炎症性疾患(膠原病)が多い – 続発性CFでは女性/男性 = 1.4, 年齢差, 人種差は認めない – HCV(+)患者143名中, 37%がCF >50mg/Lであった 又, CF(+)患者中, 89%でCG陽性であった (Am J Med 2008;121:624-31) – 経口避妊薬によるCFもある – その他の病態として, 高度の動脈硬化, Homocystinuria, 妊娠, Factor XII欠損症, 心筋 塞の報告もあり – CF 30名, CF+CG 19名を比較 (Clin Exp Immunol 2000;120:253-60) • 2次性はCF + CG群で有意に多い(47% vs 79%) • 皮膚病変はCF群に多く, 77% vs 58% • 静脈, 動脈血栓もCF群に多い. 13% vs 3%
  46. 46. CFの症状 • 健常人の2-9%に無症候性CFを認める – 無症候性CFでは血中のCF < 50mg/Lであることが多い 症候性CFでは血中CF > 1g/dLとなる – 出血症状も認める. CF量が多いほどRiskも高くなる – 出血 + 塞の合併は5%で認める (J Lab Clin Med 1963;61:203-10) 症状(UpToDate 16.3) 頻度 Cold Sensitivity 50-80% 有痛性潰瘍 45-50% 紫斑 25-30% Livedo 25-30% 蕁麻疹 5-15% Raynaud現象 15% Segmental swelling 5-15% 下肢の結節 5-10% 静脈血栓症 5-10% 動脈血栓症 3-5% 関節痛 5-10%
  47. 47. • 60名のCryofibrinogenemia患者で症状を評価 – 515名のCryofibrinogen(+)患者中, 455名にCryoglobulin(+) – Cryofibrinogen(+), Gryoglobulin(-)の60名を評価したStudy (The Am J of Med 2009;122:1128-35) – 60名中36名(60%)がEssential CF, 24名(40%)がSecondary CF – 症状頻度; 初発症状 Essential Secondary Total Skin lesion 80.5% 54.1% 70.0% – Essential, Secondary間で 関節痛 11.1% 16.6% 13.3% 血栓症 11.1% 25.0% 16.6% Nervous lesion 8.3% 8.3% 8.3% 症状頻度 Essential Secondary Total 紫斑 66.6% 16.6% 46.6% Skin necrosis 44.4% 25.0% 36.6% Livedo 25% 16.6% 25.0% Raynaud現象 16.6% 20.8% 18.3% 蕁麻疹 11.1% 4.1 8.3% 寒冷過敏 52.7% 20.8 40.0% 症状, 合併症, 予後に有意差無し Secondaryの原因 膠原病 10(33.3%) 悪性腫瘍/血液 5(16.7%)  SLE 5  Non-Hodgkin 3  抗リン脂質抗体 2 1  Mycosis fungoid 1 1  多発筋炎  Colorectal Ca  SSc 1 1 血管炎 6(20%) 感染症 3(10%)  Buerger病 2  結核 1 関節痛 25.0 41.6 31.6%  HSP  Streptococcus 1 1 末梢神経症 8.3 4.1 6.6%  Giant cell arteritis 2 1 腎障害 5.5 25.0 13.3%  Behcet病 1 血栓症 55.5 25.0 43.3%  Crohn病  Herpes virus
  48. 48. Cryofibrinogenの検査 • 血漿成分のみで寒冷凝集素が存在する病態 – Cryofibrinogenの検出は条件が重要であり, 採血, 保存を37度以下で行うと寒冷凝集が起こり, 偽陰性となる 抗凝固剤としてヘパリンを用いると, Fibrinと凝固を来し, 偽陽性となる – 抗凝固剤としては, EDTAを用いることが推奨される • α1-Antitrypsin, α2-macroglobulinの上昇も認める
  49. 49. CFの治療 • Streptokinase – 25000-200000 U IV q24hr – 50000-80000 U PO • Stanozolol; 2-4mg PO bid • Steroid単剤療法は確立されていない – Prednisone(60mg/d) + Azathioprine(150mg/d)(イムラン®, アザニン®) – Prednisone(10mg/d) + Chlorambucil(4mg/d)(未承認)

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