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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. 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. 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. 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. 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. •
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. •
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. 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

23. 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.

24. 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

25. 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

26. 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

27. 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

28. • 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

29. 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)

30. 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

31. 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)

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. (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.

41. 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.

42. • 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

43. • 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

44. 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

45. 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)

46. 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%

47. 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%

48. • 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

49. 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

50. 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)