Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). Treatment is based on persistent viral clearance.
First Author, Year, Ref. | |||
---|---|---|---|
Boglione et al. 2015 [28] | Mazzaro et al. 2016 [29] | Li et al. (2017) [30] |
No. of Patients | 18 | ||
Female/Male | 10/8 | ||
Age/Years, Median (range) | 59 (33–81) | ||
Biochemical and Virological Features | |||
HBV-DNA positive, n (%) | 18 (100) | ||
HBV-DNA IU/mL, median | 6630 | ||
MC type II/type III | 17/1 | ||
Cryocrit %, median (range) | 4 (1–70) | ||
RF IU/mL, median (range) | 181 (10–5850) | ||
C4 mg/dl, median (range) | 9 (2–31) | ||
ALT IU/mL, median (range) | 51 (21–638) | ||
Creatinine mg/dl, median (range) | 1.0 (0.6–1.3) | ||
Clinical Features | |||
Purpura, n (%) | 18 (100) | ||
Arthralgias, n (%) | 11 (61) | ||
Skin Ulcers, n (%) | 3 (17) | ||
Sjögren’s syndrome, n (%) | 5 (28) | ||
Peripheral neuropathy, n (%) | 11 (61) | ||
Glomerulonephritis, n (%) | 1 (6) | ||
NHL | 2 (11) | ||
Chronic hepatitis, n (%) | 4 (22) | ||
Cirrhosis, n (%) | 1 (6) | ||
Antiviral Agent, n, Median Duration (months) | |||
Entecavir | 11 (78) | ||
Tenofovir | 6 (67) | ||
Lamivudine | 1 (58) | ||
Other treatment, n, Median Duration (months) | |||
Peg-IFN alone | 3 (17) | ||
CS-associated NAs | 4 (22) | ||
PE-associated NAs | 4 (22) | ||
RTX-associated NAs | 2 (11) | ||
Virological Response, n (%) | 18 (100) | ||
Cryocrit %, median (range) | 1 (0–14) | ||
RF IU/mL, median (range) | 181 (10–5850) | ||
C4 mg/dl, median (range) | 7 (1–24) | ||
ALT IU/mL, median (range) | 16 (12–34) | ||
Cryoglobulinemic Vasculitis Complete Response | |||
Purpura, n (%) | 14 (78) | ||
Arthralgia, n (%) | 8 (44) | ||
Skin Ulcers, n (%) | 2 (11) | ||
Sjögren’ssyndrome, n (%) | 2 (11) | ||
Peripheral neuropathy, n (%) | 6 (33) | ||
Cryoglobulinemic Vasculitis Partial Response | |||
Purpura, n (%) | 4 (22) | ||
Arthralgia, n (%) | 3 (17) | ||
Peripheral neuropathy, n (%) | 5 (28) | ||
Glomerulonephritis, n (%) | 1 (6) | ||
NHL | 2 (11) | ||
Number of Patients | 7 | 17 | 12 |
Female/male | ¾ | 10/7 | 4/8 |
Age/years, median (range) | 60 (49–65) | 56 (45–70) | 47(29–68) |
Clinical Features | |||
Purpura, n (%) | 3 (43) | 17 (100) | 7 (58) |
Arthralgias, n (%) | 0 | 12 (71) | 3 (25) |
Raynaud’s phenomenon, n (%) | 0 | 3 (14) | 0 |
Sicca Syndrome, n (%) | 0 | 2 (9) | 0 |
Skin Ulcers, n (%) | 2 (29) | 1 (6) | 0 |
Peripheral neuropathy, n (%) | 4 (57) | 5 (29) | 2 (17) |
Glomerulonephritis, n (%) | 0 | 3 (18) | 12 (100) |
Gastrointestinal vasculitis, n (%) | 0 | 0 | 2 (17) |
Chronic hepatitis, n (%) | NA | 8 (47) | NA |
Cirrhosis, n (%) | NA | 5 (29) | NA |
Biochemical and Virological Features | |||
MC type II/type III | NA | 15/2 | 3/9 |
Cryocrit %, median (range) | 3.4 (2.5–6) | 3 (1–14) | NA |
Rheumatoid Factor IU/mL, median (range) | NA | 119 (88–5850) | 694 (67–2730) |
C4 mg/dl, median (range) | NA | 8.0 (4–31) | 6.0 |
ALT IU/mL, median (range) | 79 (68–105) | 71 (39–82) | 44 (10–102) |
Creatinine mg/dl, median (range) | NA | 1.0 (0.7–1.2) | 2.8 (0.0–9.8) |
HBV-DNA positive, n (%) | 7 (100) | 17 (100) | 12 (100) |
HBsAg positive, n (%) | 7 (100) | 17 (100) | 10 (83) |
Author, Year | Pts n. | Antiviral Agent, Dose Duration, Weeks (w), (n) | Other Treatment, (n) | Negative HBV-DNA |
Laboratory Features |
Clinical Manifestations, (n) | Immune Response/ ALT Response |
Cryoglobulinemic Vasculitis Response,(n) |
---|---|---|---|---|---|---|---|---|
Before Treatment | After Treatment | |||||||
Cakir et al. 2006 [35] | 1 | Lamivudine 100 mg/day = 76 w; Adefovir 10 mg/day = 108 w | 100% | Cryocrit: Pos; RF:1110; C4:7; ALT: 125; | Purpura, Fatigue, Arthralgia, Cirrhosis | Cryocrit: Neg RF: normal ALT: normal |
CR: Purpura; Fatigue Arthralgias; | |
Kawakami et al. 2008 [36] | 1 | Entecavir 0.5 mg/day | 100% | Cryocrit: Pos | Purpura, Neuropathy, | Cryocrit: Neg | CR: purpura, Neuropathy | |
Enomoto et al. 2008 [37] | 1 | Entecavir 0.5 mg/day = 20 w | 100% | Cryocrit: Pos | Purpura, Chronic hepatitis | Ccryocrit: Neg ALT: normal |
CR: Purpura | |
Conca et al. 2009 [38] | 1 | Lamivudine 100mg/day = 4 w; Lamivudine 50 mg/day = 232 w | 100% | Cryocrit: 7; RF: 876; C4:0.4; ALT:247 | Purpura, Cirrhosis | Cryocrit: Neg ALT: normal |
CR: Purpura | |
D’Amico et al. 2013 [39] | 2 | Tenofovir 245 mg/day = 200 w, (1); Entecavir 0.5 mg/day = 204 w, (1) | 100% | Type III; Cryocrit: Pos; RF: Pos; C4:Pos | Purpura, (2); Neuropathy, (2); Chronic hepatitis,(2); | Cryocrit: Neg(2) RF: normal (2) C4: normal (2) ALT: normal (2) |
CR: Purpura, (2); NR: Neuropathy, (2) |
|
Boglione et al. 2013 [28] | 7 | Telbivudine 600 mg/day = 48 w, (7) | 100% | Cryocrit: 3.4; ALT: 79 | Purpura, (3); neuropathy, (4); Skin ulcer, (2); Chronic hepatitis, (7) | Cryocrit: 1% (0-2) ALT median: 33 (22–44) | CR: Purpura,(3); Neuropathy, (2); NR: Peripheral neuropathy, (2); Skin ulcer, (2) |
|
Viganò et al. 2014 [40] | 1 | Entecavir 0.5 mg/72 h = 108 w | 100% | Cryocrit: 3; RF: Pos; C4: 5; ALT: 178; creatinine: 3.4 mg/dl; proteinuria: 2.5 g/24 h | Purpura, Fatigue, GN, Cirrhosis | Cryocrit: Neg RF: normal C4: normal ALT: 13: Creatinine: 0.5 mg/dlproteinuria: 40 mg/day |
CR: Purpura; Fatigue; GN | |
Yamazaki et al. 2014 [41] | 1 | Entecavir 0.5 mg/day = 28 w | CS+PE, | 100% | Type II; Cryocrit: 2%; C4: 1; ALT: 4; creatinine: 4.0 mg/dl | Purpura, Skin ulcer, GN | Cryocrit: Neg | CR: Purpura, skin ulcers; NR: GN |
Terrier et al. 2015 [22] |
3 | Lamivudine 100 mg/day, (1); Entecavir 0.5 mg/day, (2); | PE+CS+RTX, (1); PE+CYC+CS+RTX, (1) | 100%2 | Type II; Cryocrit: pos; C4: 0.24 | Purpura, (2); Arthralgia, (2); GN, (3); Chronic hepatitis, (3) | Cryocrit: Neg (1) | CR: Purpura, (2); Arthralgia, (2); GN, (3); |
Visentini et al. 2016 [42] | 1 | Tenofovir 245 mg/day = 52 w | 100% | Type II; Cryocrit: pos; RF: pos; C4 low level | Purpura, Chronic hepatitis | Cryocrit: Neg RF: normal C4: low level |
CR: Purpura | |
Mazzaro et al. 2016 [29] | 7 | Entecavir nr = 192 w, (5); Adefovir nr = 48 w, (1); Lamivudine = 192 w, (1) | CS alone previous NAs, (1) | 100% | Type II, 7; Cryocrit: 3; RF: 200; C4: 8; ALT: 72 | Purpura, 7; Arthralgia, 7; Skin ulcer, 1; Chronic hepatitis, 6; Cirrhosis, 1 | Cryocrit median: 1% RF median: 86; C4 median: 10 ALT median: 20 |
CR: Purpura, (7); Arthralgia, (5); Skin Ulcer, (1); NR: Arthralgia, (2) |
Li et al. 2017 [30] | 9 | Entecavir nr = 64 w, (7); Lamivudine nr = 24 w, (2) | CS alone, 3; CS+CYC, 1; CS+PE+RTX, (1); CS+PE+MMF, (1) | 100% | Type II, 3; Type III, 6; Cryocrit: 1900 mg/L RF: 824; C4: 6; ALT: 48; Creatinine: 2.2 mg/dl; Proteinuria: 5.0 g/day | Purpura, (4); Arthralgia, (2); Neuropathy, 2; Gastrointestinal, 2; GN, 9; | Creatinine median: 1.0 mg/dl; Proteinuria median: 1.6 g/day. |
CR: Purpura, (2); Arthralgia, (2); GN, (2); Neuropathy, (2); PR: GN, (3); Gastrointestinal, (1); NR: GN, (4); Gastrointestinal, (1); |