Cryoglobulinemic Vasculitis
Pr David Saadoun
Department of Internal Medicine and clinical Immunology
National reference centre for Autoimmune systemic diseases
Hôpital La Pitié-Salpêtrière, Sorbonne University, Paris, FRANCE
Disclosures
Consulting, research grant and lecturing fees from Abbvie, Amgen, Sanofi, Roche-Chugai, Celltrion, Hifibio, Novartis, Janssen and Glaxo Smith Kline.
Cryoglobulinemia: Clinical spectrum
Jennette JC et al Arthritis 2013
Vasculitides classification
4
Cacoub P & Saadoun D NEJM 2024
5
Etiologies of Cryoglobulinemia vasculitis
G. Boleto et al Seminars in Arthritis and Rheumatism 2020
6
Cacoub P & Saadoun D NEJM 2024
7
Cacoub P & Saadoun D NEJM 2024
8
Skin Manifestations of Cryoglobulinemia Vasculitis
9
Mononeuropathy�Multiplex 20%
Cacoub P et al AIDS 2005
Distal Polyneuropathy 80%
Neurological manifestations of Cryoglobulinemia Vasculitis
Renal pathology in cryoglobulinaemic vasculitis
a | Extracapillary proliferation in the kidney, with features of fibrinoid necrosis (arrow) and interruption of the capsule.
b | Membranoproliferative pattern with double contour appearance of the glomerular basement membrane (arrow).
c | Periodic acid–Schiff (PAS)-positive endoluminal pseudothrombi (corresponding to cryoglobulin precipitates) (arrow).
d | PAS stain shows diffuse membranoproliferative glomerulonephritis.
11
Cardiac Involvement
CNS Vasculitis
GI vasculitis
Saadoun et al A&R 2010; Casato et al J Hepatol 2004; Terrier et al Am J Cardiol 2013
Life threatening Manifestations of Cryoglobulinemia Vasculitis
Cryoglobulinemia: Monoclonal (type I) vs mixed (type II/III)
| Type I | Mixed cryoglobulinemia (type II/III) |
Clinical findings | | |
Purpura | 70% | 90% |
Skin ulcers | 30% | 15% |
Cold induced symptoms | Frequent | Rare |
Hyperviscosity syndrome | Occasionally (IgM>4g/dL) | Rarely |
Laboratory findings | | |
CG composition | mIgG or IgM | Type II (mIgMk) |
Cryocrit | 5-50% | <5% |
Low C4/RF activity | Occasionally | Frequent |
Histopathology | Vascular obstruction/thrombosis | Vasculitis |
Adapted from Muchtar et al Blood 2017
Cryoglobulinemia: Differential diagnosis
���Cryoglobulinemia: Differential diagnosis��
Cryofibrinogenemia
Saadoun et al Am J Med 2009
17
Cryofibrinogenemia vs cryoglobulinemia
Saadoun et al Am J Med 2009
18
61 yrs old patient, mIgG k (« MGUS »)
purpura, renal artery thrombosis
Leung et al, NDT 2009
Crystal-cryoglobulin
19
Cryoglobulinemia: Prognosis
Dammaco et al NEJM 2013
Natural history of Cryoglobulinemia
| HCV- | HCV+ |
| | |
Survival | | |
1-year | 91 % | 96% |
2-year | 89 % | 90% |
5-year | 79 % | 75% |
10-year | 65% | 63% |
| | |
Prognostic factors of survival in Cryoglobulinemia Vasculitis
HCV cryoVas
Liver fibrosis
Vasculitis severity
Use of immunosuppressants
Antiviral therapy
Non-HCV cryoVas
Age >60 yrs
Renal involvement
Saadoun et al JAMA internal Med 2006; Terrier et al A&R 2011
22
Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN
Prognostic significance of pts characteristics for renal outcome
Zaidan et al JASN 2016
Cryoglobulinemia: Pathogenesis
Mechanisms of HCV-related cryoglobulinaemia vasculitis
Roccatello D et al Nat. Rev. Dis. Primers 2018
Cryoglobulinemia: Treatment
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunomodulation
Chemotherapy
Plasma exchange
Steroids
27
Correlation between virological and clinical response in Cryovas
Adapted from Vassilopoulos, D. & Calabrese L. H. (2012) Nat. Rev. Rheumatol.
Sustained virological response
| PegIFN-RBV-PI1 | SOF-RBV2 | SOF-DACLA3 |
| N=30 | N=24 | N=40 |
Complete clinical response At Week 12 At end of therapy (W24) | 46.6% 66.7% | 71% 87.5% | 90.2% 90.2% |
Virological response At week 12 After end of therapy (W36) | 73.9% 66.6% | 92% 74% | 100% 100% |
Clearance of cryoglobulin (W24) | 22.2% | 41.6% | 50% |
Serious adverse event | 46.6% | 8% | 0% |
Steroids and/or Rituximab use | 43% | 16% | 4.8% |
Cryovas: Anti HCV therapy
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunomodulation
Chemotherapy
Plasma exchange
Steroids
30
NATURAL INTERFERON-α VERSUS ITS COMBINATION WITH 6-METHYL-PREDNISOLONE IN THE THERAPY OF TYPE II MIXED CRYOGLOBULINEMIA:
A LONG-TERM, RANDOMIZED, CONTROLLED STUDY
Dammacco F et al, Blood 84: 3336-3343, 1994.
GROUP 1
(15 Pts)
IFN-α: 3 mu s.c. THREE TIMES A WEEK
GROUP 2
(18 Pts)
6-METHYL-PREDNISOLONE (PDN): 16 mg/d
GROUP 3
(17 Pts)
IFN-α: 3 mu s.c. THREE TIMES A WEEK
PLUS
PDN: 16 mg IN THE DAYS FREE FROM IFN THERAPY
31
MONTHS OF TREATMENT
0
10
20
30
40
50
60
70
1
2
3
4
5
6
7
8
9
10
11
12
Complete remission (%)
6.7
CONTROLS (n=15)
IFNa + Medrol (16mg/d) (n=17)
52.9
IFNa (n=15)
53.3
Medrol (16mg/d) (n=18)
16.7
13
Randomized controlled trial in HCV-Cryovas
Dammaco et al Blood 1994
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunomodulation
Chemotherapy
Plasma exchange
Steroids
Evidence-based recommendations on the management of Cryovas
Ramos Cazals et al Journal of Hepatology 2017
Level of evidence: 3
Level of agreement: 9.42/10
Strength of recommendation: C
Plasma exchange may be added to other therapies, especially in patients with severe/ life-threatening cryoglobulinemic vasculitis
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
Immuno-modulators
Rituximab
Arm A: 12 HCV CryoVas patients
Rituximab (375 mg/ m2/week for 4 weeks)
D0
W4
W12
W24
W48
Inclusion
Randomization
Primary study
Endpoint*
End of study
visit
Visits
Arm B: 12 HCV CryoVas patients
Best available therapy (Plex, Steroids, MTX) for 24 weeks
Patients in whom antiviral therapy had failed to induce remission �
*Remission at W24 was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0
Sneller et al Arthritis & Rheum 2012
36
Arm A: 12 HCV CryoVas patients
Rituximab (375 mg/ m2/week for 4 weeks)
D0
W4
W12
W24
W48
Inclusion
Randomization
Primary study
Endpoint*
End of study
visit
Visits
Arm B: 12 HCV CryoVas patients
Best available therapy (Plex, Steroids, MTX) for 24 weeks
Patients in whom antiviral therapy had failed to induce remission �
10 (83%) patients in the rituximab group vs 1(8%) in the control group were in remission at 6 months
a result that met the criterion for stopping the study (P < 0.001).
Sneller et al Arthritis & Rheum 2012
37
Sneller et al Arthritis & Rheum 2012
The median duration of remission for rituximab-treated patients who reached the primary end point was 7 months.
38
Arm A: 28 CryoVas patients (25HCV)
Rituximab (1g at day 1 and 15) #
D0
W4
W12
W24
W48
Inclusion
Randomization
Primary study
Endpoint*
Arm B: 29 CryoVas patients (28 HCV)
Non Rituximab therapy (Plex, Steroids, CYC or Aza) for 48 weeks
Severe CRyoVas: skin ulcers, neuropathy, glomerulonephritis�
*Survival of treatment at 12 months
De Vita et al Arthritis & Rheum 2012
# 2nd course of RTX if relapse
W96
39
The median duration of response to RTX was 18 months
De Vita et al Arthritis & Rheum 2012
40
Cryoglobulinemia: Treatment Safety
Factors associated with flare of Cryovas
Sene et al Arthritis & Rheum 2009; Desbois et al J Rheumatol 2020
Delay RTX to Cryovas flare: 24h to 9 days
<30min
Day 7
42
Cryoglobulinemia: Treatment of relapsing cryovas
43
Variables | Low dose RTX (N=48) | Standard dose RTX (N=208)* |
Clinical response | | |
Overall response | 81% | 86% |
CR | 50% | _ |
Immunological response | | |
CR | 44% | 41% |
PR | 10% | 21% |
Relapse rate (Month 12) | | |
Relapsers | 41% | 32% |
Median time to relapse | 6 (4-12) | 7 (4-12) |
Side effects | | |
Total nbr AE | 11.5% | 19.9% |
SAE | 1.9% | 5.9% |
M. Visentini et al. Autoimmunity Reviews 14 (2015) 889–896
Low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis
Phase 2, single-arm two-stage trial of low-dose rituximab (250 mg/m² × 2) in 52 patients with HCV-associated Cryovas who were non-responder to antiviral therapy
* Pooled data from literature
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunomodulation
Chemotherapy
Plasma exchange
Steroids
45
Saadoun et al ACR 2013
RTX 375 mg/m2 day 1, Fludarabine 40 mg/m² day 2-4, and CYC 250 mg/m² days 2-4,
every 4 weeks, for 3 to 6 cycles
46
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
HCV eradication
Immunomodulation
Plasma exchange
Steroids
47
Arm A: 24 patients
Belimumab 200mg/week SC for 24 weeks
D0
W4
W12
W24
W48
Inclusion
Randomization
Primary study
Endpoint*
End of study
visit
30mg/d
0
Prednisone (mg/day)
Arm B: 24 patients
Placebo of Belimumab 200mg/week SC for 24 weeks
Induction therapy
with Rituximab IV
whithin 6 weeks
�
*Complete clinical response rate of vasculitis symptoms at W24 with corticosteroid withdrawal (prednisone at 0 mg/day) at W12�
Multicenter randomized double-blind study comparing
RTX plus belimumab vs RTX + placebo of belimumab in non-infectious Cryovas
TRIBECA STUDY
Multicenter phase 2 single-arm proof-of-concept trial assessing the efficacy and safety of Obinutuzumab in the treatment of non-infectious active CryoVas refractory or intolerant to Rituximab��� CRYOBI STUDY
Primary endpoint: Complete remission of CryoVas at 6 months with corticosteroid withdrawal in at least 50 % of patients
Chronic HCV infection
Poly- oligoclonal
B-cell expansion
Autoantibodies
RF - IC
Mixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cell
proliferation
Overt lymphoma
Immuno-modulators
Low dose IL2
50
Reversible Quantitative Deficit in Treg Lymphocytes in HCV-Cryo Vasculitis
CD25high (% of CD4+)
4
4
5
6
Before treat.
On Treat.
Early F/U
Late F/U.
**†
**†
-CR
-NR/PR
After Treat.
A
0
20
40
60
80
100
0
1
2
3
CD
25
high
(
cells
/
μ
l)
Cryoglobulins (
g/l
)
R
²
-
0
.
1
, p<
0
.
005
0
20
40
60
80
100
0.0
0.2
0.4
CD
25
high
(
cells
/
μ
l)
C
4
(
g/l
)
R
²
-
0
.
16
, p<
0
.
005
Saadoun, Blood 2004. Landau Arthritis Rheum 2008
51
Saadoun et al., NEJM 2011
52
Therapeutic strategies in mixed cryoglobulinemia
Mild disease
(Purpura, arthralgia,
mild neuropathy)
Life threatening
(Rapidly progressive GN,
cardiac, digestive vasculitis)
Rituximab & steroids
± plasmapheresis
± belimumab
Steroids, plasmapheresis,
Rituximab ± CYC
or bendamustin
Low dose steroids
Colchicine
Treatment of underlying diseases
(HCV, NHL..)
Severe disease
(Active renal disease,
Mononeuritis multiplex, skin necrosis)
53
Cryoglobulinemia: Monoclonal (type I) vs mixed cryovas
54
| Type I | Mixed cryoglobulinemia (type II/III) |
Therapeutical findings | | |
Avoidance of cold | Frequent | Rarely |
PLEX | Frequent | Occasionnally |
Underlying disease | MGUS, MM, WM, CLL, B-NHL (rarely) | AID (pSS, SLE..), HCV, B-NHL, essential |
| Targeted treatment based on mIgM or IgG | Rituximab based therapy |
Adapted from Muchtar et al Blood 2017
Isatuximab in type I cryoglobulinemia: A prospective pilot study
ICE (Isatuximab CryoglobulinEmia) STUDY
Phase 2 pilot prospective study of 21 patients with type I cryoglobulinemia treated by Isatuximab
*Complete clinical response rate of cryoglobulinemia vasculitis symptoms at week 20
*
Active type I IgG cryovas
Therapeutic strategies in type I cryoglobulinemia
m IgM cryo
B cell targeted TT
m IgG or IgA cryo
Plasma cell targeted TT
Bortezomib
or IMIDs (Lenalidomide..)
or Anti CD38
± plasmapheresis,
± autologous stem cell transplantation
or other Myeloma therapy
Avoid cold exposure++
Rituximab
± Bendamustin or CYC
± Plasmapheresis
or other CLL/B NHL therapy
Avoid cold exposure++
Treatment of underlying diseases
(Myeloma, CLL, NHL..)
57