Table 3.
Summary of study characteristics on risk factors for relapse in type 2 & 3 mixed cryoglobulinemia.
| Type 2 & 3 Mixed cryoglobulinemia | ||||||||
|---|---|---|---|---|---|---|---|---|
| Study *only NICV sample |
Aetiology | Clinical manifestations | Immunological features | Intervention with follow up duration (months) |
Clinical response |
Immunological response | Treatment-associated adverse events | Outcome |
| Zaja 2003 (*n = 3) |
pSS 33.3% *
EMC 66.6% * |
Cutaneous 100% Articular 75% Neuropathy100% |
CG 156–1,500 mg/dl IgM 1.2 14 g/L Low C4 2 mg/dl RF 79 526 IU/ml |
CS + RTX Follow up 9–31 months |
Yes | Yes | Mixed cohort | Relapse 33%; Malignancy developed in 66.6 % |
| Cruz 2006 (n = 9) |
EMC 56% MGUS 11% CTD 33% (SS, MCTD) |
Cutaneous 89% Articular 100% Neuropathy 67% Nephropathy 44% |
Low CG Low C4 |
CS + AZA 56% CS + CYC 11% ± RTX/ MTX Follow up 19.3 ± 14 months |
CR 44% PR 56% |
Not described | Not described | Relapse 22%; Progressive PAH due to underlying MCTD in one patient |
| Saadoun 2006 (*n = 116) |
CTD 34% HM 26% EMC 27% |
Cutaneous 56% Articular 28% Neuropathy 8% Nephropathy 32% |
CG: CTD/HM 1.2 ± 1.6; EMC 0.9 ± 1.7 Type 2 MC 82% Low C4 68.4% RF 58% |
CS ± CYC/AZA, PLEX Mean follow up 49.4 ± 41.6 months |
Noted in 25% | Not described | Not described | Relapse 52%; 4-6-fold increased risk B-cell NHL; Death 20% |
| Matignon 2009 (n = 20) |
pSS 45% BCL 5% EMC 50% |
Cutaneous 80% Articular 35% Neuropathy 30% Nephropathy 85-100% |
MG 85% Low C4 95% Low C3 30% RF+ 85% |
CS ± CYC/AZA/fludarabine/ chloraminophene/ anti-CD20/ IFN Follow up 3–264 months |
Noted in 65% | Noted in 20% | Not described | Renal relapse 35%; Extrarenal relapse 25%; Death 40% |
| Terrier 2010 (n = 23) |
pSS 39% BCL 35% EMC 35% |
Cutaneous 83% Articular 35% Neuropathy 52% Nephropathy 30% |
CG 0.77 g/L Type II monoclonal IgMκ 74% Low C4 0.04 |
RTX ± CS/CYC/MMF/AZA/MTX/PLEX Follow up 6 months |
CR 73% PR 13% |
CR 50% PR 38% NR 13% |
Severe infections 26%; Infusion-related reactions 48% |
Relapse 55%; Death 13% |
| Foessel 2011 (*n = 31) |
AID 42% LM 12% EMC 39% Infectious (HepB/ Parvo B19) 6% |
Cutaneous 90% Neuropathy 45% Nephropathy 36% |
CG EMC 2.8 ± 3.1 g/l AID 2.5 ± 2.9 g/l Low C4 100% RF 80%–100% |
CS ± RTX/AZA/ CYC/MMF/MTX/IFN/Lenalidomide Median follow up 67.2 (3–240 months) |
Yes | Yes | 27.6% in the non-malignant cohort | Relapse during CS taper 100%; Disease flare after RTX 6% |
| Terrier 2012 & 2013 (n = 242) |
EMC 48% CTD 31% HM 21% |
Cutaneous 83% Articular 40% Neuropathy 52% Nephropathy 35% GI 5% CNS 2% Pulmonary 2% |
CG 0.94 ± 1.61 g/L C4 0.07 ± 0.09 C3 0.86 ± 0.31 |
CS 100% AKA 38% RTX 35% PLEX 17% AZA/MMF 12% Mean follow up 51 ± 54 months |
Yes | Yes | Severe infections (23%) in older age >60 years, renal failure, high dose CS | Death 17% |
| Terrier 2014 (n = 145) |
EMC 38% CTD 36% HM 26% |
Cutaneous 87% Articular 42% Neuropathy 55% Nephropathy 35% |
CG 0.75 ± 1.14 g/L C4 0.06 ± 0.07 C3 0.84 ± 0.33 |
CS/CS + CYC/ CS + RTX/PLEX Mean follow up 65 ± 54 months |
Noted in 70% (n = 73) Relapse with CR 50% (n = 20) |
Noted in 36% (n = 31/86) Relapse with complete IR 4% (1/28) |
Not described | Relapse within 12 months 28%; Median time to relapse 9.5 months (3-12) after induction |
| Bryce 2016 (*n = 6) |
LPD 66.6% SS+MALT Lymphoma 33.3% EMC 16% GD 16% |
Cutaneous 37-75% Nephropathy 37% |
Cryocrit 13 % C4 <3 mg/dl RF 56-580 IU/ml |
RTX ± R-CHOP/CLB/ CS/PLEX Median follow up 2.3 years ± 2.4 years |
Yes | Yes | None | Death 25% |
| Zaidan 2016 (n = 230) |
pSS 22.5% LPD 28.7% EMC 48.8% |
Cutaneous 71.3% Articular 28.7% Neuropathy 42.5% GI 11.3% Pulmonary 5% |
Type II MC 84% Low C4 45% Low C3 + C4 18% |
CS alone 27.6% RTX + CS 21.1% CYC + CS 36.8% CYC + RTX + CS 10.5% Mean follow up 49.9 ± 45.5 months |
Noted in 60% | Noted in 31.3% | RTX + CS severe infections 29.1%, BCL/WM 8.9%, Increased early mortality when used first line |
Relapse 42.7% with renal flare 75%; Death 24% |
| Colantuono 2017 (*n = 2) |
EMC 5% | Cutaneous 89% Neuropathy 78% Nephropathy 41% |
Not described | RTX ± retreatment | Yes | Yes | Infusion-related reactions and infection | Relapse 100% |
| Marson 2018 (*n = 42) |
Not described | Cutaneous 47.8% Neuropathy 54.7% Nephropathy 27% |
Pre-apheresis serum CG > 0.5mg/dL or Cryocrit> 0.5% |
AT± RTX/CYC/AZA/IV Ig/IV prostanoids/colchicine | Yes | Not described | None | Unable to segregate |
| Lesniak 2021 (n = 3) |
EMC 67% CTD 33% |
Cutaneous 100% Articular 100% Neuropathy 100% GI 100% |
CG 3.5 ± 1.7g/L Low IgG 319 ± 73mg/dl |
RTX ± CS/MMF | Yes | Yes | Infectious pneumonia 67% | Relapse 100% |
| Fenoglio 2022 (#n = 8) |
EMC 54.5% | Cutaneous 40% Neuropathy 80% Nephropathy100% |
Mean Cryocrit 2.5% C4 4.9 C3 71 RF 467 |
RTX Mean follow up 38.4 (6–144 months) |
Yes | Yes | RTX infusion-related severe reaction with anti-RTX antibodies and infection 12% | Relapse 37 %; Death due to atherosclerosis 37% |
| Pouchelon 2022 (n = 26) |
AID 51% HM 12% EMC 42% |
Cutaneous 81% Articular 48% Neuropathy 60% Nephropathy 39% GI 6% |
CG 0.54g/L Cryocrit 7.9% Low C4 88% Low C3 25% RF+ 85% |
GC/RTX/AKA/belimumab Mean follow up 26 months (IQR 8–38) |
Noted in 20%–86% | Noted in <50% | Severe infections with PLEX, anti-CD20 + Belimumab | Not reported |
| Roubertou 2022 (*n = 21) |
SLE 100% | Cutaneous 15-49% Articular 92-93% Neuropathy 12-15% Nephropathy 38-45% |
Type III CG 80% Hypergamma- globulinemia 76% Mean Cryoprecipitate 31.1mg/L (8.6-81.8) Low C4 90% Low C3 81% Decreased CH50 81% RF 0% |
CS/RTX/AZA/ MTX/CYC Mean follow up 13.2 (±8.9) years |
Noted in 92% | Lack of correlation |
Cytopenia and drug-induced hepatitis 23% | Relapse 3% |
| De Vita 2012 (*n = 4) |
HCV-unrelated 7% (93% HCV+ in total sample n=57) | Cutaneous 12% Neuropathy 58% Nephropathy 30% |
C4 6.62 ± 8.05 mg/dL RF 528.55 ± 840.12iU/ml |
GC + RTX GC + AZA/CYC/PLEX Follow up 24 months |
Noted in 25% | Yes | Infections, cardiovascular events & hemorrhagic alveolitis 26% | Relapse within 12 - 18 months in RTX switch group/ RTX; Death 11% |
| Desbois 2020 (*n = 1) |
Infectious (HCV) 86% EMC 14% |
Cutaneous 100% Neuropathy 86% GI 29% |
Median CG 1.35g/L RF + |
CS + RTX ± PLEX |
Not described | Not described | Not described | Relapse of flare 8 days (2-16 days); Death 57% after median of 3.3 months |
| Argyropoulou 2020 (n = 71) |
pSS 100% (NHL - MALT 48%) |
Cutaneous 90% Articular 71.8% Neuropathy 25% Nephropathy 11% |
Type II CG 97% Monoclonal gammopathy in 45.5% Low C4 88.6 RF + 95.7% |
CS/Hydroxychloroquine/AZA/MTX/CYC/RTX/PLEX | Not described | Not described | Not described | Lymphoma 33% within 5 years CV onset |
| Michaud 2015 (n = 29) |
CTD 28% SS 17% Systemic sclerosis 7% SLE 3% |
Cutaneous 94% Nephropathy 39% |
Cryofibrinogen 62% (70 ± 174 mg/L) CG 89 ± 124 Low C4 50% Low C3 28% |
CS/RTX/CYC/RTX + CYC/AZA/MTX/PLEX | Not described | Not described | Not described | Cryofibrinogenemia is associated with severe phenotype CV and malignancy |
| Retamozo 2016 (*n = 21) |
pSS 100% | Cutaneous 100% Articular 76.2% Neuropathy 71.4% |
Cryocrit 6.58 Low C4 95.2% Low C3 55% RF + 85.7% Monoclonal gammopathy 68.4% |
Not included Median follow up 128.4 months |
Not described | Not described | Not described | Death 6% at mean follow- up 110.5 months; Developed BCL 9% |
| Galli 2017 (*n = 160) |
EMC 43% CTD 46.8% HM 3% |
Cutaneous 62% Articular 77% Neuropathy 45% Nephropathy 32% |
Cryocrit 2 %(0.5 - 4%) Median C4 4 (2-12 mg/dL) Median RF 109 (20 – 372) |
Not included | Not described | Not described | Not described | Shorter treatment exposure influencing persistence of CG in sera |
| Boleto 2020 (*n = 266) |
SLE 28.9%, pSS 10.7% NHL 5.4%, WM 4 % EMC 23.8% |
Cutaneous 54.7% Articular 10.1% Neuropathy 49.6% Nephropathy 21.6% |
Monoclonal Ig 5.3g/L Median C4 0.16g/ L RF 20.8 UI/mL |
Not included | Not described | Not described | Not described | Not reported |
*Cohort isolated from ICV; # Inclusive of type I; AE, adverse event; AID, autoimmune disease; AKA, alkylating agents; ASCT, autologous stem cell transplant; AT, apheresis therapy; AZA, azathioprine; BCL, B-cell lymphoma; CNS, central nervous system; CR, complete response; CS, corticosteroids; CTD, connective tissue disease; CG, cryoglobulins; CH50, complement total; CLB, chlorambucil; CV, cryoglobulinemia vasculitis; CYC, cyclophosphamide; EMC, essential mixed cryoglobulinemia; GC, glucocorticoids; GD, Gaucher’s disease; GI, gastrointestinal; HCV, hepatitis C virus; HM, hematological malignancy; IFN, interferon; Ig, immunoglobulins; IR, immunological response; IV, intravenous; LM, lymphoid malignancy; LPD, lymphoproliferative disorders; MC, mixed cryoglobulinemia; MCTD, mixed connective tissue disease; MG, monoclonal gammopathy; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MMF, mycophenolate mofetil; MTX, methotrexate; NHL, non-Hodgkin's lymphoma; NR, no responders; PAH, pulmonary arterial hypertension; PLEX, plasmapheresis; PNS, peripheral nervous system; PR, partial response; RF, rheumatoid factor; RTX, rituximab; SAE, severe adverse events; SLE, systemic lupus erythematosus; SS, Sjögrens syndrome; pSS, primary Sjögrens syndrome; PR, partial response; WM, Waldenström macroglobulinemia.