Cryoglobulinemic vasculitis

1. Keerti Bhanushali
06/20/2014
CRYOGLOBULINEMIC VASCULITIS
AND RENAL DISEASE

2. OBJECTIVES
• Discovery of cryoglobulins, definitions and classification
• Discussion of etiology and epidemiology
• Understanding of pathogenesis of cryoglobulinemic vasculitis and role
of HCV
• Clinical features and renal involvement
• Laboratory diagnosis and reviewing histopathology
• Prognosis and Outcome
• Discussion of the management options

3. HISTORY
 Wintrobe and Buell discovered cryoglobulins in
1931 in the course of evaluating a 56-year-old
woman with anemia, Raynaud’s phenomenon, and
symptoms of hyperviscosity who ultimately turned
out to have myeloma.
 His experience helped to define the hallmark of
cryoglobulins—antibodies that precipitate under
conditions of cold and solubilize on re-warming.1
1. Wintrobe MM and Buell MV: Hyperproteinemia associated with
multiple myeloma. Bull Johns Hopkins Hosp 52: 156–165, 1933.

4. HISTORY
• The term ‘cryoglobulin’ was coined by Lerner and Watson in 1947.¹
• Precipitation of cryoglobulins is dependent on temperature, pH,
cryoglobulin concentration, and weak noncovalent factors.²
• Cryoglobulinemic disease was described in 1966 by Meltzer and
colleagues³- they reported 29 patients with cryoglobulins and a
common clinical presentation (purpura, arthralgia, and weakness),
accompanied by organ dysfunction and raised serum concentrations
of rheumatoid factor.
1. Lerner A, Watson C. Am J M Sc 1947;214:410–415.
2. Grey HM, Kohler PF. Semin Hematol 1973;10(2):87–112
3. Meltzer M, Franklin EC. Am J Med 1966; 40: 828–36.

5. DEFINITION
• Cryoglobulins - immunoglobulins that precipitate in vitro at
temperatures < 37°C and redissolve after rewarming.
• Cryoglobulinemia - refers to the presence of cryoglobulins in serum.
• Cryoglobulinemic disease or cryoglobulinemic vasculitis - used to
describe patients with symptoms related to the presence of
cryoglobulins.¹
1. Ferri C. Mixed cryoglobulinaemia. Orphanet J Rare Dis 2008; 3: 25

6. BROUET’S CLASSIFICATION
Brouet et al.1 popularized a system of classifying cryoglobulinemia on the
basis of the components of the cryoprecipitate:
• Type I: isolated monoclonal immunoglobulin, generally either IgM or
IgG.
• Type II cryoglobulins: mixture of monoclonal IgM and polyclonal IgG.
The IgM component of type II cryoglobulins has rheumatoid factor
activity (ie, these immunoglobulins bind to the Fc portion of IgG).
• Type III cryoglobulins: mixture of polyclonal IgM and IgG.¹
• Other forms of cryoglobulinemia have been reported.²
1. Brouet JC, Clauvel JP, et al. Am J Med 1974; 57:775–88.
2. Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62.

7. Fig 1: Classification of cryoglobulinaemias¹
1. Brouet JC, Clauvel JP, et al. Am J Med 1974; 57:775–88.

8. ETIOLOGY
1. Ramos-Casals M, Trejo O, et al. Mixed cryoglobulinaemia: new concepts. Lupus 2000; 9: 83–91
Table: Main causes associated with cryoglobulinemia since 1990¹

9. ETIOLOGY
Infections
• Ferri and colleagues¹ confirmed the detection of circulating HCV-RNA
in nearly 90% of Italian patients with mixed cryoglobulinemia, although
later studies found wide geographical variations.
• HCV is predominantly associated with type II cryoglobulinemia.
• HBV is reported to be associated with mixed cryoglobulinemia.²
• With HIV positive patients, the percentage with cryoglobulinemia
ranges from 7% to 17% but rises to between 35% and 64% in those
coinfected with HCV.
• Highly-active antiretroviral therapy lowers the frequency of
cryoglobulinemia in HIV.³
1.Ferri C, Greco F, et al. Clin Exp Rheumatol 1991;9: 621–24.
2.Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62.
3.Kosmas N, Kontos A, et al. J Med Virol 2006; 78: 1257–61.

10. ETIOLOGY
Auto-immune diseases
• In primary Sjögren’s syndrome, cryoglobulinemia is associated with
extraglandular involvement, an enhanced risk of B-cell lymphoma, and
poor survival.¹
• Prevalence of cryoglobulinemia is five times higher in patients with
both Sjögren’s syndrome and HCV compared with those not infected
with HCV.²
• Cryoglobulins are detected in nearly 10% of patients with systemic
lupus erythematosus and rheumatoid arthritis, but clinical
manifestations of cryoglobulinemic vasculitis are much less common.³
1.Tzioufas AG, Boumba DS, et al. Arthritis Rheum 1996; 39: 767–72.
2. Ramos-Casals M, Loustaud-Ratti V, et al. Medicine (Baltimore) 2005; 84: 81–89
3. García-Carrasco M, Ramos-Casals M, et al. Semin Arthritis Rheum 2001; 30: 366–73.

11. • Presence of cryoglobulinemia
seems to identify a particular clinical
subset of Sjogren’s syndrome,
characterized by a poor prognosis
due to more severe internal organ
involvement and frequent evolution
to malignant lymphomas.¹
• In some patients, differential
diagnosis may be very difficult;
therefore, it may be necessary to
classify these cases as
cryoglobulinemic vasculitis
Sjogren’s overlap syndrome.²
Fig 1: Overlap between primary Sjogren’s syndrome
(SS) and cryoglobulinemic vasculitis (CV)³
1. Ioannidis JPA. Vassiliou VA, et al. Arth Rheum 2002; 46:741–747.
2. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol 2002; 55: 4–13
3. Ferri and Mascia. Current Opinion in Rheumatology 2006, 18:54–63

12. ETIOLOGY
Malignancy
• B-cell lymphoproliferative diseases are the major cause of
cryoglobulinemia associated with malignancy.
• Type I cryoglobulinemia – predominant in patients with Waldenström’s
macroglobulinemia, multiple myeloma, or chronic lymphocytic
leukemia.
• Mixed cryoglobulinemias - mainly in B-cell lymphomas.¹
• Cryoglobulins can be detected in patients with solid cancers.²
1. Trejo O, Ramos-Casals M, et al. Semin Arthritis Rheum 2003; 33: 19–28.
2. Saadoun D, Sellam J, et al. Arch Intern Med 2006; 166: 2101–08.

13. ETIOLOGY
Essential cryoglobulinemia
• Nearly 10% of cases of mixed cryoglobulinemia are regarded as
idiopathic or essential
• Percentage rises to 25% in HCV-negative patients.¹
1. Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62.

14. EPIDEMIOLOGY
• The prevalence of cryoglobulinemia remains unknown.¹
• Age group: 45-65 yrs
• F to M ratio: 2-3/1
• Prevalence of HCV in patients with mixed cryoglobulinemia ranges
from 30% to nearly 100%, highest prevalence being in Mediterranean
patients.
• Conversely, between 12% and 56% of HCV infected patients have
circulating cryoglobulins, highest frequency being in Mediterranean
patients.
• Risk of mixed cryoglobulinemia is related to duration of HCV infection,
with an annual incidence of cryoglobulinemia of 3%.²
1. Trendelenburg M, Schifferli JA. Ann Rheum Dis 1998; 57: 3–5.
2. Sansonno D, Carbone A, et al. Hepatitis C virus infection, cryoglobulinaemia, and
beyond. Rheumatology (Oxford) 2007; 46: 572–78.

15. Prevalence of cryoglobulinemia in patients with chronic HCV infection¹
>40% in red,
20–40% in
green, <20% in
blue.
1. Manuel Ramos-Casals, John H Stone, et al. Lancet 2012; 379: 348–60

16. PATHOGENESIS
Immunoglobulin structure
• Structural properties of immunoglobulins influence their propensity to
form cryoglobulins.
• Murine IgG3 is the major isotype found in cryoglobulins in mice.
• IgG3 carbohydrate moieties can also influence precipitation; increased
sialylation or galactosylation can promote clearance and inhibit
cryoprecipitation of IgG3 in a murine model.¹
• Much less is known about structural features that contribute to
cryoprecipitation of human immunoglobulins, although IgG3 isotype
does appear to be over-represented in type 1 cryoglobulinemia and in
HCV-associated mixed cryoglobulinemia.²
1. Kuroda Y, Kuroki A, et al. J Immunol 2005; 175:1056– 1061.
2. Nasr SH, Markowitz GS, et al. Kidney Int 2004; 65:85–96.

17. PATHOGENESIS
Infection and autoimmunity
• Rheumatoid factor production is associated with several infections,
including viral (i.e. HBV, HCV, HIV), bacterial (i.e. subacute bacterial
endocarditis, Treponema pallidum) and parasitic (i.e. Trypanosoma
cruzi and Plasmodium spp).¹
• In most infections, rheumatoid factor production is transient, and may
function physiologically to promote more rapid clearance of immune
complexes and enhance antigen presentation to T lymphocytes.²
• In mixed cryoglobulinemia rheumatoid factor is strongly associated
with HCV infection.
• Rheumatoid factor production is also prevalent in several autoimmune
diseases, such as rheumatoid arthritis, Sjogren syndrome, SLE and
other connective tissue disorders.¹
1. Newkirk MM. Rheumatoid factors: host resistance or autoimmunity? Clin Immunol 2002; 104:1–13.
2. Roosnek E, Lanzavecchia A, et al. J Exp Med 1991; 173:487– 489.

18. PATHOGENESIS
Model of innate immunity triggered rheumatoid factor production¹
1. Alpers and Smith. Current Opinion in Nephrology and Hypertension 2008, 17:243–249

19. PATHOGENESIS
HCV and rheumatoid factor production
• HCV is a single-stranded RNA virus, and possesses a genome that
may be a ligand for TLR7 and TLR8.
• HCV-containing immune complexes may also promote rheumatoid
factor production during this chronic persistent infection in humans
through the costimulation of antigen receptors and TLRs.¹
• Another mechanism for development of cryoglobulins in HCV-infected
patients: HCV envelope protein E2 interacts with CD81, the cellular
receptor for HCV that is required for infection of hepatocytes.
• CD81 is also present on B lymphocytes and the E2–CD81 interaction
can lead to lymphoproliferation, a hallmark of mixed
cryoglobulinemia.¹
1. Rosa D, Saletti G, et al. Proc Natl Acad Sci U S A 2005; 102:18544–18549.

20. PATHOGENESIS
• HCV E2 protein is also a target of antibody responses. Monoclonal
immunoglobulins from some lymphomas from HCV-infected patients are shown
to bind E2.²
• Persistent HCV infection may stimulate B lymphocyte proliferation and
differentiation though antigen receptors and CD81, and some of the clones
may have immunoglobulins that cross-react with IgG, leading to rheumatoid
factor production.
2. Quinn ER, Chan CH, et al. Blood 2001; 98:3745–3749.

21. PATHOGENESIS
The pathogenesis of cryoglobulinemic vasculitis may include
particular hepatitis C virus (HCV) genotypes and proteins, host
factors, and possibly other unknown environmental agents.¹
1. Ferri and Mascia. Current Opinion in Rheumatology 2006, 18:54–63

22. Proposed Pathogenetic Model of Hepatitis C Virus (HCV)–Related Cryoglobulinemic
Vasculitis.
Dammacco F, Sansonno D. N Engl J Med 2013;369:1035-1045

23. PATHOGENESIS
Cryoglobulinemic glomerulonephritis
• Immune complexes containing immunoglobulins, complement and
TLR agonist activity may also promote local inflammation at the site of
immune complex deposition.¹
• One recent study demonstrated increased expression of TLR3 in
mesangial cells in HCV-associated GN.²
• Evidence obtained from the thymic stromal lymphopoietin (TSLP)
transgenic mouse model indicates that TLR4 is constitutively
expressed by podocytes and TLR4 expression is upregulated in the
setting of cryoglobulinemic MPGN.
• Correlative studies of cultured podocytes link this upregulated TLR4
expression to release of chemokines and activation of mononuclear
leukocytes that characterizes the glomerular injury of cryoglobulinemic
MPGN.³
1. Smith KD, Alpers CE. Curr Opin Nephrol Hypertens 2005; 14:396–403.
2. Wornle M, Schmid H, et al. Am J Pathol 2006; 168:370–385.
3. Astrakhan A, Omori M, Nguyen T, et al. Nat Immunol 2007; 8:522–531.

24. PATHOGENESIS
Pathogenesis of tissue injury
• Two major mechanisms are at play to varying degrees across the
different types of cryoglobulinemia:
i. cryoglobulin precipitation in the microcirculation - Vascular occlusion
is more frequent in type I cryoglobulinemia, which is usually
accompanied by high cryoglobulin concentrations, and can be
associated with hyperviscosity syndrome and cold-induced acral
necrosis.
ii. immune-complex-mediated inflammation of blood vessels - more
frequent in mixed cryoglobulinemias, particularly type II.¹
1. Sansonno D, Tucci FA, et al. J Immunol 2009; 183: 6013–20

25. CLINICAL FEATURES
• Percentage of patients with circulating cryoglobulins who develop
symptoms varies from 2% to 50%.
• The triad of purpura, arthralgia, and weakness, is reported in 80% of
patients at disease onset.¹
• Hyperviscosity syndrome - develops mainly in patients with type I
cryoglobulinemia associated with hematological neoplasia, and is
uncommon in patients with mixed cryoglobulinemia (<3%).²
• The key symptoms are neurological (headache, confusion), ocular
(blurry vision, visual loss), and rhino-otological (epistaxis, hearing
loss). Massive intratubular cryoprecipitation leading to rapidly
progressive renal failure has been reported.
• The physical examination should include funduscopy to exclude
hyperviscosity-related retinal changes, especially hemorrhages.
1. Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62.
2. Della Rossa A, Tavoni A, et al. Scand J Rheumatol 2010; 39: 167–70.

26. CLINICAL FEATURES
• Patients usually become symptomatic at viscosity measurements that
exceed 4·0 centipoise, but some patients are symptomatic with lower
viscosities.
• Symptomatic hyperviscosity requires urgent treatment (eg, plasma
exchange).¹
• Cryoglobulinemic vasculitis:
• Articular involvement (joint pain in the hands, knees, and wrists),
weakness and fatigue.
• Cutaneous purpura is probably the most characteristic manifestation
of cryoglobulinemic vasculitis (54–82%), cutaneous ulcers, digital
necrosis.²
1. Menke MN, Treon SP. Clinical malignant hematology. New York: McGraw-Hill, 2007: 937–41
2. Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62

27. 1. Ramos-Casals M, Stone J, et al. Lancet 2012; 379: 348–60

28. CLINICAL FEATURES
Renal involvement
• About 20% of patients present with nephropathy at diagnosis and 30%
have renal complications during the disease course.¹
• Renal features are indolent in nearly half the patients, with proteinuria,
microscopic hematuria, red blood cell casts, and varying degrees of
renal failure. Nephrotic (21%) or nephritic (14%) syndromes are less
frequent.
• More than 70% of patients present with hypertension.
• 40–60% have a raised serum creatinine concentration (>1·5 mg/dL) at
diagnosis.²
• Recurrence of cryoglobulinemia in the renal allograft has been
reported in patients receiving a kidney transplant.³
1. Roccatello D, Fornasieri A, et al. Am J Kidney Dis 2007; 49: 69–82.
2. Beddhu S, Bastacky S, et al. Medicine (Baltimore) 2002; 81: 398–409.
3. Basse G, Ribes D, et al. Clin Nephrol 2006; 66: 395–96.

29. CLINICAL FEATURES
• Renal involvement is usually an acute or chronic type-I MPGN with
sub-endothelial deposits.
• Represents 70–80% of cryoglobulinemia renal diseases.
• Strongly associated with the type II IgM kappa mixed
cryoglobulinemia.¹
1. Terrier and Cacoub. Curr Opin Rheumatol 2013, 25:10–18

30. CLINICAL FEATURES
• Neurologic - peripheral neuropathy, paresthesiae, rapidly progressive
sensory-motor involvement with severe functional impairment.¹
• Less common –
• Gastrointestinal involvement - Intestinal ischemia, fever, bloody stools,
intestinal perforation.
• Pulmonary involvement - effort dyspnea and dry cough, interstitial
lung fibrosis should be suspected; bronchoalveolar lavage shows a
predominance of macrophages, with slightly increased neutrophils or
lymphocytes, acute alveolar hemorrhage.
• CNS – stroke, encephalopathy.
• Rare - myocardial vasculitis, pericarditis or congestive heart failure.²
1.Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62
2.Retamozo S, Diaz-Lagares C, et al. London: Springer-Verlag, 2011: 133–62.

31. CLINICAL FEATURES
• Trejo et al.¹ collected sera from 7,043 patients and tested for
circulating cryoglobulins (between 1991 and 1999). A cryocrit of 1% or
more was detected in 443 (6.29%) patients. Clinical and serologic
characteristics of these patients were retrospectively collected in a
protocol form.
1. Trejo O, Ramos-Casals M, et al. Medicine (Baltimore) 2001; 80: 252–62.

36. CLINICAL FEATURES
• Ferri, et al. ¹ conducted a study that included 231 MC patients
recruited between 1972 and 2001 at the Rheumatology Unit of the
University of Pisa.
• All patients underwent wide clinico-serologic and virologic
assessment.
• Cumulative survival rates were computed by the Kaplan-Meier
method; moreover, the prognostic relevance of the main variables was
investigated by Cox model analysis.
1. Ferri, Sebastiani, et al. Seminars in Arthritis and Rheumatism, Vol 33, No 6 (June), 2004: pp 355-374

41. DIAGNOSIS
Detection of serum cryoglobulins:
• Appropriate sample collection and handling is crucial.
• Blood is collected in prewarmed syringes and tubes, transported,
clotted, and centrifuged at 37–40°C, ensuring that the
temperature never falls below 37°C. The serum is stored at 4°C
for up to 7 days. Precipitation of type I cryoglobulins usually occurs
within hours. Mixed cryoglobulins, particularly type III, can need
days to precipitate.
• Usually reported as cryocrit – (percent of total volume)
• Cryoglobulin concentration is usually more than 5 g/L in type I
cryoglobulinemia, but generally lower in types II and III.¹
1. Vermeersch P, Gijbels K, et al. Clin Chem 2008; 54: 39–43.

42. Cryocrit determination in a patient with mixed cryoglobulinemia (MC)
1. Ferri C et al, Sem Arthritis Rheum 2004, 33:355–74.).

43. • Expert laboratory interpretation that considers the patient in the
appropriate clinical context is essential.
• Cryoglobulin concentrations can fluctuate, depending on their in-vivo
precipitation in target vessels. Cryoglobulin should be assayed serially
when there is a high degree of suspicion of disease.
False positive:
• Healthy individuals have low concentrations of cryoglobulins (<0·06
g/L),
• Mixed polyclonal cryoglobulins often occur transiently during infection.
False-negative:
• Improper sample collection or inconsistent laboratory techniques.

44. DIAGNOSIS
• Other tests including CBC, renal and liver profile.
• Low complement levels (particularly C4) and raised titres of serum
rheumatoid factor are usually observed in mixed cryoglobulinemias.
• HCV testing (antibodies and serum HCV-RNA detection)
• Testing for other viruses (hepatitis B virus, HIV) and autoimmune
diseases (antinuclear, anti-DNA, anti-Ro/La, anticitrullinated
antibodies) is recommended, even in patients known to have HCV.
1. Sargur R, White P, et al. Ann Clin Biochem 2010; 47: 8–16.

45. HISTOPATHOLOGY
• Skin biopsy: of purpuric lesions reveal leukocytoclastic vasculitis of
the capillaries and postcapillary venules.
• Renal biopsy: shows proliferative (highly cellular) glomerular
infiltrates. Eosinophilic and PAS positive subendothelial
cryoprecipitate material might be detected.
• Renal biopsy detects type I MPGN in more than 70% of patients.
• More specific histopathological findings are hyaline intraluminal
thrombi that contain IgM, IgG, and C3 as endomembranous deposits
and glomerular infiltration by monocytes.
• Glomerular crescents (10–20%), renal necrotising vasculitis (5–30%),
and interstitial inflammation are less common.
• Other histopathological patterns - focal, mesangioproliferative, or
membranous GN.

46. Fig 2. Cryoglobulinemic glomerulonephritis with
membranoproliferative and mesangial proliferative features.

47. www.unckidneycenter.org

48. PROPOSITION OF CLASSIFICATION CRITERIA
FOR CRYOGLOBULINEMIA VASCULITIS
(1) Patients were classified as having CryoVas, if at least two of the three
items (questionnaire, clinical, laboratory) were positive.
(2) The patient must be positive for serum cryoglobulins in at least two
determinations at 12 weeks’ interval or less.
(3) Questionnaire item: at least two out of the following:
• (a) Do you remember one or more episodes of small red spots on
your skin, particularly involving the lower limbs?
• (b) Have you ever had red spots on your lower extremities, which
leave a brownish color after their disappearance?
• (c) Has a doctor ever told you that you have viral hepatitis?
1. De Vita S, Soldano F, et al. Ann Rheum Dis 2011; 70:1183–1190.

49. (4) Clinical item: at least three out of the following four (present or past)
• (a) Constitutional symptoms: fatigue, low-grade fever, fever (>388C,
no cause), fibromyalgia.
• (b) Articular involvement: arthralgias, arthritis.
• (c) Vascular involvement: purpura, skin ulcers, necrotizing vasculitis,
hyperviscosity syndrome, Raynaud’s phenomenon.
• (d) Neurologic involvement: peripheral neuropathy, cranial nerve
involvement, vasculitic central nervous system involvement.
(5) Laboratory item: at least two out of the following three (present)
• (a) Reduced serum C4.
• (b) Positive serum rheumatoid factor.
• (c) Positive serum M component.

50. PROGNOSIS AND OUTCOME
• Saadoun et al.¹ conducted a retrospective study – they followed up
151 consecutive HCV RNA–positive patients with vasculitis
prospectively between 1993 and 2009 and they were analyzed for
clinical, biologic, and therapeutic factors associated with survival.
• The 1-year, 3-year, 5-year, and 10-year survival rates were 96, 86, 75,
and 63, respectively.
• Deaths were mainly related to serious infections and end-stage liver
disease.
• Baseline factors associated with a poor prognosis were the presence
of severe liver fibrosis [hazard ratio (HR) 5.31], central nervous
system involvement (HR 2.74), kidney involvement (HR 1.91), and
heart involvement (HR 4.2).
1. Saadoun et al. Arthritis & Rheumatism Vol. 63, No. 6, June 2011, pp 1748–1757

51. PROGNOSIS
Kaplan–Meier estimate of the survival rates in CryoVas according
to the type of cryoglobulin and hepatitis C virus status.
1. Terrier and Cacoub. Curr Opin Rheumatol 2013, 25:10–18

52. PROGNOSIS AND OUTCOME
• Roughly half of patients have chronic cryoglobulinemic disease with
no involvement of vital organs. A third of patients have moderate-to-
severe disease, with chronic renal failure or cirrhosis, and nearly 15%
present with sudden life-threatening disease.
• Prognosis is influenced heavily by both cryoglobulinemic damage to
vital organs and by under lying diseases and comorbidities.¹
• Glomerulonephritis results in acute renal failure in 10% of patients or
can evolve progressively to chronic renal failure.
• 10-year survival rates of GN range between 33% and 49% in older
studies and nearly 80% in a study in 2007.²
1.Ferri C, Sebastiani M, et al. Semin Arthritis Rheum 2004; 33: 355–74.
2.Roccatello D, Fornasieri A, et al. Am J Kidney Dis 2007; 49: 69–82.

53. PROGNOSIS AND OUTCOME
Risk of neoplasia
• Expansion of the peripheral B-lymphocyte pool and lymphoid infiltrates
within the liver and bone marrow are often seen in patients with mixed
cryoglobulinemia.
• B-cell lymphoma, the main neoplastic complication in patients with
mixed cryoglobulinemia, has been reported in 5–22% of patients with
mixed cryoglobulinemia.¹
• Associated HCV infection confers a 20–30% increased risk of B-cell
lymphoma.
• Liver cancer, the second most frequently diagnosed neoplasia in
cryoglobulinemic patients, is attributable to the close association with
HCV.²
1. Monti G, Pioltelli P, et al. Arch Intern Med 2005; 165: 101–05.
2. Saccardo E, Novati P, et al. Dig Liver Dis 2007; 39 (suppl 1): S52–54.

54. TREATMENT
HCV related cryoglobulinemic vasculitis
• Combination peginterferon alfa and ribavirin is now considered
standard of care for the management of HCV infection.
• The approach is also effective in patients with HCV-related
cryoglobulinemic vasculitis.
• Cacoub et al.¹ showed complete clinical response and sustained
virologic response in 7 of 9 patients (78%) who were treated with
peginterferon alfa and ribavirin.
• Mazzaro et al.² - 86 patients with cryoglobulinemic vasculitis were
treated with peginterferon alfa and ribavirin for 6 or 12 months,
depending on the HCV genotype.
• HCV genotype 1 or 4 - 12 months - only 36% had a sustained virologic
response.
• HCV genotype 2 or 3 - 6 months - 64% had a sustained virologic
response.
1. Cacoub P, Saadoun D, et al. Arthritis Rheum 2005;52:911-5.
2. Mazzaro C, Monti G, et al. Clin Exp Rheumatol 2011;29:933-41.

55. • Ribavirin cannot be administered in –
 Patients with Cr.Cl of < 50ml/min and those undergoing hemodialysis.
 Patients with renal impairment should be monitored for the
development of hemolytic anemia, and the daily dose of ribavirin
should be adapted to the GFR.
 If the serum creatinine level increases to more than 2.0 mg per
deciliter (177 µmol per liter), therapy with peginterferon alfa and
ribavirin must be discontinued.

56. Triple therapy regimens in HCV
• Telaprevir and boceprevir have already been approved by the Food
and Drug Administration (FDA).
• In two phase 3 trials of triple-therapy regimens in patients infected
with HCV genotype 1 who had not previously received treatment,
sustained virologic response rates were 68 to 75% — significantly
higher than those obtained with peginterferon alfa and ribavirin
alone.¹¸²
• In previously treated patients, however, sustained virologic response
rates were - 30% among patients with no previous response to 85%
among patients with a previous response and subsequent relapse. ³
1. McCone J Jr, et al. N Engl J Med 2011;364:1195-206.
2. Jacobson IM, et al. N Engl J Med 2011;364:2405-16.
3. Bacon BR, et al. N Engl J Med 2011;364:1207-17.
4. Zeuzem S, et al. N Engl J Med 2011;364:2417-28.

57. • In an open-label, prospective cohort study, 23 HCV genotype 1–
positive patients with cryoglobulinemic vasculitis were treated with the
triple-therapy combination of peginterferon alfa and ribavirin with
either telaprevir or boceprevir.
• Results - At week 24, HCV RNA undetectable in 70% and a complete
clinical response achieved in 57% patients.
• However, a high rate of hematologic side effects (mainly grade 3 and
4 pancytopenia) was recorded.
1. Saadoun D, et al. Ann Rheum Dis 2013 April 20 (Epub ahead of print).

58. ROLE OF RITUXIMAB
• Sansonno D et al.¹ - Four weekly intravenous infusions of rituximab
were administered to 20 patients with HCV-related cryoglobulinemic
vasculitis that was resistant to interferon alfa therapy.
• Results - reduction in the serum cryoglobulin level and a significant
decrease in rheumatoid factor and in anti-HCV antibody titers — in
80% of the patients; in 75% of these patients, the remission was
sustained throughout 12 months of follow-up.
• Treatment caused a transient increase in HCV RNA levels, whereas
levels of alanine aminotransferase were mostly unchanged. Close
monitoring of these measures is warranted.
1. Sansonno D et al. Blood 2003;101:3818-26.

59. • Sneller MC et al.¹ performed a RCT - 24 patients with HCV-associated
cryoglobulinemic vasculitis who had not had a response to treatment
with interferon alfa and ribavirin or who had had unacceptable side
effects with this treatment -12 received rituximab and the remaining 12
continued to receive maintenance or increased immunosuppressive
therapy.
• Results - At study month 6, 83% of the patients in the group receiving
rituximab had a complete response, as compared with 8% in the
control group.
1. Sneller MC, et al. Arthritis Rheum 2012; 64:835-42.

60. • Dammacco F et al.¹ performed a study assessing the addition of
rituximab to peginterferon alfa and ribavirin in order to improve
response rates in HCV positive cryoglobulinemic vasculitis.
• The triple-drug regimen was administered to 22 patients for 48 weeks
and 15 patients received peginterferon alfa and ribavirin without
rituximab. Follow-up proceeded for 36 months after end of treatment.
• Among patients treated with the triple-drug regimen, complete-
response rate was 54.5%; among those who received peginterferon
alfa plus ribavirin without rituximab, the rate was only 33.3% (P<0.05).
1. Dammacco F, et al. Blood 2010;116: 343-53.

61. Proposed Therapeutic Algorithm for HCV-Related Cryoglobulinemic Vasculitis (CV),
According to Arbitrarily Assessed Disease Activity.
Dammacco F, Sansonno D. N Engl J Med 2013;369:1035-1045

62. Drugs for the Treatment of HCV-Related Cryoglobulinemic Vasculitis, According to the Therapeutic
Target.
DAMMACCO F, SANSONNO D. N ENGL J MED 2013;369:1035-1045.

63. TREATMENT
Noninfectious mixed cryoglobulinemic vasculitis:
• Mild-to-moderate CryoVas - avoidance of cold temperatures, resting in
case of purpura, and nonaggressive medications, such as NSAIDs,
colchicine, and disulone.
• Severe CryoVas - based on a combination of corticosteroids and
immunosuppressants, rituximab or plasmapheresis.¹
1. Terrier and Cacoub. Curr Opin Rheumatol 2013, 25:10–18

64. • Rituximab was highly effective in patients with CryoVas, however,
tolerance was marked by the occurrence of side effects in almost half
of patients, including severe infections in 26%. These infections
occurred in a particular subset of patients with age more than 70
years, essential type II CryoVas, renal failure with GFR less than 60
ml/min and using high-dose corticosteroids.
Arthritis Care & Research. Vol. 62, No. 12, December 2010, pp 1787–1795

65. • Rituximab and corticosteroids showed greater therapeutic efficacy
compared with corticosteroids alone and alkylating agents plus
corticosteroids to achieve complete clinical, renal, and immunologic
responses and a prednisone dosage less than 10 mg per day at 6
months. However, this regimen was also associated with severe
infections, particularly when high doses of corticosteroids were used,
whereas death rates did not differ between the therapeutic regimens.
BLOOD, 21 JUNE 2012. VOLUME 119, NUMBER 25

66. TREATMENT
Type I cryoglobulinemic vasculitis:
• Related to malignant hemopathy: treatment of hemopathy and based
on polychemotherapy, but specific treatment may also be indicated,
including plasma exchange or iloprost, in particular for ulceronecrotic
cutaneous lesions.
• Underlying multiple myeloma: Treatment approaches for severe type I
CryoVas should systematically involve plasmapheresis at the onset of
the disease to achieve a rapid control of the cryoglobulinemia, and
specific myeloma treatments should be introduced early to avoid
relapse. ¹
1. Payet J, Livartowski J,et al. Leuk Lymphoma 2012

67. • Related to MGUS: therapeutic management is more hazardous,
ranging from corticosteroids alone to alkylating agents or rituximab-
based regimen and other new biological agents such as bortezomib,
thalidomide and lenalinomide, in severe and/or refractory patients.
• The efficacy of rituximab in type I CryoVas remains controversial.¹
1. Terrier and Cacoub. Curr Opin Rheumatol 2013, 25:10–18

68. FOOD FOR THOUGHT…
• Why do cryoglobulins deposit in the kidneys?
• What are the physiochemical properties of some immunoglobulins and
immune complexes that cause them to precipitate in the cold?
• Why do some HCV-infected patients get this disorder and not others?
• Why does HCV-associated cryoglobulinemia develop long after initial
infection and what triggers its development?
• Why are some cryoglobulins more pathogenetic than others?