Keerti Bhanushali

06/20/2014

CRYOGLOBULINEMIC VASCULITIS

AND RENAL DISEASE

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

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.

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.

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

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.

Fig 1: Classification of cryoglobulinaemias¹

1. Brouet JC, Clauvel JP, et al. Am J Med 1974; 57:775–88.

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

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.

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.

• 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

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.

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.

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.

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

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.

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. Trypanosomacruzi 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.

PATHOGENESIS

Model of innate immunity triggered rheumatoid factor production¹

1. Alpers and Smith. Current Opinion in Nephrology and Hypertension 2008, 17:243–249

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.

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.

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

Proposed Pathogenetic Model of Hepatitis C Virus (HCV)–Related Cryoglobulinemic Vasculitis.

Dammacco F, Sansonno D. N Engl J Med 2013;369:1035-1045

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 cryoglobulinemicMPGN.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.

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

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.

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

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

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.

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

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.

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.

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

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.

Cryocrit determination in a patient with mixed cryoglobulinemia (MC)

1. Ferri C et al, Sem Arthritis Rheum 2004, 33:355–74.).

• 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.

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.

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.

Fig 2. Cryoglobulinemic glomerulonephritis with

membranoproliferative and mesangial proliferative features.

www.unckidneycenter.org

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.

(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.

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

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

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.

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.

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 virologicresponse.

• HCV genotype 2 or 3 - 6 months - 64% had a sustained virologicresponse.

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.

• 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.

T

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.

• 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).

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.

• 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.

• 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.

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

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.

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

• 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

• 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

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

• 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

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?