1. Cryoglobulinemia Andrew J Avery A.M. Report 08/19/09

2. Introduction Precipitation of blood proteins at temperatures lower than 37ºC is referred to as cryoprecipitation Cryoglobulins are either immunoglobulins or a mixture of immunoglobulins and complement components that precipitate from both serum and plasma (if just plasma, then called cryofibrinogen)

3. Introduction Wintrobe and Buell are credited with the first description of the cryoprecipitation phenomenon. In 1933, they described a patient with signs and symptoms of hyperviscosity associated with multiple myeloma

4. Cryoglobulins

5. Prevalence The prevalence of clinically-significant cryoglobulinemia has been estimated at approximately 1:100,000 Detectable levels of circulating CGs have been seen in a significant proportion of patients with chronic infections and/or inflammation: HIV-15-20% Connective Tissue Dz-15-25% HEP C-40-50%

6. Brouet Classification Uses the immunological analysis of the CG to delineate the clonality of the responsible CG Type I: Criterion is presence of isolated monoclonal Ig; ≈5-25% of cases; most commonly ass. w/ LPD Type II: A mixture of polyclonal Ig in association with a monoclonal Ig; ≈40-60% of cases; most commly ass. w/ chronic viral inf Type III: Mixed cryoglobulins consisting of polyclonal Ig; ≈40-50% of cases; most commonly ass. w/ CTD

7. Etiology and Pathogenesis CGs are often detectable in the serum of healthy pts, thus speculated that CGs reflect the ongoing physiological clearance of endogenous immune complexes by Igs with RF activity Pathogenic CG responses may result from several factors: next slide

8. Etiology and Pathogenesis Chronic immune stimulation and/or lymphoproliferation, resulting in the production of higher concentrations of mono-, oligo-, or polyclonal CG. Immune complex formation among CG and/or their target antigens Defective and/or insufficient clearance of the resulting immune complexes, which accumulate and mediate disease

9. Signs & Sx Type I Type II Type III Purpura+++++++ Gangrene/Acrocyano++++/+++/- Arthralgias>Arthritis++++++ Renal++++ Neurologic+++++ Liver+/-+++++ Clinical Manifestations

10. Cutaneous: Nearly all pts with CG syndromes develop Cutaneous: Nearly all pts with CG syndromes develop erythematous macules to purpuric papules of the lower extremities (90-95%). More commonly in Type I CG are infarction, hemorrhagic crusts and ulcers (10-25%); raynaud phenomenon, livedo reticularis, acrocyanosis; and post-inflammatory hyperpigmentation (30-50%).

11. Palpable Purpura

12. Clinical Manifestations Musculoskeletal: Arthralgias and myalgias are common in type Type II and III CGs (>70%). Most commonly affect Musculoskeletal: Arthralgias and myalgias are common in type Type II and III CGs (>70%). Most commonly affect metacarpophalangeals, proximal phalangeals, knees, and ankles Neuropathy: Affects 70-80% of pts with mixed CG (Type II & III). Thought to be 2/2 vasculitis Pulmonary: Generally affects Types II & III (40-50%). PFTs often reveal evidence of small airways disease and impairment of gas exchange; sx generally range from dyspnea to cough and pleurisy

13. Clinical Manifestations Renal: Renal: Renal disease in mixed CG often results from immune complex disease; less frequently 2/2 thrombotic dz (more common in Type I) Membranoproliferative glomerulonephritis seems to be more common in mixed CG Isolated proteinuria or hematuria occur much more frequently than nephrotic or nephritic syndromes or acute renal failure.

14. Clinical Manifestations Other: Sjogrens syndrome (4-20%); Raynaud phenomenon (≈50%); Other: Sjogrens syndrome (4-20%); Raynaud phenomenon (≈50%); hepatomegaly, abnormal liver function tests or abnormal liver biopsy (≈90%); lymphadenopathy (≈20%); splenomegaly (≈30%); abdominal pain (≈20%). All of the above are more common in Types II & III CNS, heart, and retinal vessels are rarely affected unless in association with hyperviscosity due to type I CG

15. Cutaneous Pathological Findings Mixed CG most often reveal leukocytoclastic vasculitis (50%), less commonly inflammatory or noninflammatory purpura (10-20%), noninflammatory hyaline thrombosis (10%), or post-inflammatory sequelae (10%) Type I CGs more often induce noninflammatory thrombotic lesions, sometimes with evidence of cutaneous infarction or hemorrhage

16. Skin lesion in mixed cryoglobulinemia (PAS Stain)

17. Renal Pathological Findings Light and immunofluorescence microscopy: In Mixed CG, most common is membranoproliferative glomerulonephritis (60-80%), with endocapillary proliferation and subendothelial and/or intraluminal deposits of CGs, immunoglobulin, and/or complement proteins Type I CG generally produce noninflammatory glomerulopathies, including thrombotic and hypocellular lesions, without evidence of vasculitis.

18. Renal involvement in type II cryoglobulinemia

19. Laboratory Findings Measureable Cryoglobulins: Types II & III Measureable Cryoglobulins: Types II & III (1 to 5 mg/dL); Type I (5 to 10 mg/dl) Complement: Normal in Type I; Decreased CH50, C1q, C2 and C4 and normal C3 in Types II & III Elevated ESR and CRP Autoantibodies: Types II & III often have elevated RF, ANA (many others as well) Evidence of Viral Inf: HCV, HBV, HIV, EBV

20. Treatment Mild Dz: Mild Dz: Mild symptoms, such as fatigue, arthralgias and myalgias, in the absence of clear evidence for end-organ damage. Initial trx is cold avoidance and nsaids. Low dose prednisone for inflam sx not responsive to nsaids Mod-Severe Dz: pathologically-proven, CG- related, end-organ-threatening vasculitis or thrombosis -Type I (malignancy related): chemo and/or radiation for bone lesions

21. Treatment Type I (non-malignancy)-Prednisone and Cycylophosphamide Type I (non-malignancy)-Prednisone and Cycylophosphamide Types II & III- Types II & III-generally involves immunosuppression and may also require plasmapheresis; May be combined with antiviral therapy when indicated Severe Dz: hyperviscosity syndrome or vasculitis in Type I CG, or life or organ threatening vasculitis in mixed CG (Types II or III) warrants the addition of plasmapheresis to quickly reduce the CG burden

22. Prognosis The presence of CG does not seem to confer a significant morbidity or mortality risk over and above the underlying conditions Survival: Mean survival is approximately 70% at 10 years after the onset of symptoms, 50% at 10 years after diagnosis, with death typically resulting from infection and cardiovascular disease