Cryoglobulinemia

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Cryoglobulinemia

• RHEUMATOLOGY ROTATION
• PGY4
• Hamid Mojab

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Case Presentation - Ms. P

• 36 year-old female, writer
• PMHx IVDU, ex-smoker
• No meds, no allergies
• Malaise, fever, arthralgias x 1 week
• Prescribed Ciprofloxacin, no change
• 3 day hx of chills, sore left wrist, rash

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Ms. P Physical Exam

• Looks unwell Diaphoretic
• BP 140/80 HR 96 RR 18 O2 sat 98 Temp 38.5C
• HN anterior cervical lymphadenopathy, ? ulcers
• Resp clear BS bilaterally
• CVS JVP flat, N S1S2, ? murmur/rub, ? edema
• Abdo soft, non-tender, ? HSM
• Derm raised violaceous lesions lower legs
• MSK active joints (left wrist, right ankle)
• Neuro grossly normal, ? asterixis

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Ms. P Evaluation

• Hb 105 WBC 12.2 Plt 170, normal coags
• ESR 78, AST 123 ALT 139 ALP 108 Bili 20
• Na 140 K 3.7 HCO3 22 Cl 103
• Cr 170 Urea 15
• Urinalysis protein 1, blood 2
• Microscopy many RBCs, heme granular casts,
• RBC casts
• Joint aspirate cell count 25,000 with 78 PMN,
  gram stain negative, culture pending
• EKG and CXR normal

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Ms. P Evaluation

• Admitted, IV fluids started
• Derm/Rheum/Nephro/ID consult!
• Skin biopsy taken
• No Abx started
• Blood/Urine/Throat/Rectal CS, Hepatitis
  serology, HIV, RF, ANA, ANCA, C3/C4,
  cryoglobulins sent

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Ms. P Evaluation

• Skin biopsy leukocytoclastic picture
• ANA positive 180 homogenous
• RF positive 1 1280
• C3 normal ? C4
• ANCA negative
• Cultures negative
• 24 hour urine 1.4g protein
• Hep B sAg negative, Hep sAb positive
• Hep C Ab positive
• Abdo U/S small nodular liver with no focal
  lesions, N sized kidneys, borderline spleen,
  normal flows

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Cryoglobulins

• Described by Wintrobe and Buell in 1933
• Immunoglobulins (Ig) that precipitate in cold
  (lt37C), dissolve on rewarming
• Classification based on composition of Ig

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Brouet Classification

• Type I (5-25) monoclonal Ig (IgA, IgM, IgG)
• Type II (40-60) essential mixed contains both
  a polyclonal IgG monoclonal IgM Rheumatoid
  Factor
• Type III (40-50) mixed, but both IgG and RF IgM
  are polyclonal

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Brouet Classification
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Pathophysiology

• Mediated by deposition of Ag-Ab complexes in
  small sized arteries

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Pathophysiology
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Clinical Presentation- Type I

• May be asymptomatic
• Classically produces signs related to
  hyperviscosity ? thrombosis
• Raynauds
• Digital ischemia? gangrene
• Livedo reticularis
• Purpura

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Clinical Presentation-Type II/III

• Constitutional cutaneous symptoms purpura,
  arthralgias, myalgias ? Meltzers Triad
• Cutaneous
• MSK
• Pulmonary
• Neurologic
• Hematologic
• Renal

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Clinical Presentation-Cutaneous

• Develop in nearly all patients
• May precede extracutaneous manifestations by
  decades
• Purpura of lower extremities
• Ulcers
• Raynauds
• Livedo reticularis
• Acrocyanosis
• Post-inflammatory hyperpigmentation

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Clinical Presentation-MSK

• Myalgias
• Arthralgias (MCP, PIP, knees, ankles)
• Arthritis or myositis rare

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Clinical Presentation-Neuro

• Mononeuritis multiplex
• Cranial nerve palsy

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Clinical Presentation-Pulmonary

• Dyspnea
• Cough
• Pleuritis
• BOOP, pulmonary hemorrhage, pulmonary vasculitis
  rare

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Clinical Presentation-Heme

• Anemia (normochromic, normocytic)
• Factitious thrombocytosis, leukocytosis
• Underlying malignancy (e.g., lymphoma)

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Clinical Presentation-Renal

• Present in 20 at time of dx
• Type II 35-60
• Type III 12-20
• Variable presentation
• HTN
• Proteinuria
• Hematuria
• ?Cr
• ESRD

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Renal Histology

• Classically in Type I Membranoproliferative GN
• Focal and mesangioproliferative GN
• Membranous GN
• Thrombotic microangiopathy

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Renal Histology- MPGN

• Thickening of BM
• Cellular proliferation (esp. macrophages)
• Intraluminal thrombi (precipitated CG)
• Diffuse IgM deposition
• Subendothelial deposits fingerprints

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Cryoglobulin Thrombi
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Fingerprint Pattern
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Diagnosis

• History
• Physical exam
• Hypocomplementemia
• Circulating cryoglobulins

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Diagnosis
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Disease Severity

• Severe disease manifested by
• progressive renal failure
• distal necroses requiring amputation
• advanced neuropathy

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Treatment

• Treat underlying cause (Type I)
• Start treatment in any symptomatic disease
• Corticosteroids
• Plasmapheresis
• Cytotoxic agents (cyclophosphamide)
• Anti-virals (IFN ? Ribavirin)
• Rituximab in refractory case

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Treatment of Renal Disease
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Indications For Aggressive Therapy In Idiopathic
Mixed Cryoglobulinemia

• progressive renal failure
• distal necroses requiring amputation
• advanced neuropathy

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Aggressive Therapy In Idiopathic Mixed
Cryoglobulinemia

• plasmapheresis (to remove the circulation
  cryoglobulins)
• steroids (1000 mg of intravenous
  methylprednisolone daily times three, followed by
  conventional oral prednisone) and
  cyclophosphamide to prevent new antibody
  formation

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Treatment

• Optimal method for assessing the efficacy of
  plasmapheresis is
• uncertain
• reasonable prescription - exchange one plasma
  volume three times weekly for two to three weeks
• Limited evidence suggesting that combination
  therapy is beneficial in patients with HCV
• Induced cryoglobulinemia i.e., ribavirin and
  interferon-alfa therapy (Six months)
• HCV induced cryoglobulinemia refractory to
  interferon alfa alone

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Treatment

• Ribavirin
• contraindicated in renal insufficiency.
• In one study
• two patients with moderate renal insufficiency
  (serum creatinine 159 and 195 µmol/L
• successfully treated with aproportionate
  reduction in the ribavirin dose
• optimal dose and duration of interferon
  uncertain

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Treatment

• Rituximab
• Is anti-CD20 chimeric monoclonal antibody
  rituximab, which depletes B cells, appears
  promising
• as investigational treatment
• is indicated for refractory treatment
• partially controlled by previously recommended
  treatment
• given once per week for four weeks
• effectively treated skin manifestations
• peripheral neuropathy
• low-grade B cell lymphoma, and/or arthralgias
• 15 patients with resistant or difficult to manage
  disease

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Cryoglobulinemia-Prognosis

• Mean survival 70 at 10 years after onset of
  symptoms, 50-70 at 10 years after diagnosis
• Death typically from infection and CVD
• Complications (renal failure) predict poorer
  outcomes

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ESRD-Prognosis

• Survival on dialysis similar to patients with
  other causes of ESRD
• Renal transplant can be successful
• Significant disease can recur in 50-70 even if
  in remission at time of transplant

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Back to the Case.

• Skin biopsy leukocytoclastic picture
• ANA positive 180 homogenous
• RF positive 1 1280
• C3 normal ? C4
• ANCA negative
• Cultures negative
• 24 hour urine 1.4g protein
• Hep B sAg negative, Hep sAb positive
• Hep C Ab positive
• Abdo U/S small nodular liver with no focal
  lesions, N sized kidneys, borderline spleen,
  normal flows

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Back to the Case.

• Cryoglobulins cyrocrit of 8 with mixed IgG and
  polyclonal IgM
• Treated initially with plasmapheresis and
  steroids
• Later switched to IFN-? ribavirin once ARF
  resolved

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Red Flag

• be alert for symptoms suggestive of
  cryoglobulinemia
• purpuric rash
• arthralgias
• Raynaud phenomenon
• in chronic HCV infected patients
• should measure serum cryoglobulins

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Questions?