Cryoglobulinemia
RHEUMATOLOGY ROTATION
PGY4 Hamid Mojab
Case Presentation - Ms. P
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36 year-old female, writer
PMHx: IVDU, ex-smoker No meds, no allergies Malaise, fever, arthralgias x 1 week
Prescribed Ciprofloxacin, no change
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3 day hx of chills, sore left wrist, rash
Ms. P – Physical Exam
Looks unwell Diaphoretic
BP 140/80; HR 96; RR 18; O2 sat 98%; Temp 38.5°C
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H&N: 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
Ms. P – Evaluation
• Admitted, IV fluids started
• Derm/Rheum/Nephro/ID consult! • Skin biopsy taken • No Abx started • Blood/Urine/Throat/Rectal C&S, Hepatitis serology, HIV, RF, ANA, ANCA, C3/C4, cryoglobulins sent
Ms. P – Evaluation
• Skin biopsy: leukocytoclastic picture • ANA positive 1:80 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
Cryoglobulins
• Described by Wintrobe and Buell in 1933
• Immunoglobulins (Ig) that precipitate in cold (<37°C), dissolve on rewarming • Classification based on composition of Ig
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
Brouet Classification
Type I
Multiple Myeloma
Type II
Hep C/ Hep B
Type III
Autoimmune disease (SLE, RA, PAN, Sjogren’s, HSP)
Waldenstrom’s
HIV
Infection (Hep C, EBV, CMV, Toxo, SBE, HIV, Malaria)
Miscellaneous (biliary cirrhosis)
MGUS
Lymphoma/CLL
CLL
Essential
Essential
Pathophysiology
• Mediated by deposition of Ag-Ab complexes in small sized arteries
Pathophysiology
Interaction between predisposed host and environmental trigger
Ig production 2° to chronic immune stimulation + lymphoproliferation
Defective + insufficient clearance of immune complexes
Tissue accumulation
Clinical Presentation- Type I
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May be asymptomatic
Classically produces signs related to hyperviscosity thrombosis • • • • Raynaud’s Digital ischemia gangrene Livedo reticularis Purpura
Clinical Presentation-Type II/III
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Constitutional + cutaneous symptoms purpura, arthralgias, myalgias “Meltzer’s Triad” Cutaneous
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MSK Pulmonary Neurologic Hematologic Renal
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Clinical Presentation-Cutaneous
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Develop in nearly all patients May precede extracutaneous manifestations by decades Purpura of lower extremities Ulcers
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Raynaud’s Livedo reticularis Acrocyanosis Post-inflammatory hyperpigmentation
Clinical Presentation-MSK
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Myalgias
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Arthralgias (MCP, PIP, knees, ankles) Arthritis or myositis rare
Clinical Presentation-Neuro
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Mononeuritis multiplex
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Cranial nerve palsy
Clinical Presentation-Pulmonary
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Dyspnea
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Cough Pleuritis BOOP, pulmonary hemorrhage, pulmonary vasculitis rare
Clinical Presentation-Heme
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Anemia (normochromic, normocytic)
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Factitious thrombocytosis, leukocytosis Underlying malignancy (e.g., lymphoma)
Clinical Presentation-Renal
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Present in ~ 20% at time of dx
Type II: 35-60%
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Type III: 12-20% Variable presentation • HTN • Proteinuria • Hematuria • Cr • ESRD
Renal Histology
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Classically in Type I Membranoproliferative GN
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Focal and mesangioproliferative GN Membranous GN Thrombotic microangiopathy
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Renal Histology- MPGN
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Thickening of BM
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Cellular proliferation (esp. macrophages) Intraluminal thrombi (precipitated CG) Diffuse IgM deposition Subendothelial deposits “fingerprints”
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Cryoglobulin Thrombi
Fingerprint Pattern
Diagnosis
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History
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Physical exam Hypocomplementemia Circulating cryoglobulins
Diagnosis
Disease Severity
Severe disease manifested by:
– progressive renal failure – distal necroses requiring amputation – advanced neuropathy
Treatment
Treat
Start
underlying cause (Type I)
treatment in any symptomatic disease
Corticosteroids Plasmapheresis
Cytotoxic
agents (cyclophosphamide) (IFN ± Ribavirin) in refractory case
Anti-virals
Rituximab
Treatment of Renal Disease
HCV + HCV -
PEG-IFN
Ribavirin
Non-peg IFN
(renal clearance)
Steroids Cytotoxic Agents Plasmapheresis
Rituximab
?
RRT
Indications For Aggressive Therapy In Idiopathic Mixed Cryoglobulinemia
progressive renal failure
distal necroses requiring amputation advanced neuropathy
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
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
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
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
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
ESRD-Prognosis
Survival on dialysis similar to patients with other causes of ESRD
Renal transplant can be successful Significant disease can recur in 5070% even if in remission at time of transplant
Back to the Case…….
• Skin biopsy: leukocytoclastic picture • ANA positive 1:80 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
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
Red Flag
be alert for symptoms suggestive of cryoglobulinemia – purpuric rash – arthralgias – Raynaud phenomenon in chronic HCV infected patients should measure serum cryoglobulins
Questions?