Cryoglobulinemia,,,Dr. Sajid Mumtaz Sodhar

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Case presentation in kkch, Tabuk.:

Case presentation in kkch , Tabuk . 55 yrs male, referred from peripheral hospital, vague h/o intermittent low grade fever, body ache, artharlgia , followed by shortness of breath, easy fatiguability , rashes on both hands (since 2days)there is h/o wt: loss (but not significant) for last one month. No h/o cough,abdominal pain or D&V. No h/o contact with TBC pt:. No h/o travel outside. Smoker but denying taking illicit drugs. NO h/o any chronic illness. Family signed DAMA and went to Jordin after 8 days of admission

At the time of arrival:

At the time of arrival “Sodhar Courtesy”

At the time of arrival:

At the time of arrival “Sodhar Courtesy”

After 1 week,:

After 1 week, “Sodhar Courtesy” “Sodhar Courtesy”

C.T brain advised (a bit confused & disriented to time n place):

C.T brain advised (a bit confused & disriented to time n place) “Sodhar Courtesy” “Sodhar Courtesy”

Case Presentation - :

Case Presentation - 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

Ms. P – Physical Exam:

Ms. P – Physical Exam Looks unwell Diaphoretic BP 140/80 ; HR 96; RR 18; O2 sat 98%; Temp 38.5°C 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

Ms. P – Evaluation :

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 :

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 :

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

Cryoglobulinemia:

Cryoglobulinemia Dr. Sajid Mumtaz Sodhar

Cryoglobulins :

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:

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:

Brouet Classification Type I Type II Type III Multiple Myeloma Hep C/ Hep B Autoimmune disease (SLE, RA, PAN, Sjogren’s, HSP) Waldenstrom’s HIV Infection (Hep C, EBV, CMV, Toxo, SBE, HIV, Malaria) MGUS Lymphoma/CLL Miscellaneous (biliary cirrhosis) CLL Essential Essential

Pathophysiology:

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

Pathophysiology:

Pathophysiology

Clinical Presentation- Type I:

Clinical Presentation- Type I May be asymptomatic Classically produces signs related to hyperviscosity  thrombosis Ra ynaud’s Digital ischemia  gangrene L ivedo reticularis Purpura

Clinical Presentation-Type II/III:

Clinical Presentation-Type II/III Constitutional + cutaneous symptoms purpura , arthralgias , myalgias  “Meltzer’s Triad” Cutaneous MSK Pulmonary Neurologic Hematologic Renal Disease States Cryoglobulins are described in many clinical conditions such as lymphoproliferative disorders, viral infections, and connective tissue diseases. Physical findings on patients with cryoglobulinemia may include purpura, vasculitis with multisystem involvement, glomerulonephritis, synovitis with joint swelling and pain and serositis-pleural effusion and pain

Clinical Presentation-Cutaneous :

Clinical Presentation-Cutaneous Develop in nearly all patients May precede extracutaneous manifestations by decades Purpura of lower extremities Ulcers Raynaud’s Livedo reticularis Acrocyanosis Post-inflammatory hyperpigmentation

Clinical Presentation-MSK :

Clinical Presentation-MSK Myalgias Arthralgias (MCP, PIP, knees, ankles) Arthritis or myositis rare

Clinical Presentation-Neuro :

Clinical Presentation-Neuro Mononeuritis multiplex Cranial nerve palsy

Clinical Presentation-Pulmonary:

Clinical Presentation-Pulmonary Dyspnea Cough Pleuritis BOOP, pulmonary hemorrhage, pulmonary vasculitis rare

Pulmonary hemorrhage:

Pulmonary hemorrhage

Clinical Presentation-Heme:

Clinical Presentation-Heme Anemia (normochromic, normocytic) Factitious thrombocytosis, leukocytosis Underlying malignancy (e.g., lymphoma)

Clinical Presentation-Renal:

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

Renal Histology :

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

Renal Histology- MPGN:

Renal Histology- MPGN Thickening of BM Cellular proliferation (esp. macrophages) Intraluminal thrombi (precipitated CG) Diffuse IgM deposition Subendothelial deposits “fingerprints”

Cryoglobulin Thrombi:

Cryoglobulin Thrombi

Fingerprint Pattern:

Fingerprint Pattern

Diagnosis:

Diagnosis History Physical exam Hypocomplementemia Circulating cryoglobulins

Diagnosis:

Diagnosis

PowerPoint Presentation:

Determine Cryocrit Percent Determine percent CRYOCRIT on all positive cryoglobulins. Spin cryocrit tube at 2000 rpm/4°C/10 min. Determine percent by reading calibrations from 1 to 100. If crit is <= 2%, report. If crit is greater than 2%, centrifuge for another 20 minutes. (Large cryocrits need 30 minutes to sufficiently pack)

Disease Severity:

Disease Severity Severe disease manifested by: progressive renal failure distal necroses requiring amputation advanced neuropathy

Treatment:

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

Treatment of Renal Disease:

Treatment of Renal Disease HCV + HCV - PEG-IFN Non-peg IFN  Ribavirin  (renal clearance)  Steroids   Cytotoxic Agents ?  Plasmapheresis   Rituximab   RRT  

Indications For Aggressive Therapy In Idiopathic Mixed Cryoglobulinemia :

Indications For Aggressive Therapy In Idiopathic Mixed Cryoglobulinemia progressive renal failure distal necroses requiring amputation advanced neuropathy

Aggressive Therapy In Idiopathic Mixed Cryoglobulinemia :

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:

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:

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:

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:

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:

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

Back to the Case…….:

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…….:

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:

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

PowerPoint Presentation:

Jasakumallah khair Questions?