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Cryoglobulins

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... from East Africa. RFC: ?lupus nephritis. PMHx: 1) 1999: Sicca, ... Treatment of lupus nephritis. Systematic review (Flanc RS et al, Cochrane Library 2004) ... – PowerPoint PPT presentation

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Title: Cryoglobulins


1
Cryoglobulins
  • Dr. An-Wen Chan
  • Rheumatology Rounds
  • Tuesday August 17, 2004

2
History
  • 27 yo Black female from East Africa
  • RFC ?lupus nephritis
  • PMHx
  • 1) 1999 Sicca, ?Sjogrens. 0.83L, ANA, RF
    (540)
  • 2) April 2004 Raynauds with digital infarcts
  • 0.48L, ANA (1640), -dsDNA/ENA, cryos, low C3
    C4
  • 3) Infertility

3
History physical exam
  • Meds
  • None
  • HPI
  • 4 week Hx of diarrhea, fever, malaise
  • to hospital pericardial effusion, Cr 150
  • hemoptysis
  • to ICU for hypoxic respiratory failure
  • Physical exam
  • noncontributory

4
Laboratory tests
  • Hgb 125, WBC 12.4 (0.23L), platelets 98
  • Cr 155, U/A blood, WBCs
  • Normal lytes, LFTs
  • ESR 25
  • Serology
  • ANA (1640), RF 335, cryoglobulins
  • dsDNA, anti-GBM, ANCA, Hep B/C
  • Low C3, low C4
  • Renal biopsy Diffuse prolif GN
  • Cryos on EM

5
Summary
  • 27 F with pulmonary-renal syndrome consistent
    with cryoglobulinemic vasculitis.
  • Course in ICU
  • improved renal function with pulse steroids,
    PLEX
  • recurrent pulmonary hemorrhage with steroid
    tapering
  • daily oral cyclophosphamide added (1.5mg/kg)
  • today still ventilated, Cr 100, -cryoglobulins

6
Lupus nephritis
  • WHO Classification
  • I. Normal glomeruli
  • II. Pure mesangial alterations
  • III. Focal segmental GN
  • IV. Focal proliferative GN (worst prognosis)
  • V. Diffuse GN
  • VI. Advanced sclerosing GN
  • diagnosis is important for treatment and
    prognosis

7
Treatment of lupus nephritis
  • Systematic review (Flanc RS et al, Cochrane
    Library 2004)
  • 25 eligible RCTs with biopsy-proven DPLN (909
    patients)
  • CYC or azathioprine (n12)
  • PLEX (n7)
  • Cyclosporine (n2)
  • MMF, misoprostol, IVIG, methylprednisolone
  • Variable quality
  • Allocation concealment (12)
  • Blinding (8)
  • Intention-to-treat analysis (56)

8
Efficacy data - Total mortality
9
Efficacy data - ESRD
10
Efficacy data - Doubling of creatinine
11
Safety data - Major infections
12
Safety data - Ovarian failure
13
Results summary
  • CYC reduced risk of doubling Cr increased risk
    of ovarian failure
  • Azathioprine reduced overall mortality
  • Neither had significant effect on ESRD or major
    infection
  • Overall, no significant difference in efficacy
    between CYC and azathioprine
  • PLEX not shown to be useful

14
Pulse vs continuous CYC
  • Austin et al (1986)
  • Parallel group, 5-arm, unblinded RCT of 38
    patients
  • Interventions Prednisolone plus
  • 1) Pulse CYC (0.5-1g/m2 IV q3mths)
  • 2) Continuous CYC (up to 4mg/kg po od)
  • 3) Azathioprine
  • 4) CYC and azathioprine
  • 5) Nothing
  • Median follow-up 3 years

15
Pulse vs continuous CYC
  • Yee et al (2004) - EULAR trial
  • Parallel group, 2-arm, unblinded RCT of 32
    patients
  • Interventions 1) Pulse CYC
  • 10mg/kg IV q3wks x 4,
  • then po q4wks x 9mths,
  • then po q6wks x 12 mths
  • 2) Continuous CYC (2mg/kg po od x 3mths)
  • steroid, followed by Aza steroid
  • Median follow-up 3 years

16
Pulse vs continuous CYC Trial quality
  • Poor quality
  • Unclear allocation concealment
  • Unblinded
  • Allow rescue Rx (performance bias)
  • Small sample size
  • Not ITT

17
Pulse vs continuous CYC Trial results
Austin (1986) EULAR trial (2004)
Continuous Pulse Continuous
Pulse n18 n20
n16 n13 Mortality 7 4
1 2 ESRD 4 1 2
0 Neutropenia - - 3
1 Infections 3 2 4 5 Ovarian
failure 7/10 8/17 1 1 Hemorr.
cystitis 3 0 1 0
18
Pulse vs continuous CYC - further data
19
Conclusions
  • Despite limited trial data, cyclophosphamide and
    azathioprine have been shown to improve outcomes
    in lupus nephritis
  • Cyclophosphamide steroids is considered 1st
    line treatment, with an effect on creatinine but
    not ESRD/mortality
  • Optimal dosing regimen remains unclear, although
    pulse cyclophosphamide may have fewer adverse
    effects

20
Cryoglobulins Brouet classification
  • Immunoglobulins /- complement that precipitate
    from serum in the cold and redissolve on
    rewarming
  • Type I (5-25)
  • monoclonal Ig (IgM, IgG IgA, light chain)
    fractions
  • Observed in MM, Waldenstroms
  • Hyperviscosity/ thrombosis

21
Cryoglobulins
  • Type II (60) mixed
  • polyclonal IgG and monoconal IgM or IgA
    rheumatoid factor activity against the Ig
  • Essential MC
  • HepC chronic infection, HIV
  • EBV, HepB
  • Type III (25-30)
  • both IgG and RF IgM are polyclonal
  • SLE, lymphoproliferative malignancies, HCV, CTDz
    (Sjogren)

22
Cryoglobulins
  • Physiologic vs pathologic (chronic immune
    stimulation, augmented IC formation, decreased IC
    clearance)
  • Deposition of antigen-antibody complexes in
    small/ medium-sized arteries-vasculitis
  • Mixed Cryo HepC related (95)
  • Anti HCV antibodies
  • HCV RNA in the plasma and cryoprecipitate
  • Polyclonal IgG anti-HCV Abs within the
    cryoprecipitate
  • Virus binds B lymphocytes via CD 81, lowering
    the activation threshold , facilitating
    lymphoproliferation, production of
    autoantibodies?

23
Clinical Manifestations
  • Palpable purpura (LEUE)
  • Nonspecific systemic symptoms
  • Arthralgias
  • Lympadenopathy
  • Hepatosplenomegaly
  • Peripheral neuropathy
  • Low C4

24
Renal Disease
  • 20 of patients at the time of diagnosis
  • Asymptomatic hematuria and proteinuria, low
    complement and N creatinine, HBP
  • ARF, nephrotic syndrome less common
  • Eventually occurs in 35 to 60 of patients with
    type II disease, 12 in type III

25
Renal Disease
  • Thickening of the GBM and cellular proliferation
    (MPGN)
  • Specific findings
  • Intraluminal thrombi composed of precipitated
    cryoglobulins on light microscopy
  • Diffuse IgM deposition in the capillary loops on
    IF
  • Subendothelial deposits, fingerprint pattern

26
Renal Disease
  • Thickening of the GBM and cellular proliferation
    (MPGN)
  • Specific findings
  • Intraluminal thrombi composed of precipitated
    cryoglobulins on light microscopy
  • Diffuse IgM deposition in the capillary loops on
    IF
  • Subendothelial deposits, fingerprint pattern

27
MPGN (PAS microthrombi, hypercellular)
28
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29
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30
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31
Diagnosis
  • History, purpura, low C4,
  • Demonstrating circulating cryoglobulins
  • Cryocrit
  • Immunofixation, double diffusion in agar for type
    of abnormal protein
  • Chemical quantification
  • Biopsy

32
Treatment
  • Indications for active therapy are organ
    threatening disease (ARF, amputation, advanced
    neuropathy)
  • Type I- Rx underlying malignancy
  • Type II/III Plasmapheresis/Steroids/Cyclophosphami
    de, Antiviral, ?Rituximab

33
Plasmapheresis
  • Plasmapheresis (to remove the circulation
    cryoglobulins)
  • Steroids (1000 mg of intravenous
    methylprednisolone daily times three, followed by
    conventional oral prednisone)
  • Cyclophosphamide to prevent new antibody
    formation
  • ?steroids enhance HCV replication

34
Plasmapheresis
  • Uncontrolled observations 15 patients (DAmico et
    al. 1984)
  • reduction in the plasma creatinine concentration
    in 55 to 87 of patients
  • 4-39 Rx needed, average 13

35
Plasmapheresis
  • Rx
  • Eexchange one plasma volume three times weekly
    for two to three weeks

36
Plasmapheresis Efficacy
  • Changes in the percent cryocrit after
    plasmapheresis do not correlate closely with
    clinical activity
  • Percent solubility of the cryoglobulins at 37ºC
    or a decline in the temperature at which the
    cryoproteins precipitate may be a better index of
    the response to therapy (not commonly performed
    tests)

37
Plasmapheresis Efficacy
  • Successful plasmapheresis should
  • lead to rapid resolution of purpuric lesions
  • Return toward baseline if there has been a recent
    elevation in the plasma creatinine concentration
  • signs of neuropathy are not likely to remit
    during short-term therapy.

38
Antiviral Therapy
  • ?-interferon has been recommended in MC patients
    with HCV induced viremia
  • Randomized trial (Misisani et al. NEJM
    1994330751)
  • HCV RNA fell to undetectable levels in 60 of
    patients in the ?-interferon group
  • Improvement in the cutaneous vasculitis,
    cryoglobulin titers, and in the plasma creatinine
    concentration

39
Antiviral Therapy
  • All who responded relapsed upon D/C of
    ?-interferon
  • Anecdotal observations of reversal of MPGN after
    ?-interferon

40
Antiviral Therapy
  • Evidence for efficacy of combination IFN
    ribavirin in HepC MC
  • Case series of 9 patients refractory to IFN alone
    (Zuckerman et al. J Rheumatol 2000 27 2172)
    cryo decreased, skin vasculitis, symptoms
    improved
  • Pegylated IFN ribavirin recommended if no CRF
    contraindication.

41
Antiviral Therapy
  • ?-interferon immunostimulating activity may
    aggravate renal disease and vasculitic lesions?
    use in patients with low-grade kidney
    involvement, delay 2-4 months in severe disease
    Rxed with PLEX immunosuppression (?unable to
    clear HepC anyway)

42
Rituximab
  • Human/mouse chimeric antiCD20 Ab
  • Interferes with B cell autoimmunity unknown
    mechanism
  • Eliminates peripheral CD20 B lymphocytes
  • Total IgG and IgA unchanged, IgM moderately
    decreased
  • Well tolerated, rare allergic reaction
  • Case reports of use in mixed type II

43
Rituximab
  • Zaja et al. Blood 2003 1013827-3834
  • 14 consecutive type II MC (12 HCV related, all
    HIV-, 1 Sjogren, 2 essential)
  • Cutaneous vasculitis improved in all, RF, cryo,
    steroid use decreased in all treated
  • Proteinuria improved in 1 patient with MPGN
  • No serious infection, 1 patient had retinal
    artery thrombosis NYD

44
Rituximab
  • Sansonne et al. Blood 2003 1013818
  • 20 patients mixed cryo resistant to IFN Rx
  • Rituximab q week for 4 weeks 80 response
    initially, 12 in remission at one year
  • HepC viral levels doubled in responders however

45
Rituximab
  • Arzo et al. Ann Rheum Dis 2002 61922-924
  • Case report 71F essential type II MC (HepC-)
  • Palpable purpura6y, neuropathy 2y
  • ARF postop-BxMPGN, cryocrit 1.7, RF 396
  • Rx prednisone 60 4 months- no response
  • Rx Rituximab qweek6 weeks, crea down to 120,
    cryo neg., improved purpura/neuropathy, 8 month
    remission
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