The Case of Ms' C

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The Case of Ms. C

• Kumudini Gnanapandithen, PGY 3
• SMH Rheumatology Rotation
• January 17, 2006

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The Case Ms. C

• ID 60F, originally from Hong Kong
• PMH asthma (dx 2 yrs ago, stable)
• cholelithiasis
• hiatus hernia
• ? smoker, ? ETOH
• Allergy PENN
• FHx Lung Ca (mother/3 mat. Uncles)
• Pulmonary TB (father)
• Pemphigus vulgaris (sister)

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The Case Ms. C

• Travelled to HK and China Sept-Nov 05
• Dec 30 paresthesias progressing to weakness legs
  bilat. Severe/crampy abdo pain, frequent BMs,
  fever (38), chills, malaise.
• Jan 1 ER visit. d/cd on cipro
• Jan 3 returned to ER. BRBPR worsening abdo
  pain, worsening leg weakness, fever, vomiting.
  Admission.
• Inv Hb 120, plts 167, wbc 13.7, E? elevated
  U/A blood
  Flex Sig areas of
  sigmoid inflammation/necrosis. CT abdo
  signif thickened peritoneum, stranding,
  non-specific inflammation distal
  sigmoid/rectum.

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The Case Ms. C

• Jan 9 Despite ceftriaxone/flagyl, worsening abdo
  and neuro symptoms, febrile, BRBPR, hematuria,
  lethargy.
  
• WBC 23, Plt 33.
• Transferred to SMH

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The Case Ms. C

• On Exam
• Gen Oriented, fatigued
• Vitals BP 130/70 HR 100 T 38.2 SpO2 96 RA
• H/N pale
• Chest clear
• CVS Bilat SOA, bilat splinter hemorrhages
• Abdo Soft, generalized tenderness
• Neuro Bilat severe weakness of hip, knee
  flex/ext, foot drop with sensory abnormality.
  No spinal level.
• Derm Echymoses bilat in UEs and LEs. No rashes.
• MSK No active joints.

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The Case Ms. C

• Investigations
• CBC Hg 101, plt 33, wbc 23.7, N? 13.5, E? 7.48
• Lytes/Cr normal
• LFTs ALP 153, otherwise normal
• U/A blood
• Cultures All blood, urine, stool cultures/O P
  negative, AFB
• INR 1.73/ PTT normal
• Lactate 1.4

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The Case Ms. C

• Investigations
• CXR Normal
• CT abdo 5cm clot in IVC originating at R renal
  vein, IMV clot. Non-specific colitis of sigmid
  and rectum. Signif pelvic inflamm. (IVC filter
  inserted).
• Flex Sig Areas of non-specific inflammation of
  simoid/rectum. Area of sigmoid necrosis.
  Ischemic colitis diagnosed.

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Differential Diagnosis?
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DDx

• Infectious - schistosomiasis, helminth
  infections.
• Hematologic - Eosinophilic leukemia, CML, T-cell
  leukemia, idiopathic hypereosinophilic syndrome,
  drug reaction.
• Vasculitic PAN, Churg-strauss, SLE
• Paraneoplastic - ?lung, ?ovarian

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Further Investigations

• ESR 24
• C3 0.63/ C4 0.18
• RF lt20
• CK 45
• Plt Ab IgM
• Anticardiolipin Ab Negative
• Mesenteric Angiogram - Normal
• BM aspirate/Bx - Eosinophil hyperplasia with good
  maturation of the cell line. No leukemic
  changes.
• 2DE normal
• MRI spine signif iliopsoas inflammation, no
  cord lesions
• Pending - Sural nerve Bx, CT chest, pANCA, ANA,
  Hep serologies, hypercoag w/u.

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• Polyarteritis Nodosa (PAN)
• Churg-Strauss Syndrome (CSS)
• Hypereosinophilic Syndrome (HES)

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Polyarteritis Nodosa (PAN)

• Definition
• Necrotizing inflammation of medium sized or small
  arteries that spares the smallest blood vessels
  (arterioles ? venules) and is not associated with
  GN
• Affects multiple organs, especially the skin,
  peripheral nerve, gut, kidney, and heart.
• Thought to be immune complex mediated
• Patients with classic PAN are typically
  ANCA-negative
• Epidemiology
• Rare
• Annual incidence rates range from 2-9
  cases/million/yr.
• Most occur in the 4th or 5th decade
• Malefemale 21
• A minority have active Hep B infection

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Clinical Presentation

• Systemic symptoms
• Cutaneous vasculitis palpable purpura, livedo
  reticularis, digital gangrene, or tender nodules.
  
• PNS - infarction of multiple mixed motor and
  sensory nerves resulting in mononeuritis
  multiplex. If present -highly suggestive of
  vasculitis
• Renal - vasculitis with hypertension 50 of pts.
  (kidneys are the most commonly involved organ at
  autopsy)
• GI - abdominal angina, hemorrhage, perforation
• CVS -myocarditis, MI - occlusion of the
  coronaries. CHF, uncontrolled hypertension
• Rupture of renal or mesenteric micoaneurysms can
  simulate an acute abdomen

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The American College of Rheumatology 1990
criteria for the classification of Polyarteritis
Nodosa

• Weight loss of gt 4 kg since beginning of illness
• Livedo reticularis
• Testicular pain or tenderness
• Myalgias, weakness, or leg tenderness
• Mononeuropathy or polyneuropathy
• Development of hypertension
• Elevated BUN/creatinine unrelated to dehydration
  or obstruction
• Presence of hepB Sag/SAb
• Arteriogram demonstrating aneurysms or occlusions
  of the visceral arteries
• Biopsy of small or medium-sized artery containing
  granulocytes

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Lab Findings

• Normocytic anemia
• Thrombocytosis
• Elevated ESR
• Microscopic hematuria (absence of GN)

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Tissue Diagnosis

• Diagnosis must be confirmed by Bx of clinically
  affected organ
• Biopsy of a symptomatic nerve/ muscle (65
  sensitive)
• Biopsy of asymptomatic site (lt30 sensitive)
• mesenteric angiography (60 sensitive)
• Renal biopsy should be avoided unless angiography
  rules out microaneurysms susceptible to rupture
• Biopsy of GI lesions rarely provide confirmation
  of vascultitis

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Prognosis

• Untreated
• one-year and five-year survival rates 50 and 13
• Renal failure, mesenteric, cardiac, or cerebral
  infarction are the major causes of death
• Treated
• 80 survival at five years

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Therapy

• Corticosteroids
• Many remain steroid-dependent
• Long-term remissions can be induced with
  cyclophosphamide
• Combination therapy improves survival in severe
  disease
• Severe disease - renal insufficiency, mesenteric
  artery ischemia, mononeuritis multiplex

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Livedo Reticularis
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Renal Angiography in PAN
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Mesenteric Angiography in PAN
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PAN Histology

• calf muscle shows occlusion of the vessel due to
  thrombus (Thr) and fibrinoid necrosis (FN) of the
  vessel wall resulting in the weakness associated
  with aneurysm formation

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Churg-Strauss Syndrome (CSS)

• Characteristics
• allergic rhinitis
• Asthma
• prominent peripheral blood eosinophilia
  (gt5000/?L)
• Commonly affected organs lung, skin
• Other organ system CVS, GI, CNS

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CSS epidemiology

• Approximately 10 of patients with a major form
  of vasculitis are recognized to have CSS
• No gender predominance
• mean age at diagnosis is 50 years

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CSS clinical Presentation

• Sequential phases
• Prodromal phase atopic disease, allergic
  rhinitis (recurrent sinusitis, and nasal polyps),
  and asthma (95of pts)
• Eosinophilic phase peripheral blood
  eosinophilia and eosinophilic infiltration of
  organs, especially the lung, skin and GI tract.
• Vasculitic phase life-threatening systemic
  vasculitis of the medium and small vessels,
  associated with vascular and extravascular
  granulomatosis. Heralded by nonspecific
  constitutional symptoms and signs, especially
  fever, weight loss, malaise.

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ACR Criteria for CSS

• Presence of 4 or more of these criteria (in pt
  with documented vasculitis) has sensitivity of
  85 and a specificity of 99.7  
• Asthma
• Eosinophilia of gt10 percent on diff
• Mononeuropathy (including multiplex) or
  polyneuropathy
• Migratory or transient pulmonary opacities
  radiographically
• Paranasal sinus abnormality
• Biopsy containing a blood vessel showing the
  accumulation of eosinophils in extravascular
  areas

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CSS Clinical Features

• CVS Acute pericarditis, CHF, and MI.
• Neuro Peripheral neuropathy, usually
  mononeuritis multiplex (upto 75 pts) Cerebral
  hemorrhage and infarction.
• Renal FSGS (85), associated with necrotizing
  features and crescents. Eosinophilic infiltrates
  rare.
• HTN (29 pts). may reflect the frequency of
  renal infarction
• GI Eosinophilic gastroenteritis, abdo pain (59
  pts), diarrhea, GIB and colitis, may coincide
  with the vasculitic phase
• MSK Myalgias, polyarthralgias, arthritis
  uncommon and present only during the vasculitic
  phase of the disorder.

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Diagnosis

• Peripheral eosinophilia (5000 to 9000/µL) most
  characteristic finding
• pANCA (70-75)
• nonspecific
• Normochromic, normocytic anemia
• Marked elevation in ESR
• Leukocytosis
• Elevated IgE
• Circulating immune complexes
• Hypergammaglobulinemia
• RF at low titer
• CXR and CT
• Surgical lung biopsy is the gold standard
• sural nerve biopsy   

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CSS
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CSS
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CSS Histology

• Intra and extravascular granulomas, tissue
  eosinophilia, necrotising vasculitis

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Prognosis

• Untreated
• 50 mortality within 3 months of the onset of
  vasculitis.
• Treated
• Survival rate gt70 at five years if treated
• Most deaths occur in vasculitic phase    
• MI/ CHF (50 deaths)
• Cerebral hemorrhage
• Renal failure
• GIB
• Status asthmaticus

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CSS Treatment

• Corticosteroid therapy
• Responsiveness to Rx and recurrence followed by
  eosinophil count and ESR
• Late relapses after a successful Rx uncommon
• Cycxlophosphamide, imuran and high-dose IVIG in
  patients with severe, fulminant disease
• Plasma exchange - meta-analysis involving 140
  patients with GN due to CSS found it added no
  benefit to treatment with steroid

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Hypereosinophilic Syndrome (HES)

• Definition
• Blood eosinophilia of gt1500/µL, gt6 mo
• etiologically distinct diseases
• Clinical diagnosis/ diagnosis of exclusion
• Eosinophilic infiltration and mediator mediator
  release affects multiple organs causing clinical
  sequelae.

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HES

• Mechanisms for dysregulated overproduction of
  eosinophils
• Overproduction of eosinophilopoietic signals (eg,
  IL-3, IL-5, GM-CSF), possibly secondary to
  abnormalities in T-cell clones which normally
  produce these molecules
• Abnormalities of the eosinophilopoietic cytokines
  per se, perhaps related to enhanced or prolonged
  biologic activity
• Defects in the receptors for eosinophilopoietic
  signals
• Defects in the normal suppressive regulation of
  eosinophilopoiesis

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HES

• Etiologies for hypereosinophilia among patients
  with HES include
• Clonal abnormalities in the eosinophil lineage
• respond well to steroids     
• Atypical myeloproliferative variant (increased
  vit B12).
• Often refractory to steroids. respond to Gleevec
      
• T lymphocytic variants (underlying aberrations in
  T lymphocytes

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HES epidemiology

• Very rare
• menwomen 91
• Most patients are diagnosed when they are between
  20 and 50 years of age
• onset of HES is often insidious

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HES clinical Presentation

• Systemic symptoms
• Affected organs
• nervous system, lungs, cardiac and spleen
  (45-60)
• liver, ocular, GI (20-30)
• CVS - Eosinophilic myocarditis. Extracellular
  deposition of E? granule proteins and evidence of
  E? infiltration at sites of myocardial injury
• Heme - Anemia (50 pts), thrombocytopenia/thromboc
  ytosis/ signif thromboembolic events.
• BM E? and E? precursors. Chromosome studies are
  normal in the majority of pts

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HES Clinical Presentation

• Neuro Cerebral thromboemboli, encephalopathy,
  peripheral neuropathy/mononeuritis multiplex
• Mononeuritis multiplex 50 of the neurologic
  manifestations
• Bx axonal loss but no evidence of vasculitis or
  E? infiltration
• Cutaneous - angioedema/urticarial lesions,
  erythematous papules/nodules
• Bx perivascular infiltration with E? without
  vasculitis.
• Lung Chronic, nonproductive cough asthma is not
  a common feature. E? infiltration of the lung
  with fibrosis
• GI - Eosinophilic gastritis, enteritis, and/or
  colitis
• MSK - Arthralgias and large joint effusions

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Treatment of HES

• 1-5 day trial of prednisone early in the course
  of HES to ascertain whether blood eosinophilia is
  suppressible to normal levels or below
• Response to corticosteroids associated with
  better prognosis.
• If blood eosinophilia is suppressed, daily doses
  are slowly tapered to an alternate day schedule
  at the lowest dose that maintains control of the
  eosinophil count.
• Patients with HES likely to sustain responses to
  monotherapy with prednisone are those with
  angioedema, urticaria, and increased serum IgE
  concentrations and those with a prolonged
  eosinopenic response to a single dose of
  prednisone
• eosinopenia occurs within four hours of
  corticosteroid administration

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Treatment HES

• Interferon (IFN)-alpha has been effective in
  small case series. Mechanism of action not
  understood.
• Steroid-unresponsive HES chlorambucil,
  vincristine, etoposide, cytarabine.
• Tyr kinase inhibitors/gleevec at low dose
  promising
• Bone marrow transplantation There is limited
  experience

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Prognosis

• Initial case series 3-year survival of only 12
• Most patients in early series presented with
  advanced disease and significant cardiovascular
  compromise many deaths were due to heart failure
  or other complications of endomyocardial damage
• Earlier diagnosis, close cardiac monitoring have
  improved outcomes
• Findings which connote a better prognosis
  include
• Prolonged eosinopenia in response to
  corticosteroid administration, An elevated serum
  IgE concentration
• The absence of findings associated with
  myeloproliferative disorders high Vit B12,
  splenomegaly, cytogenetic abnormalities,
  myelofibrosis, myeloid dysplasia and basophilia

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HES
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Back to the Case

• Treated with high dose pulse steroids
• Next am
• Pt felt remarkably well, abdo pain signif
  improved
• Afebrile
• Wbc 11.34
• Plts 117
• E? 0.31

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