Rheumatology Rounds 3-23-07 A rose by any other name . . . .

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Rheumatology Rounds3-23-07A rose by any other
name . . . .

• Amit Golding
• 2nd year fellow

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Amit Golding MD PhD March 23 2007
Disclosures
No Relevant Financial Relationships with
Commercial Interests
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Objectives

• Educational Presentation
• Diagnostic approach to patients with overactive
  eosinophils and elevated IgE
• Discussion of Churg Strauss Vasculitis versus
  Hypereosinophilic Syndrome

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Clinical History

• 65 yo woman develops generalized pruritus and
  maculopapular rash.
• A few months later, she develops a persistent
  cough and is diagnosed with bronchial asthma.
• February 2004, she wakes up with double vision
  and work-up reveals a right cerebellar infarct.
  She is also noted to have ptosis and myosis on
  the right and given a diagnosis of Horners
  syndrome.
• While hospitalized for stroke a chest x ray shows
  a right upper lobe infiltrate for which she is
  empirically treated with antibiotics for
  community acquired pneumonia.
• She subsequently develops frequent fevers as high
  as 102 and night sweats as well as generalized
  fatigue and muscle weakness. ESR is elevated at
  115 with polyclonal hypergammaglobulinemia.
• An evaluation of the weakness includes positive
  (LEMS) antibody testing for Lambert Eaton
  syndrome, although this was not confirmed by
  nerve conduction testing.

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Clinical History Continued . . .

• A malignancy work-up is initiated, focusing
  especially on lungs because of positive smoking
  history and Lambert Eaton (often associated with
  small cell lung cancer). RUL positive by PET.
  August 2004 Bronchoscopy with BAL RUL reveals
  primarily macrophages and no malignant cells are
  found.
• The RUL infiltrate later resolves and subsequent
  CT of chest in 2005 shows No significant
  axillary, mediastinal, or hilar LAN. No pleural
  or pericardial effusions. Pulmonary parenchyma
  demonstrates scattered bilateral increased
  interstitial marking primarily at the periphery.
  Scattered bullous changes are also noted which
  may indicate COPD/emphysema.

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Clinical History Continued . . .

• March 2004, she develops crampy abdominal pain
  and explosive watery stools. A colon biopsy
  reveals collagenous colitis (later confirmed by
  pathology at JHH).
• Treatment for collagenous colitis is initiated
  with prednisone 40 mg daily as well as mesalamine
  (Asacol) and colestopil (Colestid).
• She initially has a good response with reduced
  diarrhea, however GI symptoms recurred when
  prednisone is tapered below 10 mg daily.

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Clinical History Continued . . .

• She is then seen by an outside rheumatologist who
  refers her for a mesenteric angiogram to evaluate
  for vasculitis as underlying cause of GI and
  constitutional symptoms. She is tapered off
  prednisone prior to the angiogram
• October 2004 Angiogram shows mild narrowing of
  proximal left renal artery, proximal superior
  mesenteric artery. There is no typical beading
  pattern of diffuse stenotic lesions noted which
  are typical of vasculitis.

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Clinical History Continued . . .

• December 2004 she is evaluated by Dr. Bayless in
  JHH GI division. She is on prednisone 10 mg
  daily at the time. He initiates budesonide
  (Entocort) and has her taper off of prednisone
  over a 3 month period.
• She is referred by Dr. Bayless for repeat
  colonoscopy because of a few episodes of
  BRBPR?March 2005 colonoscopy mild chronic
  inflammatory infiltrates of plasma cells and
  lymphocytes. Eosinophils are also present. No
  increase in intraepithelial lymphocytes.
• On follow-up in June 2005, her diarrhea symptoms
  remain well-controlled on budesonide and
  mesalamine.

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Clinical History Continued . . .

• In September, 2005 she follows up with her
  neurologist (previously seen for cerebellar
  stroke and possible Lambert Eaton), who orders a
  ANA, which is positive at 11280 in a homogeneous
  pattern, ESR elevated at 65, and IgE elevated at
  2,254 eosinophils normal at 3.5.
• She is then referred to JHH rheumatology for
  evaluation of positive ANA and elevated ESR.

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First contact Nov. 2005chief complaints are
fatigue and pruritic rash

• She describes generalized fatigue
• this is in fact is one of the symptoms that
  troubles her the most as she feels as if she is
  much less active than she previously was and
  feels less active than she should be at the age
  of 67.
• For the last 1 or 2 months, she has had a
  significant pruritic maculopapular red rash
  primarily over her back and the skin overlying
  her breasts, which is constantly itching her and
  on occasion interfering with sleep.  She has
  taken Benadryl with some relief on occasion.
• Diarrhea and cough are well controlled

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Additional Review of Systems

• HEENTno significant sinus symptoms, dry eyes, or
  dry mouth no alopecia, no recurrent oral ulcers
• Skinno malar rash, no discoid rash, no
  photosensitive rash no ulcers
• Cardiopulmonaryno chest pain, no palpitations,
  no leg swelling, no significant dyspnea
• Vascularno Raynauds, no history of blood clots
  or miscarriages

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PMH and Meds

• Advair Diskus
• Cozaar
• Prevacid
• Premarin
• Levoxyl
• HCTZ
• Budesonide
• Asacol
• Colestid
• Aspirin

• HTN
• Graves s/p ablation
• GERD
• Benign positional vertigo
• Closed head injury in 1989
• S/P tonsillectomy and hysterectomy

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SH and FH

• Social History
• Retired, married with 2 children
• 40 PYH (later quit in 2006)
• Insignificant alcohol

• Family History
• Father died at the age of 46 with an MI mother
  died at the age of 30 in a motor vehicle
  accident.
• Maternal aunt has history of Raynauds and
  possibly lupus.
• Maternal grandparents have history of stroke
• Paternal grand-parents have history of coronary
  artery disease.
• One daughter with history of asthma and one son
  who in good health

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Physical Exam at first encounter

• bp 130/70, pulse 80, afebrile, 188lbs
• HEENT--No oral ulcers or malar rash normal
  saliva
• Lungs--clear to auscultation bilaterally
• CardiovascularRRR, Normal S1 and S2,  No
  murmurs, rubs or gallops. JVP is not
  elevated.  Carotids are 2 plus bilaterally
  without bruits. Radials are 1 plus bilaterally
  and dorsalis pedis are 1 plus bilaterally
• Abdomen soft, nontender, nondistended with
  positive bowel sounds
• Neuro examno obvious Horners signs of ptosis,
  myosis, and anhidrosis. Strength 5/5 in upper and
  lower extremities including proximal and distal
  muscles
• Joint exam--no synovitis
• Skin exam--a maculopapular rash with excoriations
  on her low back and buttock as well as on her
  upper chest no evidence of palpable purpura

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Summary of clinical presentation by organ system
Summary of relevant laboratory data
ESR elevation Polyclonal Hypergammaglobulinemia Ig
E elevation Normal blood eosinophil
count Positive high-titer ANA (IgE-ANA?)
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Does she have Churg-Strauss Syndrome?
Christian Pagnoux, Philippe Guilpain and Loic
Guillevin Current Opinion in Rheumatology 2007,
192532
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Diagnostic criteria CSS and frequency of organs
involved
Keogh and Specks
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Typical lab and pathology findings in CSS

• Path--necrotizing vasculitis affecting small to
  medium-sized vessels, often with eosinophil
  infiltration into vessel wall and occasional
  granulomas BAL typically with prominent
  eosinophils various organs showing eosinophilic
  infiltrates with or without vasculitis
• Labs
• Elevated ESR/CRP
• Peripheral eosinophilia, frequently gt 1,500
• Elevated IgE
• ANCA, especially MPO (eosinophils have
  myeloperoxidase too) in 38-50 and ANCA
  positivity in some series associated with higher
  incidence of more severe vasculitis involving
  P/CNS and Kidney

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Additional Work-up

• P/C-ANCA and MPO/PR3 all negative
• ANA (repeat) 11280 H pattern, however more
  recent have been negative
• Anti-Gliadin/Transglutaminase negative
• IgE
• ESR
• Eos
• SPEPNo MGUS
• WBC 8.7-9.4 (normal diff.)
• BUN/Creatinine stable at 29/1.3

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Progression of GI symptomsAcute Abdomen/Small
Bowel Obstruction

• In May of 2006, she went to the ED because of
  severe abdominal pain and projectile vomiting
• Abdominal X-ray Abnormal bowel gas pattern
  consistent with small bowel obstruction.
• 5/12/2006 Ressected small bowel obstruction
  transmural defect at site of obstruction
  adjacent small bowel shows mild acute and chronic
  inflammatory cells extending through muscularis
  propria into the submucosa. no mention of
  vasculitis or thromboembolism
• Biopsy later reviewed by Dr. Montgomery at JHH
  ACUTE ENTERITIS WITH ULCERATION. FOCAL EXPANDED
  MUSCULARIS MUCOSAE AND SUBMUCOSA FIBROSIS IN
  KEEPING WITH PRIOR HEALED TRANSMURAL INJURY.
  SEROSAL ADHERIONS. ZONES WITH MURAL EOSINOPHILIC
  ENTERITIC PATTERN PROMINENT EOSINOPHILS IN
  MUSCULARIS PROPRIA. FOCAL MURAL SCLEROSIS.

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(No Transcript)
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Eosinophilic Enteritis
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Consideration of Primary or secondary
hypereosinophilic syndromeSummary of
HES/comparison to CSS
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Causes of Eosinophilia and Definition of
Hypereosinophilic Syndrome
Finella Brito-Babapulle British Journal of
Haematology, 2003, 121, 203223
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What is driving this process of IgE elevation/
eosinophilic enteritis/dermatitis/asthma in our
patient?

• An obvious suspect T cell making
  Th2/pro-eosinophil cytokines, especially IL-5
• Published literature has identified abnormal T
  cells that overproduce IL-5 leading to a HES-type
  picture
• Simon et al ABNORMAL CLONES OF T CELLS PRODUCING
  INTERLEUKIN-5 IN IDIOPATHIC EOSINOPHILIA in NEJM
  1999Among 60 patients with idiopathic
  eosinophilia, 16 had circulating T cells with an
  aberrant immunophenotype. Evidence of clonal
  rearrangements of the T-cell receptor was
  obtained in 8 of the 16 patients. Moreover, the
  aberrant T cells produced large amounts of
  interleukin-5 in vitro.

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Eureka Moment

• Because of increasing total IgE and suspicion for
  underlying hematologic malignancy/aberrant T cell
  population, she was urged to see a hematologist/
  oncologist.
• Bone marrow biopsy revealed 31/400 cells positive
  for BCR-ABL translocation (PCR negative in
  peripheral blood).
• Currently being evaluated for clonal TCR
  rearrangements.
• Plan for repeat bone marrow confirmation of
  BCR-ABL as she otherwise does not clearly have
  CML, i.e. no leukocytosis or thrombocytosis.
• If BCR-ABL confirmed, she may then be a candidate
  for Imatinib (Glevac).

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New treatments for HES/IgE mediated syndromes

• Imatinib found to be especially potent in HES
  patients with novel tyrosine kinase produced by
  deletion on chromosome 4
• Mepolizumab (Anti-IL-15)
• Omalizumab (Anti-IgE)

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Thank You
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Work up for elevated IgE
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chronic granulocytic leukaemia (CGL) with
eosinophilia
The cytogenetic hallmark of CML is the
Ph chromosome that results from a reciprocal
t(922)(q34q11.2) translocation or its variants
t(V922) (3). The molecular consequence of this
translocation is the formation of the
BCR/ABL gene fusion usually located on the Ph
chromosome