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

1. Rheumatology Rounds3-23-07A rose by any other name . . . . Amit Golding 2nd year fellow

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

4. 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 Horner�s 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.

5. 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.� Clinical History Continued . . .

6. 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.

7. 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. Clinical History Continued . . .

8. 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. Clinical History Continued . . .

9. 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 1:1280 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. Clinical History Continued . . .

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

11. Additional Review of Systems HEENT�no significant sinus symptoms, dry eyes, or dry mouth; no alopecia, no recurrent oral ulcers Skin�no malar rash, no discoid rash, no photosensitive rash; no ulcers Cardiopulmonary�no chest pain, no palpitations, no leg swelling, no significant dyspnea Vascular�no Raynaud�s, no history of blood clots or miscarriages

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

13. SH and FH Social History: Retired, married with 2 children 40+ PYH (later quit in 2006) Insignificant alcohol

14. 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 Cardiovascular�RRR, 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 exam�no obvious Horner�s 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

15. Summary of clinical presentation by organ system

17. Diagnostic criteria CSS and frequency of organs involved

18. 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 > 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

19. Additional Work-up P/C-ANCA and MPO/PR3 all negative ANA (repeat) +1:1280 H pattern, however more recent have been negative Anti-Gliadin/Transglutaminase negative IgE ESR % Eos SPEP�No MGUS WBC 8.7-9.4 (normal diff.) BUN/Creatinine stable at 29/1.3

20. Progression of GI symptoms�Acute 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.

22. Eosinophilic Enteritis

23. Consideration of Primary or secondary hypereosinophilic syndrome�Summary of HES/comparison to CSS

24. Causes of Eosinophilia and Definition of Hypereosinophilic Syndrome

25. 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 1999:Among 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.

26. 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).

27. 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)

28. Thank You

29. Work up for elevated IgE