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The Case of the Sassy Blistering Woman

The Case of the Sassy Blistering Woman. www.AssignmentPoint.com. Introducing J.M. ID: 65 yo F with two week history of “blisters” Admitted initially to St. Joseph’s hospital, but then transferred to UWMC for further evaluation when KOH prep of blister fluid from heel showed hyphal elements

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The Case of the Sassy Blistering Woman

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  1. The Case of the Sassy Blistering Woman www.AssignmentPoint.com

  2. Introducing J.M. • ID: 65 yo F with two week history of “blisters” • Admitted initially to St. Joseph’s hospital, but then transferred to UWMC for further evaluation when KOH prep of blister fluid from heel showed hyphal elements • Blisters began on each heel, then progressed up the legs, and then involved the hands. Started as red spots, progressed to blisters and painful bumps. • 4-day history of eruption on the face • Blisters began 3 days after patient started furosemide for ankle edema • Cold-like symptoms occurred shortly before first blisters appeared • Review of systems unremarkable. No F/C/NS/wt loss. Excellent appetite. No arthralgias/myalgias. Organ-based ROS all negative.

  3. J.M.’s Past Medical History • Pyoderma gangrenosum since 2001– flares if prednisone < 20 mg/day. Had skin grafts in 2001 on legs. • “monoclonal gammopathy” of some type with recent bone marrow biopsy • HTN • Hyperlipidemia • Osteoporosis • Fibrocystic breast disease • Active 45 pack-year smoking history • S/P hysterectomy • H/O colonization with MRSA

  4. J.M.’s Medication History • Allergies/Intolerances: codeine, diazepam • Prednisone 20 mg qd • Azathioprine 50 mg bid • Furosemide 40 mg qd (started 17 days ago) • Simvastatin • Potassium chloride • Premarin • ASA • Alendronate • Alprazolam • Celexa • MVI

  5. Physical Examination • VS: T = 35.9o C, P = 106, BP = 111/67, RR = 20, SaO2 = 93% on RA • Gen: sassy elderly female lying in bed in NAD, interactions appropriate. • HEENT: anicteric, OP clear. • Neck: no masses/LAD. Normal JVP. • Abdomen: No masses, no HSM. • LN: No cervical, axillary or inguinal LAD. • Ext: No clubbing. Trace bilateral LE pitting edema. Good peripheral pulses. • Neuro: alert and oriented with no focal deficits noted.

  6. Physical Examination

  7. Physical Examination

  8. Physical Examination

  9. Physical Examination

  10. Physical Examination

  11. Laboratory and diagnostic studies • Chem 7: Na = 129, K = 3.4, Cl = 85, HCO3 = 25, BUN = 35, Cr = 1.1, Glu = 144 • CBC: WBC = 19.6 with neutrophils = 18.03 (92%), Hct = 34 (MCV 91) • Ca/Mg/Phos, LFTs, INR unremarkable • UA and urine culture normal • Blood cultures with no growth • Direct exam of blister fluid on left leg x 3 showed 2-4+ WBCs, no organisms. Bacterial, fungal and viral cultures negative. Viral FA negative. • CXR: emphysematous changes with no masses or infiltrates • EKG: NSR with RAD, LV hypertrophy by voltage criteria

  12. Differential diagnosis • Acute febrile neutrophilic dermatosis • Pyoderma gangrenosum • Drug reaction • Cutaneous malignancy • Infection secondary to immunosuppresion

  13. Histopathology “Right palm plaque” “Left leg bulla”

  14. Histopathology

  15. Differential diagnosis • Acute febrile neutrophilic dermatosis • Pyoderma gangrenosum • Drug reaction • Cutaneous malignancy • Infection secondary to immunosuppresion

  16. Sweet’s original report in 1964 • 8 female patients between 32 and 55 seen over 15 years • Patients were ill • One or more asymmetric erythmatous patches progressing to raised painful plaques (0.5-4 cm) • Some plaques gave the illusion of a “multiocular blister”, some had small central pustules • Active phase was 1-2 months depending on treatment with steroids • No scarring • No other physical exam abnormalities • Infection workups unrevealing • Five of eight had one or more recurrences • Neutrophilic infiltrates seen on pathology • Diff dx: erythema multiforme, erythema elevatum diutinum, pyoderma gangrenosum, erythema nodosum, bromide/iodide eruption • Postulated a steroid responsive reactive process

  17. 1964 • Martin Luther King wins the Nobel Peace Prize and the Civil Acts Right is signed by LBJ • The Palestine Liberation Organization is founded • Khruschev is deposed in Moscow and replaced by Brezhnev • Conflict in Vietnam escalates as US warships are attacked in the Gulf of Tonkin • Nelson Mandela given life sentence (but will be freed in 1990 and elected president of S. Africa in 1994) • Japan unveils the “bullet train” (130 mph top speed)

  18. 1964 • “I Want To Hold Your Hand” tops the charts • The Rolling Stones begin their first tour of the US • The mini-skirt debuts and is a hit worldwide • Sidney Poitier wins an Oscar for his performance in “Lilies of the Field” (Best picture? “Tom Jones”) • Caldecott Medal awarded to Maurice Sendak for “Where the Wild Things Are” • Cassius Clay wins the world heavyweight title • Summer Olympics held in Tokyo, winter Olympics held in Innsbruck • St. Louis beats the Yankees (4-3) for the World Series title (Bob Gibson is the MVP)

  19. Sweet’s syndrome • Fever • Neutrophil leukocytosis of the blood • Painful plaques/nodules on the limbs, face and neck • 0.5 – 12 cm in size, enlarge over days-weeks • red-purple in color • single or multiple, often asymmetric • can be bullous/vesicular in appearance • Histologically dense infiltrates with mature PMNs • usually infiltrate in superficial dermis, +/- eos and lymphs • can be diffuse or perivascular • papillary edema common • epidermis usually spared; occasional spongiosis, exocytosis, subcorneal pustule • No evidence of infection • Responds to corticosteroids

  20. Additional features of Sweet’s syndrome • Pathergy – biopsy sites, trauma, radiation tx, sunburn • Oral lesions – mucosal ulcers, swollen tongue • Eyes – conjunctivitis, scleritis, iritis, glaucoma, hemorrhage • Bones – arthralgias, aseptic osteomyelitis, aseptic osteitis, neutrophils in synovial aspirates • CNS – aseptic meningitis, neuro sxs, central pareses, pysch sxs • Liver – lab abnormalities • Kidney – lab abnormalities • Intestines – lower GI sxs • Lungs – lesions on bronch, abnormalities on CXR • Musculoskeletal – myalgias

  21. Clinical settings of Sweet’s syndrome • “Classic” Sweet’s syndrome • Malignancy-associated Sweet’s Syndrome (MASS) • Drug-induced Sweet’s syndrome

  22. Classic Sweet’s syndrome • F:M ~ 4:1 • No racial preference • Ages 30-50 (youngest reported 7 wks old) • Idiopathic • Infections (Strep - URI, Yersinia -GI) • Pregnancy • Inflammatory bowel disease

  23. Malignancy-associated Sweet’s syndrome • M=F • Incidence difficult to establish (7-56%). Cohen and Kurzrock reviewed 448 patients with Sweet’s; 20% had evidence of a solid or hematologic tumor • Hematologic malignancies: AML most common • Solid tumors: GU, breasts, GI tract

  24. Diagnostic criteria for classic Sweet’s or MASS • Major criteria (both required) • Abrupt onset of painful erythematous plaques or nodules • Dense neutrophilic infiltrate (without evidence of LCV?) • Minor criteria (two of four required) • Fever > 38o C • History of associated illness or malignancy • Response to treatment with potassium iodide or steroids • Three of four lab abnormalities: • WBC > 8000 • Neutrophils > 70% • ESR > 20 • Positive CRP Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282 Su WP and Liu HN, Cutis (1986) 37, 167-174

  25. Malignancies IBD Autoimmune Infection Other Diseases reported in association with Sweet’s syndrome • AML • Myelodysplasia • CML • Multiple myeloma • Solid tumors (GU, GI and breast) • Crohn’s • Ulcerative colitis • Rheumatoid arthritis • SLE • Thyroid disease (Grave’s, Hashimoto’s) • Post-infection (bacterial, fungal, parasitic) • Behcet’s • Sarcoidosis • Erythema nodosum • Pregnancy

  26. Drug-induced Sweet’s syndrome • F:M = 3:1 • G-CSF is big culprit • All-trans-RA, CBZ, hydralazine, OCPs, minocycline, nitrofurantoin, TMP-SMX • M.W. Cobb: JAAD 1989, “Furosemide-induced eruption simulating Sweet’s syndrome” • Clinical and histological features of Sweet’s syndrome, but no fever

  27. Diagnostic criteria for drug-induced Sweet’s syndrome • All five criteria required • Abrupt onset of painful plaques or nodules • Dense neutrophilic infiltrate (without evidence of LCV?) • Fever > 38o C • Temporal relation between drug onset and clinical • onset OR temporally related recurrence after re- • challenge with drug • Temporal relation between withdrawal of drug OR • resolution with systemic corticosteroids Adapted from Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282 and Walker DC and Cohen PR, J Am Acad Dermatol (1996) 34, 918-923

  28. Clinical features in Sweet’s syndrome Classic Heme Solid Drug- Malignancy Tumor Induced • Epidemiology • Female 80 50 (33/66) 59 71 • Prior URI/GI infxn. 75-90 16 (11/69) 20 21 • Recurrence 30 69 (37/54) 41 67 • Symptoms • -Fever > 38C 80-90 88 (50/57) 79 100 • -Musculosk. involv. 12-56 26 (18/69) 34 21 • -Ocular involv. 17-72 7 (5/69) 15 21 • Lesion locations • -Upper extrem. 80 89 (58/65) 97 71 • -Head/neck 50 63 (41/65) 52 43 • -Trunk/back 30 42 (27/65) 33 50 • -Lower extrem. Infreq. 49 (32/65) 48 36 • -Oral mucous memb. 2 12 (8/65) 3 7 • Lab findings • -Neutrophilia 80 47 (29/62) 60 38 • -Elev. ESR 90 100 (25/25) 95 100 • -Anemia Infreq. 68 (40/49) 50 50 • -Abnormal renal fxn. 11-50 15 (10/69) 7 0 Adapted from Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282

  29. Vasculitis and the histopathology of Sweet’s syndrome • 28 biopsy specimens from 21 patients satisfying diagnostic criteria for Sweet’s syndrome (classic or MASS) • Vasculitis: fibrinoid necrosis and intramural inflammation • Vasculitis as defined found in 6/28 specimens (21%) • Evidence of RBC extravasation and intramural inflammatory cells seen in 21/28 specimens (79%) • Specimens with vasculitis examined by IF for presence of IgG, IgM, IgA and C3 with appropriate controls • No immune complex deposition detected with Sweet’s samples • Proposal: vasculitis can be seen as an epiphenomenon in Sweet’s syndrome Malone JC et al., Arch Dermatol (2002) 138, 345-349.

  30. Pathogenesis of Sweet’s syndrome ?

  31. The non-infectious neutrophilic dermatoses • Non-angiocentric • Psoriasis • Reiter’s syndrome • Subcorneal pustular dermatosis (Sneddon-Wilkinson) • Acne fulminans • Neutrophilic eccrine hidradenitis • Blastomycosis-like pyoderma (pyoderma vegetans) • Angiocentric • Vessel wall destruction (leukocytoclastic vasculitis, polyarteritis nodosa) • No vessel wall destruction • Acute febrile neutrophilic dermatosis (Sweet’s) • Pyoderma gangrenosum • Behcet’s disease • Pustular vasculitis • Bowel-associated dermatosis-arthritis syndrome (BADAS) • Rheumatoid neutrophilic dermatosis • Pyostomatitis vegetans • Pustular eruption of ulcerative colitis • Neutrophilic dermatosis of the dorsal hand • Familial Mediterranean fever

  32. Overlapping of the neutrophilic dermatoses Behcet’s EED Sned-Wilk PG Sweet’s Clin. Appear. papules ulcers pustules papules ulcers, nodules nodules Sweet’s-like, PG-like Pathergy yes yes -- -- yes Oral involv. ulcers ulcers -- -- ulcers Eye involv. conjunctivitis keratitis, -- keratitis, uveitis, Iritis, scleritis vasculitis vasculitis vasculitis Joint involv. arthritis arthritis arthritis arthritis arthritis Associations heme malig. heme malig. heme malig. heme malig. heme malig. IBD IBD IBD IBD e. nodosum e. nodosum e. nodosum sarcoid sarcoid thyroid dz. thyroid dz. thyroid dz. RA RA RA RA SLE SLE SLE Behcet’s Behcet’s PG PG Sweet’s, PG Histopath superficial ulcer subcorneal sup/mid dermis LCV dermis pustules LCV

  33. IL-17 Stem cell IL-3 CFU-GEMM CFU-GM IL-6 all-trans retinoic acid GM-CSF CFU-G myeloblast G-CSF T promyelocyte myelocyte MP metamyelocyte B band N E KC

  34. IL-8 C5a LTB4 PAF fMLP IgG Chemoattractants and chemotaxis Phagocytosis C3b IL-1 IL-2 TNFa G-CSF GM-CSF Neutrophil activators

  35. Classic chemoattractant Ga g Ras GTP b GTP PLC Raf Rho PI3K IP3 DAG Rac Adhesion, chemotaxis, ROS MEK PKC Ca MAPK Membrane ruffling, ROS cPLA2 AA Adhesion, ROS Adhesion, transcription, aggregation Adapted from Burg ND and Pillinger MH (2001) Clin Immunol 99, 7-17

  36. Adhesion b1 integrin CD11/CD18 L-selectin PECAM 12-HETE IL-8 C5a LTB4 PAF fMLP IgG Chemoattractants and chemotaxis Phagocytosis C3b IL-1 IL-2 TNFa G-CSF GM-CSF Neutrophil activators Keratinocytes

  37. b1 and b2 integrins 3. infiltration PECAM 2. transmigration 1. “rolling” CD11/CD18 (LAD) sialyl Lewis X E and P selectin ICAM Adapted from Von Den Driesch (2000) Clin Dermatol 18, 233-244

  38. Adhesion b1 integrin CD11/CD18 L-selectin PECAM IL-8 C5a LTB4 PAF fMLP IgG Chemoattractants and chemotaxis Phagocytosis C3b Enzymatic destruction -cathepsins -azurocidins/defensins -elastases -lysozymes -phospholipases -glycosidases IL-1 IL-2 TNFa G-CSF GM-CSF Reactive oxygen species (NADPH oxidase) Neutrophil activators

  39. IgG Phagocytosis C3b Interference with phagocytosis: dapsone

  40. Adhesion b1 integrin CD11/CD18 L-selectin PECAM • Interference with • integrin-mediated adhesion: • corticosteroids • dapsone

  41. IL-8 C5a LTB4 PAF fMLP Chemoattractants and chemotaxis IL-1 IL-2 TNFa G-CSF GM-CSF Neutrophil activators Interference with Chemotaxis: - potassium iodide - colchicine - tetracycline Inhibtion of TNFa: thalidomide

  42. Enzymatic destruction -cathepsins -azurocidins/defensins -elastases -lysozymes -phospholipases -glycosidases Reactive oxygen species (NADPH oxidase) Inhibits secretion of neutrophil lysosome: - colchicine Scavenge ROS: -dapsone Inhibit generation Of ROS: -thalidomide -tetracycline -erythromycin -metronidazole -sulfasalazine (also induces PMN apoptosis)

  43. Scientific advances since 1964 • First beta-blocker synthesized (propranalol, 1964) • First human heart transplant (1967) • Restriction endonucleases discovered (1968) • Interleukin-1 is identified (1972) • Acyclovir is developed (1972) • Computer assisted tomography invented (1973) • DNA sequencing is developed (1977) • In vitro fertilization is accomplished (1978) • Polymerase chain reaction developed (1983) • HIV identified (1984) • Dolly is cloned (1996) • Human genome working draft is completed (2000) • Fleckman declares pathogenesis of Sweet’s still unclear (2002)

  44. Treatment of Sweet’s syndrome • Spontaneous resolution • 4/8 of women in Sweet’s original report • 9 published reports from 1964-1997 • 33/208 (16%) with spontaneous resolution • Cure underlying condition – infection, cancer • Discontinue offending medications • No randomized control trials exist for documenting the effectiveness of pharmacologic interventions

  45. Corticosteroids • Still the treatment of choice • Systemic: • 0.5-1.5 mg/kg/day average from a dozen studies • Tapered over 1 – 12 weeks • Pulsed methylprednisolone 250 – 1000 g/day x 3 days • Topical: • Fluocinonide, diflorasone • Primary or adjuvant therapy • Intralesional: • TAC at 3 – 10 mg/cc • ACTH

  46. Other therapeutic agents • Potassium Iodide (>10 reports/series) • 300 - 950 mg/day • Colchicine (5 reports/series) • 1 – 1.5 mg qd/qod • Cyclosporine (5 case reports/series) • 2 – 10 mg/kg/day • NSAIDS (8 reports/series) • Indomethacin, 150 – 750 mg qd/qod • Not always useful

  47. Other therapeutic agents • Antimicrobials • Tetracycline class • Antimicrobials implicated in drug-induced Sweet’s • Sulfones (9 reports/series) • Dapsone 100 – 200 mg qod • Sulfapyridine also used for IBD • Infliximab • Crohn’s disease

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