The case of the sassy blistering woman

Andy J. Chien

University of Washington

Department of Medicine

Division of Dermatology

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.

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

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

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.

Physical Examination

Physical Examination

Physical Examination

Physical Examination

Physical Examination

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

Differential diagnosis

• Acute febrile neutrophilic dermatosis

• Pyoderma gangrenosum

• Drug reaction

• Cutaneous malignancy

• Infection secondary to immunosuppresion

Histopathology

“Right palm plaque” “Left leg bulla”

Histopathology

Differential diagnosis

• Acute febrile neutrophilic dermatosis

• Pyoderma gangrenosum

• Drug reaction

• Cutaneous malignancy

• Infection secondary to immunosuppresion

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

• 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)

• “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)

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

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

Clinical settings of Sweet’s syndrome

• “Classic” Sweet’s syndrome

• Malignancy-associated Sweet’s Syndrome (MASS)

• Drug-induced Sweet’s syndrome

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

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

Diagnostic criteria for classic Sweet’s or MASS

Major criteria (both required)1. Abrupt onset of painful erythematous plaques or nodules2. Dense neutrophilic infiltrate (without evidence of LCV?)

Minor criteria (two of four required)1. Fever > 38o C2. History of associated illness or malignancy3. Response to treatment with potassium iodide or steroids4. Three of four lab abnormalities:

- WBC > 8000- Neutrophils > 70%- ESR > 20- Positive CRP

Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282Su WP and Liu HN, Cutis (1986) 37, 167-174

Other

Infection

Autoimmune

IBD

Malignancies

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

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

Diagnostic criteria for drug-induced Sweet’s syndromeAll five criteria required

1. Abrupt onset of painful plaques or nodules2. Dense neutrophilic infiltrate (without evidence of LCV?)3. Fever > 38o C4. Temporal relation between drug onset and clinical onset OR temporally related recurrence after re- challenge with drug5. Temporal relation between withdrawal of drug OR resolution with systemic corticosteroids

Adapted from Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282and Walker DC and Cohen PR, J Am Acad Dermatol (1996) 34, 918-923

Clinical features in Sweet’s syndrome

Adapted from Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282

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

Classic Heme Solid Drug- Malignancy Tumor Induced

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.

Pathogenesis of Sweet’s syndrome

?

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

Overlapping of the neutrophilic dermatosesSweet’s PG Sned-Wilk

Oral involv. ulcers ulcers -- -- ulcers

Eye involv. conjunctivitis keratitis, -- keratitis, uveitis, Iritis, scleritis vasculitis vasculitis vasculitis

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

Clin. Appear. papules ulcers pustules papules ulcers, nodules nodules Sweet’s-like,

PG-like

EED Behcet’s

Pathergy yes yes -- -- yes

Joint involv. arthritis arthritis arthritis arthritis arthritis

Histopath superficial ulcer subcorneal sup/mid dermis LCV dermis pustules LCV

Stem cell

CFU-GEMM

CFU-GM

CFU-G

myeloblast

promyelocyte

myelocyte

metamyelocyte

band

IL-3

IL-6

GM-CSF

G-CSF

IL-17

T

MP

B

N

E

KC

all-trans retinoic acid

IgG

C3bPhagocytosis

IL-8C5aLTB4PAFfMLP

Chemoattractantsand

chemotaxis

IL-1IL-2TNFG-CSFGM-CSF

Neutrophil activators

Classic chemoattractant

G

GTP

PI3K

Adhesion,chemotaxis,

ROS

PLC

IP3 DAG

Ca PKC

Adhesion,ROS

cPLA2AA

Ras GTP

Raf Rho

Rac

Membraneruffling,

ROS

MEK

MAPK

Adhesion,transcription,aggregationAdapted from Burg ND and Pillinger MH (2001) Clin Immunol 99, 7-17

IgG

C3bPhagocytosis

IL-8C5aLTB4PAFfMLP

Chemoattractantsand

chemotaxis

CD11/CD18

L-selectin

Adhesion

1 integrin

PECAM

IL-1IL-2TNFG-CSFGM-CSF

Neutrophil activators

12-HETE

Keratinocytes

E and Pselectin

ICAM

sialylLewis X

CD11/CD18 (LAD)

1. “rolling”

PECAM

2. transmigration

1 and 2integrins

3. infiltration

Adapted from Von Den Driesch (2000) Clin Dermatol 18, 233-244

IgG

C3bPhagocytosis

IL-8C5aLTB4PAFfMLP

Chemoattractantsand

chemotaxis

CD11/CD18

L-selectin

Adhesion

1 integrin

PECAM

Reactive oxygen species(NADPH oxidase)

Enzymatic destruction-cathepsins-azurocidins/defensins-elastases-lysozymes-phospholipases-glycosidases

IL-1IL-2TNFG-CSFGM-CSF

Neutrophil activators

IgG

C3bPhagocytosis

Interference withphagocytosis:

dapsone

CD11/CD18

L-selectin

Adhesion

1 integrin

PECAM

Interference with integrin-mediated adhesion:

-corticosteroids-dapsone

IL-8C5aLTB4PAFfMLP

Chemoattractantsand

chemotaxis

IL-1IL-2TNFG-CSFGM-CSF

Neutrophil activators

Interference withChemotaxis:

- potassium iodide- colchicine

- tetracycline

Inhibtion of TNF:thalidomide

Reactive oxygen species(NADPH oxidase)

Enzymatic destruction-cathepsins-azurocidins/defensins-elastases-lysozymes-phospholipases-glycosidases

Inhibits secretion ofneutrophil lysosome:

- colchicine Scavenge ROS:-dapsone

Inhibit generationOf ROS:

-thalidomide-tetracycline

-erythromycin-metronidazole

-sulfasalazine (also inducesPMN apoptosis)

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)

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

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

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

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

Less exciting, but somebody tried it

• Salicylates • Clofazimine

– 200 mg qd x 4 wks, then 100 mg qd x 4 wks– Enhances PMN phagocytic activity– Red-gray skin pigmentation, drug-related icthyosis

• Etretinate – Good response in patient with agnogenic myeloid

metaplasia• IFN-alpha

– Systemic and IL in patient with CML• Danazol• Pentoxifylline• Antihistamines• Cytotoxic agents

– AZA, MTX, cyclophosphamide, chlorambucil

• Derm residents: ova awaiting fertilization.• Dank: alas, also just an unfertilized ovum.• Kuechle: learning to walk, awaiting first ballet lesson.• Sidbury: learning to walk, soon to be forced by older brother to

play basketball left-handed.• Hornung: in a Southern California grocery store, asking her

mother when she was going to turn four.• Kern: cynical New York second-grader.• Kirby: starting high school in Seattle. • Milner: dreaming of Bonaparte and waiting to start his

residency in dermatology at the UW

• Iwamoto: skiing in Switzerland and miserably trying to learn Swiss-German while speaking only Japanese.

• Berg: having a smashing time as a three year-old in London, not yet planning on a career in medicine.

• Lantz: happy 4-year old Republican in Vancouver, Washington• Argenyi: going through sixth grade in Budapest, Hungary,

insisting that he was a “very well-behaved boy”.• Colven: pimping fellow pre-schoolers on “Mother Goose

Nursery Rhymes” reading assignment.

• Sybert: starting tenth grade, fending off would-be suitors, and falling in love with Mr. Zaccaro, the social studies teacher.

• Still a virgin…• Fleckman: demonstrating with Mario Savio (1942-1996) and the

Free Speech Movement at Berkeley, birthplace of the “sit-in”. During 1964, a skeptical young Phil develops a distrust of news media coverage.

• Olerud: awarded first of two team MVP awards, one year before being awarded “John Olerud Award” and First Team All-American. Courting future Mrs. Olerud.

• Raugi: about to start senior year of high school with abundant hair on both head and legs, doing research for $1.25/hour at Palo Alto, trying to figure out where Vietnam was, developing a passion for golf, disdaining Beatlemania, and spending countless hours watching…

• …BULLFIGHTING FROM TIJUANA?!?

Acknowledgments

• Phil Fleckman

• Bob Underwood

Selected References• Burg, ND and Pillinger, MH (2001) “The neutrophil: function and regulation in

innate and humoral immunity” Clin Immunol 99, 7-17.• Callen, JP (2002) “Neutrophilic dermatoses” Dermatol Clin 20, 409-419.• Cohen, PR and Kurzrock, R (2000) “Sweet’s syndrome: a neutrophilic

dermatoses classically associated with acute onset and fever” Clin in Dermatol 18, 265-282.

• Cohen, PR and Kurzrock, R (2002) “Sweet’s syndrome: A review of current treatment options” Am J Clin Dermatol 3, 117-31.

• Cronstein et al. (1992) “A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of ELAM-1 and ICAM-1” Proc Natl Acad Sci USA 89, 9991-9995.

• Miyachi, Y (2000) “Pharmacologic modulations of neutrophils” Clin in Dermatol 18, 369-373.

• Schroder, J-M (2000) “Chemoattractants as mediators of neutrophilic tissue recruitment” Clin in Dermatol 18, 245-263.

• Sweet, RD (1964) “An acute febrile neutrophilic dermatosis” Br J Dermatol 79, 351-356.

• Von Den Driesch, P (2000) “Polymorphonuclears: Structure, function and mechanisms of involvement in skin disease” Clin in Dermatol 18, 233-44.