Download Sweet`s syndrome - University of Washington

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
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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
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Acute febrile neutrophilic dermatosis
Pyoderma gangrenosum
Drug reaction
Cutaneous malignancy
Infection secondary to
immunosuppresion
Histopathology
“Right palm plaque”
“Left leg bulla”
Histopathology
Differential diagnosis
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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)
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“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
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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
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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 nodules
2. Dense neutrophilic infiltrate (without evidence of LCV?)
Minor criteria (two of four required)
1. Fever > 38o C
2. History of associated illness or malignancy
3. Response to treatment with potassium iodide or steroids
4. 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
Diseases reported in association with Sweet’s syndrome
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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
Malignancies
IBD
Autoimmune
Infection
Other
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 druginduced Sweet’s syndrome
All five criteria required
1.
2.
3.
4.
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 rechallenge with drug
5. 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
Clinical features in Sweet’s syndrome
Classic
Heme
Malignancy
Solid
Tumor
DrugInduced
Epidemiology
-Female
-Prior URI/GI infxn.
-Recurrence
80
75-90
30
50 (33/66)
16 (11/69)
69 (37/54)
59
20
41
71
21
67
Symptoms
-Fever > 38C
-Musculosk. involv.
-Ocular involv.
80-90
12-56
17-72
88 (50/57)
26 (18/69)
7 (5/69)
79
34
15
100
21
21
Lesion locations
-Upper extrem.
-Head/neck
-Trunk/back
-Lower extrem.
-Oral mucous memb.
80
50
30
Infreq.
2
89 (58/65)
63 (41/65)
42 (27/65)
49 (32/65)
12 (8/65)
97
52
33
48
3
71
43
50
36
7
Lab findings
-Neutrophilia
-Elev. ESR
-Anemia
-Abnormal renal fxn.
80
90
Infreq.
11-50
47 (29/62)
100 (25/25)
68 (40/49)
15 (10/69)
60
95
50
7
38
100
50
0
Adapted from Cohen PR and Kurzrock R, Clin Dermatol (2000) 18, 265-282
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
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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 dermatoses
Sweet’s
Clin. Appear.
PG
papules
nodules
ulcers
Pathergy
yes
yes
Oral involv.
ulcers
ulcers
Eye involv.
conjunctivitis
Iritis, scleritis
Joint involv.
arthritis
Associations
Histopath
heme malig.
IBD
e. nodosum
sarcoid
thyroid dz.
RA
SLE
Behcet’s
superficial
dermis
Sned-Wilk
Behcet’s
papules
nodules
ulcers,
Sweet’s-like,
PG-like
--
--
yes
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ulcers
keratitis,
vasculitis
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keratitis,
vasculitis
uveitis,
vasculitis
arthritis
arthritis
arthritis
arthritis
heme malig.
IBD
heme malig.
IBD
e. nodosum
heme malig.
IBD
e. nodosum
sarcoid
thyroid dz.
RA
SLE
Behcet’s
ulcer
pustules
EED
heme malig.
thyroid dz.
RA
SLE
PG
subcorneal
pustules
RA
PG
Sweet’s, PG
sup/mid dermis
LCV
LCV
IL-17
Stem cell
IL-3
CFU-GEMM
CFU-GM
IL-6
GM-CSF
all-trans retinoic acid
CFU-G
myeloblast
T
MP
G-CSF
promyelocyte
myelocyte
metamyelocyte
B
N
E
KC
band
IgG
Phagocytosis
C3b
IL-8
C5a
LTB4
PAF
fMLP
Chemoattractants
and
chemotaxis
IL-1
IL-2
TNFa
G-CSF
GM-CSF
Neutrophil activators
Classic chemoattractant
g
Ga
Ras GTP
b
GTP
PLC
IP3
DAG
Ca
PKC
PI3K
Raf
Rho
Adhesion,
chemotaxis,
ROS
MEK
Rac
cPLA2
MAPK
AA
Adhesion,
ROS
Adapted from Burg ND and Pillinger MH (2001) Clin Immunol 99, 7-17
Adhesion,
transcription,
aggregation
Membrane
ruffling,
ROS
Adhesion
CD11/CD18
b1 integrin
L-selectin
PECAM
IL-8
C5a
LTB4
PAF
fMLP
IgG
Phagocytosis
C3b
12-HETE
Keratinocytes
Chemoattractants
and
chemotaxis
IL-1
IL-2
TNFa
G-CSF
GM-CSF
Neutrophil activators
b1 and b2
integrins
3. infiltration
E and P
selectin
PECAM
ICAM
2. transmigration
1. “rolling”
sialyl
Lewis X
CD11/CD18 (LAD)
Adapted from Von Den Driesch (2000) Clin Dermatol 18, 233-244
Adhesion
CD11/CD18
b1 integrin
L-selectin
IL-8
C5a
LTB4
PAF
fMLP
IgG
Phagocytosis
C3b
Enzymatic destruction
-cathepsins
-azurocidins/defensins
-elastases
-lysozymes
-phospholipases
-glycosidases
PECAM
Reactive oxygen species
(NADPH oxidase)
Chemoattractants
and
chemotaxis
IL-1
IL-2
TNFa
G-CSF
GM-CSF
Neutrophil activators
IgG
Phagocytosis
C3b
Interference with
phagocytosis:
dapsone
Adhesion
CD11/CD18
L-selectin
b1 integrin
PECAM
Interference with
integrin-mediated adhesion:
-corticosteroids
-dapsone
Interference with
Chemotaxis:
- potassium iodide
- colchicine
- tetracycline
IL-8
C5a
LTB4
PAF
fMLP
Inhibtion of TNFa:
thalidomide
Chemoattractants
and
chemotaxis
IL-1
IL-2
TNFa
G-CSF
GM-CSF
Neutrophil activators
Inhibits secretion of
neutrophil lysosome:
- colchicine
Enzymatic destruction
-cathepsins
-azurocidins/defensins
-elastases
-lysozymes
-phospholipases
-glycosidases
Reactive oxygen species
(NADPH oxidase)
Scavenge ROS:
-dapsone
Inhibit generation
Of ROS:
-thalidomide
-tetracycline
-erythromycin
-metronidazole
-sulfasalazine (also induces
PMN apoptosis)
Scientific advances since 1964
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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
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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 AllAmerican. 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
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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.