Neutrophilic dermatoses Flashcards
Overview neutrophilic dermatoses
See card.
Epidemiology Sweet’s syndrome (Age, race, female/male)
- No racial predilection, more common in Japan
- Age 30-60 but any ages
- Female predominance 4:1 (Classic), also more females if Drug
- M=F for drug
Pathogenesis Sweet’s Syndrome (including some cytokines involved)
- Unknown, possibly hypersensitivity
- Local/systemic dysregulation cytokine secretion of Il-1, G-CSF, GM-CSF, interferon Y-Genes involved: PTPN6 and MEFV
- Pathergy +
What % of Sweets has identifiable cause?
50% idiopathic
50% known association (see below)
3 main association subtypes of Sweets?
- Classic Sweet’s
- AI disease 10-15%
- 25% preceding infection
- pregnancy 2% - Malignancy assoc (15-30%); hematologic > solid organ
- Drug-induced (10%)
- Occurs 1-2 weeks following drug initiation
Associated conditions with Classical Sweets?
- Infectious-Yersinia enterocolitica*-Post-streptococcal/URTI*-Others rare (CMV, hep, HIV, fungal, mycobacterial)2. Autoimmune-IBD*, sarcoid, RA, thyroid, beeches3. Vaccines4. Pregnancy
Malignancies associated with Sweets? What percent associated with heme malignancy
15-30%
- Hematological > solid tumor
- AML most common, MDS-GU, breast, colon for solid tumors
What drugs are associated with Sweets?
GO SCHLAM G-CSF (#1), GM-CSF Cancer drugs (see below) OCPSeptraHydralazineFurosemide (Lasix) ATRA ( isotretinoin) AZA Anti-TNF MinocyclineOther new antineoplastics: Ipilimumab, Pembrolizumab, FLT3 inh, Vemurafenib; also anti-TNF
When does drug related sweets occur post drug? Criteria for drug-sweets?
2 weeks post. Same major criteria just need all 3 minor of: -temporal association w/ drug-fever-resolves with drug d/c
Diagnostic criteria Sweet’s
Need 2M2mMajor: 1. Abrupt onset of typical (painful!) skin lesions 2. Histopath consistent w/ Sweet’sMinor1. Fever or constitutional sx2. Leukocytosis3. Associated dz or trigger 4. Excellent response to steroids
Clinical features of Sweet’s
-Rapid onset of tender/burning, non-pruritic, red, well-demarcated, edematous/“juicy” papules + plaques- may enlarge to form plaques with an uneven mamillated surface- Psuedovesicular or psuedopustular appearance due to edema, but some may actually develop vesicles or bullae or pustules-Can have central yellowish area giving targetoid appearance-Can ulcerate, look like PG (malignancy associated)
Variants of Sweets Clinically
Bullous/VesiculobullousPustularNeutrophilic dermatosis of the dorsal handGiant/Cellulitis-like/Erysipeloid-likeNecrotizingNot listed but can get papulonodules on lower legs that are either1. True erythema nodosum 2. Neutrophilic panniculitis (subcutaneous sweets)
Where does Sweet’s occur usually?
Head, neck, upper extremities.Can be anywhere.
Clinical-path features of Sweets more associated with malignancy?
- Older age
- Absence of arthralgia
- Leukopenia, anemia, thrombocytopenia
- Elevated ESR
- Vesiculobullous morphology
- Subcutaneous Sweet’s
- Lymphocytic Sweet’s
- Histioctyoid Sweet’s
- Male to female predominance equal
- More likely to be recurrent
- More likely to be refractory to treatment
- More likely to have mucosal involvement
- Less likely to have had URTI preceding onset
- Less likely to have ocular involvement
Systemic manifestation Sweets
Common: Fever (50-80%) - may be intermittent + leukocytosis (70%)
Less common: arthralgias/arthritis (non-erosive, asymmetric, favours knees, wrists), myalgias, malaise ,
Ocular: conjunctivitis, episcleritis, limbal nodules, iridocyclitis
Uncommon: neutrophilic alveolitis (cough, dyspnea, pleurisy), SAPHO, renal inv’t (proturia, hematuria, renal insufficiency, ARF)
Rare: hepatitis, acute myositis, aseptic meningitis, encephalitis, pancreatitis, GI inv’t
Natural course sweets?-how long to resolve-recurs in how many?
Resolve in 5-12 weeks
Recurs in 30%
Lab findings in Sweets
CRP/ESR in 90%
Leukocytosis with left shift
5 histologic variants sweets
- Neutrophilic
- Lymphocytic*
- Subcutaneous*
- Histiocytoid*
Cryptococcoid
Eosinophilic
*Malignancies
What is the histiocytoid variant of Sweets?
Characterized by an infiltrate composed of immature myeloid cells that can be misinterpreted as histiocytes (macrophages) OR histiocyte-like immature myeloid cells (stain + for myeloperoxidase) in dermis, +/- to fat assoc hem malig
How do you differentiate between histiocytes and immature myeloid cells in Sweets?
Myeloperoxidase + in myeloid cells
Pathology of Sweets
-Epidermis often normal but neutrophils may invade (forming subcorneal pustules).
Signif edema –> spongiosis + intraepidermal & subepidermal vesiculation
- Diffuse nodular and perivascular neutrophilic infiltrate without LCV, sometimes LCV. (Leukocytoclasia with endothelial swelling, but without the fibrinoid necrosis is the usual finding)
- Occasionally neutrophils infiltrate may extend into the subcutis, creating a SEPTAL or, less frequently, a lobular PANNICULITIS.
Isolated neutrophilic panniculitis has been described. (“Subcutaneous Sweets)
1st line treatment Sweets for:
- Few lesions
- Widespread lesions
In all–> Tx underlying cause if found
- Topical superpotent steroids or ILK, topical calcineurin inh
- Prednisone 0.5-1 mg/kg 2-6 weeks (works really fast)
Second line treatments Sweets
SSKI
Dapsone 100-200 mg/d, Colchicine 0.6 mg BID-TID
NSAIDs, Colchicine, Clofazamine, CsA, Thalidomide, IFN-α
How to give SSKI?
-Start w/ 3-5 drops tid + inc by 5 drops wkly up to 15 drops tid = 900 mg/day1 drop is about 47 mg, take w/ milk or juiceTabs are 300mg tid
Side effects and teratogenicity SSKI
- Pregnancy category D (fetal goiter, hypothyroidism dt Wolf-Chaikoff effect)- Wolf-Chaikoff: Ingestion of ++ iodine when already iodine-replete= hypothyroidism-Jod-Basedow: Ingestion of ++ iodine when deficient = hyperthyroidismAcute SE: • Nausea• Bitter burps• Taste-brass/dysgeusia (take w fruit juice)• Excessive salivation• Cold-like sx (coryza, HA)• Urticaria• Angioedema• CSVVChronic effects SSKI:• Enlarged salivary and lacrimal glands• Acneiform eruption• Iododerma• Hypo/hyper thyroidism• Hyper K (with renal dz)• Cardiotox • DH, EM, EN
What is the pathergy test?
What is pathergy and how is the test performed?
-Pustular or neutrophilic lesions occurring at sites of cutaneous trauma-Performed on flexor forearm by obliquely inserting a 20-22-gauge sterile hypodermic needle at a depth of 5 mm-A positive reaction is the development of a papule or pustule at 24-48 hours
Sweet’s, as well as other neutrophilic dz, may be seen in this genetic autoinflammatory disorder?
DIRA (deficiency of IL-1 receptor antagonist)
In patients with hematologic malignancies, especially acute myelogenous leukemia, several neutrophilic dermatoses can occur such as?
Sweet’s
Neutrophilic eccrine hidradenitis
Bullous PG
Apart from Sweets, name some other diseases with pathergy
• Pyoderma gangrenosum• Behcet’s disease• MAGIC Syndrome• Atypical eosinophilic pustular folliculitis• Down’s Syndrome• Myeloproliferative diseases• Chronic myeloid leukemia
Name 4 ocular findings in Sweets
• Conjunctivitis• Episcleritis• Limbal nodules• Iridocyclitis
Epidemiology of Pyoderma Gangrenosum
-Uncommon-F>M-20-50 yrs most common-4% in infants/kids50% have underlying dz (IBD, arthritis, haematologic dz) – (same as for Sweet’s sde)
Pathogenesis Sweet’s
Immune abnormality as associated with many underlying AI dz Enhanced Il-1, Il-1B and IL-1 receptor increased (among others)Pathergy can initiate and also aggravate
Associated diseases with PG
HAVIN Drug1. Hematological disease (15-25%)-AML*, hairy cell leukemia, MDS, monoclonal gammopathy (IgA* MC)2. Arthritis -RA, seroneg spend, IBD-associated arthritis 3. Vasculitis-Bechets, Wegners4. IBD (20%) 5. Neutrophilic diseases-PAPA, PAPASH, sub corneal pustular dermatosis6. DRUGS
Drugs associated with PG
GIGIG-CSFsskIGM-CSFInterferon
PG Clinical features-Classic
-Lower legs, pretibial #1, but can be anywhere inc MM, peristomal sites-Solitary to multiple lesions, often rapidly progressive rapidly-Classic: tender papulopustule w/ surrounding erythema/violaceous induration, OR red nodule OR bulla on violaceous base–>Then necrose, ulcerate (superficial to deep)–> Later, purulent base w/ undermined + overhanging edges, gun-metal gray or erythematous border–>Heals from the outside in w/ cribriform scarring- Pathergy (20-30% of patients)
PG in hematological malignancy or drug-related?
o Acute onset of hemorrhagic or purulent bullous lesionso Widespread, rapidly necroseo Often assoc w/ fever, signs of tox
PG in association with AI-dz like IBD
o Chronic, slowly enlarging ulcer w excessive granulation at baseo Spontan regression
Variants PG
PPUBS1. Pustular2. Pyodermatitis or pyostomatitis vegetans3. Ulcerative (classic)4. Bullous 5. Superficial granulomatous
Variants PG
PPUBS1. Pustular2. Pyodermatitis or pyostomatitis vegetans3. Ulcerative (classic)4. Bullous 5. Superficial granulomatous
Pustular PG
Multiple small, sterile pustules – usually DO NOT progress to ulcers (but can)Ass’d w/ IBD (most cases)
Pyostomatitis or pyoderma vegetans
Chronic, sterile, vegetative pyoderma of labial & buccal mucosaAss’d w/ IBDPyoderma vegetans–> large verrucous plaques with elevated borders and multiple pustules
Bullous PG
Favours face, upper extremities (esp dorsal hands)Less destructive than classic PG; overlaps w/ bullous Sweet’sAssoc w haem malignancy (AML, CML)
Superficial Granulomatous PG
Localized, superficial, vegetative or ulcerative lesionFavours trunk, typically follows surgeryResponds to less aggressive anti-inflam TxPath: sup granulomatous response, fewer neuts
Extra-cutaneous PG features
Sterile neutrophilic infiltrates may affect bones, liver, lungs, spleen, pancreas, kidneys, CNS
Pathology PG
Non-specific – Dx of exclusionEarly: neutrophilic vascular rxn, may be folliculocentricExpanding lesions: neutrophilic infiltrates w/ leukocytoclasia (leukocyte disintegration)Fully dvlped lesions: marked necrosis w/ surrounding mononuclear infiltratesChronic lesions: fibrosing inflam at borders
Workup for PG
-Hx (w/ review of drugs), PxE-Skin Bx for H&E, DIF, special stains, Cx (bacterial, mycobacterial, fungal, viral)-GI studies stool for occult blood & parasites, c-scope, radiography, LFTs-Heme studies CBC, blood smear, +/- bone marrow bxSerologic studies SPEP, IFE, ANA, APLA, ANCAs, VDRLCXR (blasto)Urinalysis
Criteria diagnosis for PG
*2M2mMAJOR1. Abrupt onset of characteristic ulcers (1-2cm/d or 50% inc in 1m + pain out of proportion w ulcer)2. Exclusion of other causes of ulcersMINOR1. Response to steroid (pred 1-2mg/k/d = 50% dec size in 1m)2. Assoc w disease (CA, IBD, Arthritis)3. Scar (cribiform) or hx of pathergy4. Histopath compatible
Treatment mild disease
Treat underlying dz (all forms) -Superpotent topical steroids- ILK-Protopic -Oral Abx (minocin, sulfonamides)-Colchicine (0.6 mg TID)- Dapsone (50-150 mg/d)-Clofazamine (100-400 mg/d)
Treatment mod-severe
-Prednisone (1 mg/kg/d) or Methylpred (1g daily x 3-5d) (TOC Bolognia) Ali Alikhan: Infliximab + cyclosporin are TOC-Cyclosporin (also 1st line – Bolognia)-Bolognia Table 26.11 – Infliximab has highest level of evidence for severe diseaseOtherS:-TNF-α inh-Thalidomide (50-150 mg/d)- CsA (2.5-5 mg/kg/d)-oral tacrolimus (0.1-0.2 mg/kg/d) -MTX, Azathioprine, MMF, Cyclophosphamide, Chlorambucil, IVIG
Wound care PG
-Sharp debridement is CONTRAINDICATED dt pathergy - loose slough can be gently removed-Moisture balance: fibres, foams + alginates to absorb exudate-Hydrogels for gentle autolytic debridement-4% sodium cromoglycate followed by occlusion w/ a hydrocolloid dressing-Infxn can be treated w/ cadexomer iodine or nanocrystalline silver-Liquid acrylates can be used to protect peri-wound skin
Epidemiology of Bechets
- Middle East, Mediterranean basin, Japan/Korea (Silk Route): Turkey highest prev, Japan/Korea F>M, Middle East M>F
- 20-35 yo
- 2-5% familial form (higher in Middle East)
Pathogenesis Bechets
- HLA-B51 allele important in Silk road cases (not prevalent in Caucasians)
- No evid to support infectious etiol Hep C, HSV, Parvo B19)
- Circulating immune complexes + neuts cause tissue damage = vascular injuries and autoimmune responses
- The neuts of Behcet’s disease ↑ superoxides, lysosomal enzymes + have enhanced chemotaxis
- ↑ TNF-α, IL-1β, IL-8 à PMN activation & interaction w/ endothelial cells
- Clonal expansion of autoreactive T-cells
Clinical features Bechets (Skin)
- Apthous stomatitis and genital ulcers
- First symptom often in 60-75%, present in almost all patients
- Erythematous papule–> yellow/white psuedomembrane–> non scarring ulcer –> heals over weeks
- 3 or more attacks per year
- *Genital ulcer-leave scars, larger, more irregular, more painful
- Acneiform lesions:
- Sterile papules and pustules on face or acral lesions
- Necrotic folliculitis (not in bolognia)
- Erythema nodosum or EN-like lesions or superficial thrombophlebitis (30%):
- 20% of time can get bechets induced EN (septal panniculitis without vasculitis)
- EN-LIKE lesions in bechets is 80%
- Lobular panniculitis with vasculitis
- SPECIFIC TO BECHETS! Strong likelihood
3.
Other skin conditions seen in bechets
- Others:
- Vesiculopustular dermatosis
- Sweets like dermatosis
- PG
- Vasculitis
- Superficial thrombophlebitis
- Pathergy
Systemic findings bechets
- Joints and Connective Tissue
- Arthritis: 30%, attacks often <2 months, non erosive, wrists/ankles/knees
- Relapsing polychondritis (MAGIC syndrome: Mouth and Genital ulcer with inflammed cartilage)
- Ocular involvement
- 90%, mostly men, can lead to blindness
- Retinal vasculitis, posterior uveitis (most common), anterior uveitis (hypopyon), a few others.
- GI
- GI ulcerations, abdo pain and bleeding. Often ulcers in small bowel (ileocecal region), but can be in esophagus and stomach. Ulcerations similar in appearance to chronic ulcerative colitis
- Neuro
- Later in disease, poor prognosis
- Menigoencephalitis, cranial nerve palsies, brainstem lesions (swallowing difficulties, laughter, crying)
- Vascular:
- Venous or arterial thrombosis, aneurysms
- Myocarditis, valve disease
- Renal: Glomerulonephritis
BADAS ans IBD dermatosis comparison
- Summary of differences BADAS:
- Don’t expect genital apthae, PG (or other pyos), neuro or ocular involvement
- Summary differences IBD:
- In IBD don’t expect neuro involvement or genital apthae
- In bechets don’t expect PG or other PYOs
Bechets criteria
- Need 4 points (O-GEPS CV)
- Oral apthoses (2) (3 in 1 yr)
- Genital apthoses (2)
- Eye lesions (2)
- Anterior uveitis, posterior uveitis, retinal vasculitis
- Pathergy
- Skin lesions
- Psuedofolliculitis, acneiform rash, EN or EN-like, skin apthae
- CNS
- Vascular
Path findings bechets
- Vasculitic–> all blood vessel sizes, dermis and subcutis, arterial and venous, neutrophilic predominantly if early lesion.
- LCV or angiocentric, neutrophilic infiltrates with leukocytoclasia and erythrocyte extravasation
- Can get histiocytes–> “granulomatous vasculitis”
- EN or EN-like lesions–> neutrophilic lobular panniculitis to a septal and lobular panniculitis with a mixed inflammatory infiltrate, fat necrosis and evidence of lymphocytic vasculitis
- Vascular thrombosis can occur, look for underlying vasculopathy
- Acneiform–> sterile neutrophilic vasculopathy
Treatment Bechets
- Mucocutan:* viscous lidocaine, ILK, colchicine, dapsone
- Severe mucocutan:* pred, thalidomide, MTX, INF-α, TNF-α inh
- Systemic:* pred, azathioprine, cyclophosphamide
- Chlorambucil, MMF, CsA, tacrolimus
- IVIG, TNF-α inh
Who gets BADAS?
- Surgical: gastric resection, jejunoileal bypass, blind loops of bowel following sx, biliopancreatic diversion
- Medical: IBD, diverticulitis, peptic ulcer dz
Pathogenesis BADAS
- Theory: bacterial overgrowth in blind loop of bowel → immune complexes containing bacterial Ags deposit in skin + synovium
- Improvement w/ Abx supports hypothesis
Clinical features BADAS
- 1-6 yrs post-sx
- Constitutional sxs (fever, arthralgia)
- Skin: erythem macules →papules, purpuric vesiculopustules w/in 48hrs, favors prox extrems + trunk
- Last 2-4 wks, may recur at 4-6wk intervals
- Can get tender subcut nodules (EN or en-like)
Systemic findings BADAS
- Arthritis: non-destructive polyarthritis, tenosynovitis
- Systemic: diarrhea → electrolyte imbalance
- Hepatic dysfxn
- Renal calculi (Ca oxalate)
- Gallstones
- Zinc, Vit A, thiamine deficiency (beriberi)
- Hyperuricemia
Pathology BADAS
- Perivascular, nodular infiltrate of PMNs w/ nuclear dust, may extend to fat
- +/- lymphocytes & histiocytes, dermal edema
-Similar to sweet syndrome, Behçet disease, and the early phase of PG.
Tx BADAS
Surgery or revision blind loop curative
Mild: oral Abx (TCN, doxycycline, minocycline, clinda, metronidazole), Colchicine, dapsone, thalidomide
Severe: Surgical revision, Pred, CsA, azathioprine, MMF, ?TNF-α inh
What does SAPHO stand for?
Synovitis
Acne
Pustolosis
Hyperostosis and osteitis
Epidemiology SAPHO
- Kids + young adults, Japan
- Unknown pathogenesis, ?AI response to microorganisms, freq assoc w/ IBD
clinical feat Sappho
Clin
- Skin: palmar + plantar pustulosis
- Follic occlusion tetrad, acne fulminans
- PsO, pustular Ps, Sneddon-Wilkinson dz
- Linear IgA BD
- Behcet’s, sweet’s sde, PG
- Lyme dz
- MSK:
- Synovitis
- Arthro-osteitis (inflam of osseous stxs of joint)
- Chronic, multifocal, sterile osteomyelitis
- Sites: anterior chest wall, axial skeleton
- Other: Fever, ↑WBC, ↑ESR
Tx Sappho
Txt
- 1st line: ILK, pred … MTX, Bisphosphonates, TNF-α inh
- 2nd line: NSAIDs, Colchicine, Sulfasalazine, Oral Abx (doxy, azithro, clinda)
