The patient with cutaneous blisters: an internists approach

dr. L. Henckaerts 13-12-2013

(Why) should an internist think about skin?

. . . .

stratum corneum

stratum spinosum

stratum granulosum

stratum basale

EPID

ERM

IS D

ERM

IS

stratum papillare

stratum reticulare

stratum corneum

stratum spinosum

stratum granulosum

stratum basale

EPID

ERM

IS D

ERM

IS

stratum papillare

stratum reticulare

Characteristics of blisters

• size (vesicles vs. bullae)

• localisation / extent? (general, local, predilection)

• mucous membranes?

• patient age

• (new) medication history? recent illness?

• aspect of blisters? (tense? size? config?)

epidermis

dermis

basement membrane

Pathologic events

epidermal cell injury/death

epidermal edema

trauma

stratum basale

loss of adhesion in or between cells:

epidermal . . . .

subepidermal

autoimmune blistering diseases

epidermis

dermis

basement membrane

stratum basale

Histologic location of blisters

intra/subcorneal e.g. SSSS

intraepidermal e.g. TEN

suprabasilar e.g. pemphigus vulgaris

subepidermal e.g. bullous pemphigoid

Case 1: woman, 83 y

• Past medical history:

– 1997 amyotrophic lateral sclerosis

– arterial hypertension

– 2012 cholecystitis

• Current medication

– Movicol 1 x/dag

– Pantomed 20 mg/dag

– Rilutek 50 mg 2x/dag

– Sipralexa 10mg/dag

– Steovit 1x/dag

• Presenting problem: since 3 weeks: - skin eruption with bullae in groins, right shoulder, ellbow - general malaise - dyspnea, orthopnea, ankle edema

R/ Flamazine, amoxyclav: not better • On clinical examination:

- T 37.1 °C, BP 135/65 mmHg, pulse 69x/min, sat 90% on room air - heart auscultation normal, lung: bilateral crepitations - abdomen: depressible, painless - bimalleolar pitting edema, increased jugular venous pressure - skin examination:

right shoulder

right elbow

groins

+ no mucosal lesions

• Lab tests:

- Hb 11.6 gr/dl, normochromic normocytic

- CRP 1.5 mg/l

- albumin normal

- liver, kidney & electrolytes function normal

• Cultures:

- urine: Klebsiella pneumoniae > 100 10**3/mL

- blood: negative

- wound: Klebsiella pneumoniae, S. aureus, S. epidermidis

• Differential diagnosis - bullous pemphigoid - lineary IgA dermatosis punch biopsy of intact bullous lesion right groin / upper leg for histology & immunofluorescence • APO report: Subepidermal blister, with some necrotic keratinocytes in the basal epithelial layers. Discrete presence of neutrophils and lymphocytes at the dermo-epidermal junction. Immunofluorescence: no deposition of complement (C1q, C3d, C4d); IgA very limited CONCLUSION: variant of bullous pemphigoid

Lancet. 2013 Jan 26;381(9863):320-32

Bullous pemphigoid

• What? - most common autoimmune blistering disease (50/million/year) - mainly affects older people - associated with neurological diseases! (Parkinson, stroke, epilepsy, MS, but also ALS!)

• Clinical presentation - prodromal phase - tense blisters & erosions, mucosal involvement 10-20% - predilection for abdomen and flexion side extremities - Nikolsky (-)

• Pathogenesis antibodies against proportion of desmosome at dermal-epidermal junction

• diagnosis:

- age, clinical aspect

- histology

- immunofluorescence (linear deposition of IgG / C3)

• treatment:

– topical or oral steroids (depending on severity/extent)

– anti-inflammatory antibiotics (e.g. doxycyclin)

– immunomodulating drugs…

right shoulder

right elbow groins

• in our patient:

topical treatment with

betametasonediproprinate

0.05% in AVA ointment

(followed by betametasonevalerate)

+ doxycycline 200mg o.d.

• Past medical history: – arterial hypertension – cataract

• Current medication: – simvastatine 20 mg/d (since years) – indapamide 2.5 mg 1co/dag (sinds 1 month)

• Presenting problem: - admission to peripheral hospital with diffuse itching rash, general

malaise, fever without focus R/ ceftriaxone, solumedrol - after 2 days: persisting fever, superficial blistering on back and

sacrum with detachment of skin R/ association of ciprofloxacin and metronidazole

- after another 3 days: persisting symptoms: extra Solumedrol, transfer university hospital

Case 2: woman, 74y

• On clinical examination: - sick patient: confused, disoriented - T 37.8°C, BP 145/70 mmHg, pulse 87/min, sat 97% on room

air - normal auscultation of heart & lungs - abdomen: no abnormalities noted - no lateralisation, no meningism - on examination of the skin….

- dark red exanthema with bullae - extensive erosions on buttocks and upper back - Nikolsky sign positive + oral erosions!

Nikolsky sign

• Lab tests: - inflammation: CRP 63 mg/l - discrete leukopenia (WBC 2800/µl) , neutrophils 2100/µl - kidney, electrolytes, albumin: normal - elevated liver function tests: AST/ALT 3x upper limit of

normal, cholestasis, bilirubin normal - CK 488 U/l (nl <= 145); LDH 530 U/l (nl 135- 250)

• Cultures: - urine: negative - blood: negative - wounds: Enterococcus faecium + HSV negatief

• Chest X-ray & abdominal ultrasound: normal

• Differential diagnosis?

- toxic epidermal necrolysis (TEN)

- Steven-Johnson syndrome (SJS)

- Stapylococcal Scalded Skin Syndrome

skin biopsy!

• APO report:

Skin biopsy with epidermis, dermis and subcutis. Old blister with confluent necrosis of the epidermis in the blister roof, beginning re-epithelialisation. Very mild inflammation in the dermis.

CONCLUSION: blister with epidermal necrosis and beginning reepithelialisation, compatible with toxic epidermal necrolysis

J Am Acad Dermatol 2007; 56: 181-200

Toxic epidermal necrolysis (TEN)

• What? - acute, mucocutaneous condition - very rare (±2 per million, 1000x higher in HIV!) - severe! important morbidity and mortality (30%)

• Etiology - drugs > infections > idiopathic - influence of genetics - influence of concomitant infection or cancer - mechanism: activation of CD8 T-cells and cytolitic molecules (FasL, granulysin) extensive apoptosis of keratinocytes loose epidermis

J Am Acad Dermatol 2012; 66: 995-1003 Orphanet Journal of Rare Diseases 2010, 5:39

J Am Acad Dermatol 2012; 66: 995-1003

0

• Clinical presentation: - initial symptoms are unspecific (fever, malaise) - early cutaneous sites: presternal region, face, palms, soles - mucosal lesions in 90%: oral, genital, respiratory, gastrointestinal,

eyes - isolated dark red lesions or erythema > confluence > detachment - ‘healthy’ skin Nikolsky positive - epidermal loosening 5-7d reepithelialisation (1-3 weeks)

• Evolution:

Orphanet Journal of Rare Diseases 2010, 5:39

Orphanet Journal of Rare Diseases 2010, 5:39

• Treatment:

- withdrawal of culprit drugs: mostly started 1 to 4 weeks before

- supportive care in a burns unit: fluid, electrolytes, nutrition, pain therapy, respiration,…

- wound care – important risk for infection!

- drug therapy?

- NO steroids

- high dose IVIG (3g/kg over 3-4 days): higher survival

- ciclosporin? anti-TNF? cyclophosphamide?

- antibiotics only if necessary

Orphanet Journal of Rare Diseases 2010, 5:39

• Past medical history: - 4/2012: STEMI inferoposterior R/ DES-stent Cx

• Current medication: - aspirin 80 mg o.d. - simvastatin 40 mg o.d. • Presenting problem: - flu-like symptoms for 1 week, with itchy vesicles at the flexor side of

his ellbows - GP: started on doxycyclin 200 mg o.d. because of extension to

hands, feet and oral mucosa

Case 3: male 58 y

• Presenting problem(2)

- 3 days later: admission to hospital with fever, extension of the maculopapulous skin rash with haemorrhagic blisters

R/ amoxicillin-clavulanate, aspirin, stomatitis cocktail

• On clinical examination:

- T 37.2 °C, BP 102/60 mmHg, pulse 70/min

- normal auscultation of heart & lungs

- normal abdominal examination

- no peripheral edema, no lymphadenopathies

- on examination of the skin ….

- numerous tense (haemorrhagic) bullae on knees, ellbows, ankles and hands - Nikolsky sign negative - no mucosal lesions now (has had oral lesions few weeks before)

• Lab tests: - pronounced inflammation: CRP 140 mg/l, WBC 19 000/µl with 85%

neutrophils - albumin 27.1 gr/l - normal liver & kidney function - auto-immune serology negative (ANF, ANCA, complement) - protein electrophoresis: small M-peak in gamma-fraction: IgA

paraprotein type lambda (0.25 gr/dl) with minimal disturbed kappa/lambda-ratio (26.49).

- urine sediment: normal

• Cultures: - wound: HSV, adenovirus, enterovirus: negative - blood: negative - serology: negative

• Differential diagnosis? - bullous sweet syndrome - viral (enterovirus, herpes, coxsackie) - vasculitis - erythema exudativum multiforme (major)

skin biopsy lesion knee

+ viral serology: herpes, HIV, CMV, EBV, hepatitis, coxsackie. + cultures of wound (HSV, enterovirus) and blood + total complement, C3, C4, EF, paraproteins, urine

• APO report: vesicular dermatitis with intra- and subepidermal blistering by edema and spongiosis. Sparse necrotic keratinocytes. DD - erythema exsudativum multiforme - allergic contact dermatitis - Coxsackie infection not excluded given oral lesions

Int J of Dermatol 2012; 51: 889-902

• What? - acute, immune-mediated - mucocutaneous = EM major only cutaneous = EM minor - usually self-limiting (may be persistent or recurrent) • Clinical presentation: - prodromal symptoms may be present - round, erythematous, edematous papules evolving to develop

targetoid lesions - distribution: often symmetrical, extremities > trunk, extensor-side

predilection - 25-60% mucosal membrane lesions: mouth ++ but also genital,

ocular, upper respiratory, pharyngeal, esophageal

Int J of Dermatol 2012; 51: 889-902

Erythema Exsudativum Multiforme

www.huidziekten.nl Int J of Dermatol 2012; 51: 889-902

• Etiology?

- 90% infection (HSV1!), < 10% medication (e.g. NSAIDs, AB, antiepileptics)

- genetic susceptibility (HLA alleles)

- mechanism: cell-mediated immune reaction againts viral-antigen positive cells > nonspecific inflammation through autoreactive T-cells

Int J of Dermatol 2012; 51: 889-902 Dent Clin N Am 57 (2013) 583–596

• Disease course: - appearance in 3-5 days, resolution in 1 – 2 weeks (<4 weeks but longer

in mucosal involvement) - hyperpigmentation, no scarring

• Treatment? - discontinue eliciting drugs - topical steroids, antihistamines, mouth wash - supportive care

- oral steroids in severe mucosal disease - consider suppressive/prophylactic antiviral therapy if recurrent HSV

induced (e.g. acyclovir 400 mg b.d.) - immunomodulating drugs if persistent (AZA, MMF)

• in our patient:

treatment with topical steroids

Bullous skin lesions

Large and difficult differential diagnosis!

Bulleus pemphigoïd TEN EEM

Other pemphigoid variants Staphylococcal scalded skin syndrome

Urticaria

Linear IgA bullous dermatosis

Acute GVHD Sweet’s syndrome

Epidermolysis bullosa acquisita

Drug-induced pemphigus Stevens Johnson syndrome

Lichen planus pemphigoides

Acute gegeneralised exanthematoud pustulosis

(AGEP)

Fixed drug eruption

… … …

To remember

• Sometimes difficult differential diagnosis, but VERY important for treatment and outcome

• We need the dermatologist and the anatomopathologist

• Ask for all (new) medications

• No empirical treatment with steroids