Grand Round Araya Keeratimahat, MD. Case Patient: A 16-year-old Thai woman, from Nakornpanom ...

Grand Round

Araya Keeratimahat, MD

Case

Patient: A 16-year-old Thai woman, from Nakornpanom

Admission date: 17 September 2014

Chief complaint: Multiple vesicles and tense bullae at trunk for 2 months

Case

Present illness: 2 months PTA she presents with multiple vesicles and

tense bullae at left arm, trunk and back. She came to nearby hospital and received dicloxacillin and chlorpheniramine for treatment. But the lesion not improved and developes the new multiple vesicles and tense bullae at neck, trunk, abdomen, groin , back and both extremities

Past history: HbE trait thallasemia Family history: nil

Case

Physical examination: General appearance: A Thai woman, not pale, no

jaundice HEENT: mildly pale conjunctivae, anicteric sclerae Lymph nodes: cervical, supraclavicular, axillary lymph

nodes cannot be palpated Heart, lung and abdomen: normal Neurologic examination: grossly intact, motor power

grade V

Case

Dermatological examination: Skin: Multiple discrete clear fluid vesicles and tense

bullae on erythematous base skin on trunk, back, groin and both extremities.Multiple well defined erythematous erosion and crust at face and neck

Oral cavity: Few small erosions at anterior of tongue and hard palate, erosion and hemorrhagic crust at both upper and lower lip.

Case

Dermatological examination: Scalp and hair : mild erythematous patch at right

frontal area, no hair loss Nail: normal Total body surface area involvement : 14%

Case

Problem list Multiple vesicle and tense bullae of young woman

Differential diagnosis Linear IgA bullous dermatosis Dermatitis herpetiformis Bullous pemphigoid Epidermolysis bullosa aquisita

Skin biopsy

10x 40x

Skin biopsy at new vesicle on Lt armThe section shows : subepidermal seperation with multiple neutrophils infiltration at upper papillary dermis

Case

Investigation Skin biopsy at new vesicle on Lt arm The section shows : subepidermal seperation with

multiple neutrophils infiltration at upper papillary dermis

DIF : Positive IgA, IgG, C3 linear pattern at dermoepidermal junction

IIF: pending

Topic

Linear IgA bullous dermatosis

LINEAR IgA BULLOUS DERMATOSIS

LABD is an immune-mediated, subepidermal vesiculobullous eruption that occurs in both adults and children.

It has been defined on the basis of immunopathology consisting of linear deposition of IgA along the cutaneous BMZ.

The childhood form is most frequently termed “chronic bullous disease of childhood” (CBDC).

Hull CM and Zone JJ. Linear IgA bullous dermatosis . In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 496-500.

Epidemiology

The true incidence of LABD is unknown. The incidence in southern England has been

estimated to be 1 in 250 000 per year. In adults, the average age of onset of LABD is

typically after fourth decade of life.

Hull CM and Zone JJ. Linear IgA bullous dermatosis . In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 496-500.Rao CL and Hall III RP. Linear Ig A Dermatosis and Chronic Bullous Disease of Childhood. In: Goldsmith LA, et al. Fitzpatrick’s dermatology of general medicine. 8th ed. New York: Mcgraw-Hill 2012: 2721-26.

Epidemiology

There appears to be a slight female preponderance, although this has not been observed in all series.

Childhood LABD occurs at a mean age of 4.5 years.


Pathogenesis

In adult and childhood LABD patients, this IgA antibody was found, on immunoblot, to react against a 97 kDa antigen in an epidermal extract.

Subsequently, the 97 kDa antigen was found to represent a cleaved ectodomain of BPAG2, referred to as LABD97


Yancey KB. The Biology of Basement Membrane Zone. In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 449-451.

Pathogenesis


Johnston RB. Weedon’s Skin Pathology, 3rd edition. 2009.:89.

Pathogenesis

LABD and CBDC are defined by the presence of a homogeneous linear band of IgA at the dermal–epidermal basement membrane zone.

A minority of patients in both groups have additional deposits of other immunoreactants, most often IgG and occasionally the third component of complement (C3).

Rao CL and Hall III RP. Linear Ig A Dermatosis and Chronic Bullous Disease of Childhood. In: Goldsmith LA, et al. Fitzpatrick’s dermatology of general medicine. 8th ed. New York: Mcgraw-Hill 2012: 2721-26.

Clinical Features

Clinical manifestations in LABD are variable and patients can present with findings suggestive of DH as well as subepidermal tense bullae that are often indistinguishable from BP.


Clinical Features

The vesiculobullous lesions often appear in a herpetiform arrangement on erythematous and/or normal-appearing skin.

Some patients present with expanding annular plaques, while others have lesions that are scattered and asymmetric.


Linear IgA bullous dermatosis.

Bullae, erosions and erythematous patches of linear IgA bullous dermatosis.


Linear IgA bullous dermatosis.

Annular and polycyclic plaques of the trunk


Clinical Features

LABD may present as a variant of mucous membrane (cicatricial) pemphigoid, with oral, nasal, pharyngeal and esophageal lesions.

The ocular form of LABD is clinically indistinguishable from ocular mucous membrane pemphigoid.


Chronic bullous disease of childhood

Clinical findings of annular erythema and blisters (often referred to as a “crown of jewels”), which developed predominantly in flexural areas, particularly the lower trunk, thigh and groin in preschool children.


Chronic bullous disease of childhood

Crown of jewels The circumferential and

linear vesicles and bullae are typical of this disorder.


Drug-induced LABD

Vancomycin being one of the more common inducers. Tense vesicles and bullae appear 24 hours to 15 days

after the offending medication is begun. DIF reveals linear deposition of IgA in the basement

membrane zone, within the lamina lucida or rarely below the lamina densa.

Most patients lack circulating IgA autoantibodies Drug-induced LABD usually remits within 2–6 weeks of

cessation of the drug .


Drug-induced LABD


Histopathology

An early lesion in patients with LABD and CBDC reveals a subepidermal bulla with collections of neutrophils along the basement membrane, often accumulating at the papillary tips.

A mild lymphocytic infiltrate may be present around the superficial dermal blood vessels without any evidence of neutrophilic vasculitis.


Histopathology

Histopathology of lesional skin from a patient with LABD showing a subepidermal blister filled with neutrophils.


Direct immunofluorescence

DIF of normal-appearing perilesional skin from a patient with LABD .

A homogeneous band of IgA is present at the DEJ.


Treatment

The majority of patients with LABD respond to either oral dapsone or sulfapyridine therapy.

Most patients with LABD have a clinical response within 48–72 hours.

The average dose of dapsone required to control LABD in adults is 100 mg daily, but doses as high as 300 mg daily.


Treatment

It is our observation that cases in which both IgG and IgA deposits are present in the BMZ are those that are likely to require additional therapy with systemic corticosteroids.

Oral prednisone in doses up to 40 mg daily to achieve complete control of the disease.


Treatment

Children usually respond to a dose of Dapsone 1–2 mg/kg daily.

The majority of our patients have been controlled by dapsone alone.


Dapsone

Chemical structure of dapsone

Dapsone is a sulfone drug, and sulfones are related to the sulfonamide family.

Dapsone is used in dermatology for its anti-inflammatory effect.4,4’-diaminodiphenylsulfone

Nunley JR and Wolverton.SE.Systemic drug : Dapsone. In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 2174-75.Sago JG and Hall III RP. Dapsone. In: Goldsmith LA,et al. Fitzpatrick’s dermatology of general medicine. 8th ed. New York: Mcgraw-Hill 2012: 2721-26.

Dapsone

Dapsone is 80% orally bioavailable Post-administration shows peaks in the serum

between 2 and 6 hours, and has a half-life of 24–30 hours.

Highly lipophilic, it has excellent cell penetration.

Nunley JR and Wolverton.SE.Systemic drug : Dapsone. In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 2174-75.

Dapsone

Dapsone and its major metabolite monoacetyldapsone are strongly protein-bound and undergo enterohepatic recirculation.

Dapsone may be found in the bloodstream up to 1 month following a single dose

Sago JG and Hall III RP. Dapsone. In: Goldsmith LA,et al. Fitzpatrick’s dermatology of general medicine. 8th ed. New York: Mcgraw-Hill 2012: 2721-26.

Dapsone

Dapsone is metabolized by N-acetylation and N-hydroxylation in the liver.

Acetylation yields monoacetyldapsone, which is then de-acetylated to dapsone, yielding an equilibrium between dapsone and monoacetyldapsone.


Dapsone

Hydroxylation via CYP enzymes produces N-hydroxy-dapsone, the metabolite which is believed to be responsible for the majority of dapsone side effects.

Both dapsone and N-hydroxy-dapsone undergo glucuronidation in the liver, which result in more water-soluble compounds that are rapidly excreted in the urine.


Dapsone

Mechanism of Action Dapsone inhibits migration of neutrophils to areas

of inflammation by inhibiting neutrophil chemotaxis to the chemoattractant signals

Inhibits the adherence of neutrophils to skin-localized IgA and endothelium.


Dapsone

Mechanism of Action Inhibit the release of inflammatory mediators

including interleukin-8 (IL-8), PGD2, and tumor necrosis factor-α (TNF-α).

Inhibit the myeloperoxidase enzyme.


Dapsone

Indication Dapsone is considered the drug of choice of Dermatitis herpetiformis (FDA-approved) LABD/CBDC Bullous eruption of SLE Erythema elevatum diutinum and also other noninfectious conditions and infectious

condition such as leprosy


DapsoneAbsolute Contraindication

Relative Contraindications

prior hypersensitivity to dapsone

a low G6PD level significant

cardiopulmonary disease an allergy to sulfonamide

antibiotics (because of the possibility of cross-reactivity).


Dapsone

Pregnancy Lactation

Pregnancy category C Dapsone is found in breast milk and can cause hemolytic anemia in breastfed infants


Dapsone

Increase Dapsone Levels (and side effects)

Decrease Dapsone Level Probenecid (via decreased

renal clearance) Trimethoprim and other

folate antagonists. Sulfonamides and

hydroxychloroquine (increase the oxidative stress on RBCs and may worsen hemolysis.

Activated charcoal Para-aminobenzoic

acid (PABA) Rifampin

Drug Interaction :


Dapsone

Major Side Effects Serious systemic side effects of dapsone may be

idiosyncratic or pharmacologic The pharmacologic and dose-dependent adverse

effects include Hemolytic anemia Methemoglobinemia


Dapsone

Hemolytic anemia Sulfones produce an oxidant stress on aging red

blood cells. In patients with glucose-6-phosphate dehydrogenase

deficiency, dapsone may produce severe hemolysis. Dapsone is begun after screening for G6PD deficiency. Drug-induced hemolysis can be confirmed and

followed by a reticulocyte count.


Dapsone

Methemoglobinemia The signs and symptoms are poor oxygenation,

including cyanosis, headache, shortness of breath, chest pain, and fatigue.

symptomatic methemoglobinemia is rare, usually occur with methemoglobin levels of 20%–30%.


Dapsone

Methemoglobinemia Methemoglobinemia in the absence of cardiopulmonary

symptoms does not require alteration of dapsone dose Patients who have mild symptoms of anemia or

methemoglobinemia suggested to take Cimetidine 400 mg 3 times daily and Lipoic acid 90 mg a day if these might ameliorate symptoms and dapsone can be continued


Dapsone

Methemoglobinemia Intravenous methylene blue, 1% solution given 1–2

mg/ kg slowly IV can be used to decrease the degree of methemoglobinemia.

Ascorbic acid 1,000 mg intravenously every 12 hours has also been used.


Dapsone

Major Side Effects The idiosyncratic adverse effects

Agranulocytosis Peripheral neuropathy Dapsone hypersensitivity


Dapsone

Agranulocytosis Usually occurs after 2–12 weeks of continuous

dapsone treatment. The patient to discontinue the drug and report

immediately if fever, a sore throat, or other signs of infection develop.

Although usually reversible within days when patients stop therapy, it may be fatal due to superseding infection.


Dapsone

Peripheral neuropathy May occur as early as during the first 4 months

of therapy. A pure motor neuropathy (involving primarily

distal extremity muscles) or pure sensory, and combined motor and sensory neuropathies have been reported.


Dapsone

Peripheral neuropathy Relatively high daily doses of dapsone (200–500

mg) and high cumulative doses in the range of 25 to 500 g have been implicated.

This is reversible with dose decrease or discontinuation.

Nunley JR and Wolverton.SE.Systemic drug : Dapsone. In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 2174-75.Sago JG and Hall III RP. Dapsone. In: Goldsmith LA,et al. Fitzpatrick’s dermatology of general medicine. 8th ed. New York: Mcgraw-Hill 2012: 2721-26.

Dapsone

Dapsone hypersensitivity A rare, but potentially severe reaction, characterized by

fever, a cutaneous eruption and internal organ involvement, which is usually seen 2–7 weeks after initiation of therapy.

The cutaneous manifestations vary from a morbilliform eruption to exfoliative dermatitis.


Dapsone Dapsone hypersensitivity The systemic manifestations include fever, pruritus,

lymphadenopathy, hepatitis, an elevated ESR, leukocytosis, and, rarely, eosinophilia.

Treatment is discontinuation of dapsone. Methylprednisolone 1g/day for 3 days may be required,

followed by a prednisone taper over 4–6 weeks.


Dapsone Dapsone hypersensitivity Any other end organ damage must be managed

supportively (dialysis for renal failure, diuretics for myocarditis, etc.)

Rechallenge with dapsone followed resolution of the sulfone syndrome is contraindicated as reinitiation of drug can produce severe symptoms within 2 to 6 hours.


Dapsone

Dapsone

Dapsone therapy monitoring includes a baseline CBC and liver function tests , measure baseline G6PD activity in all patients.

Weekly CBCs for the 1st month, monthly CBCs for the next 5 months, and semiannual CBCs thereafter while the patient remains on therapy.

Liver function tests should be repeated at 6 months and annually thereafter.


Treatment

Successful treatment of both adult and childhood LABD with antibiotics, including dicloxacillin, erythromycin, tetracycline (in those >9 years of age), and trimethoprim–sulfamethoxazole, has been reported.


Treatment

Treatment of linear IgA bullous dermatosis of childhood with flucloxacillin

Case series : 7 patients with linear IgA bullous dermatosis of childhood treated with flucloxacillin.

In 4 cases, it induced complete remission within 3 to 4 months of starting therapy with no relapses. In the other 3 cases, it successfully controlled the disease but with prompt relapse on discontinuation of the treatment.

Alajlan A,et al.Treatment of linear IgA bullous dermatosis of childhood with flucloxacillin. J Am Acad Dermatol 2006;54:652-6.)

Treatment

Mycophenolate mofetil, azathioprine and IVIg can be used as steroid-sparing agents in patients who do not respond to a combination of prednisone and dapsone or in patients with severe disease.


Prognosis

The natural course of the disease is characterized by persistence for several years with eventual spontaneous remission in many patients.

A remission rate of 10–15% was described. CBDC remits within 2–4 years.


CHARACTERISTICS THAT DIFFERENTIATE LABD, DH AND BP

LABD DH BP

Cutaneous lesion Small vesicles and/or large bullae

Grouped papules and small vesicles, often excoriated

Large tense bullae

Distribution Similar to DH or BP Extensor surfaces, symmetrical

Trunk, extremities, occasionally mucosal surfaces

Histology Subepidermal bullae with neutrophilic infiltrate

Subepidermal bullae with neutrophilic infiltrate

Subepidermal bullae with eosinophilic infiltrate

Direct IF Linear IgA at BMZ, possibly also IgG

Granular IgA in dermal papillae

Linear IgG and C3 at BMZ

Hull CM and Zone JJ. Dermatitis herpetiformis . In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 491-95.

CHARACTERISTICS THAT DIFFERENTIATE LABD, DH AND BP

LABD DH BP

Site to biopsy for direct IF

Perilesional Adjacent normal-appearing skin

Perilesional

Indirect IF Linear IgA at BMZ (70%)

Negative Linear IgG at BMZ (70%)

Enteropathy Rare >90% Normal

HLA-DQ2 30% >90% Normal (20%)

Dapsone responsiveness

Good, may also require systemic corticosteroids

Excellent Minimal to moderate

Hull CM and Zone JJ. Dermatitis herpetiformis . In: Bolognia JL, et al. Dermatology 3rd ed. Elsevier 2012: 491-95.

Progression

19/09/2014 22/09/2014

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Grand Round Araya Keeratimahat, MD. Case Patient: A 16-year-old Thai woman, from Nakornpanom ...

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