1000-2000 5 ьшò

F33.9 Major depressive disorder, recurrent, unspecified

CLINICALPEARLS

Treatment-resistant depression is common, affecting 1/3 of those with MDD.

Combination and augmentation strategies with antidepressants, antipsychotics, therapy, and mood stabilizers can be helpful.

ECT should be considered in severe and life-threatening cases.

mebooksfree.com

DERMATITIS HERPETIFORMIS

Abdul Aleem, MD Hiral N. Shah, MD, FASGE, FACG

BASICS

DESCRIPTION

Dermatitis herpetiformis (DH) presents as a chronic, relapsing, polymorphous, intensely pruritic, erythematous papulovesicular eruption with symmetrical distribution primarily involving extensor skin surfaces of the elbows, knees, buttocks, back, and scalp.

DH is an autoimmune disease associated with gluten sensitivity with genetic, environmental, and immunologic influences.

DH is distinguished from other bullous diseases by characteristic histologic and immunologic findings, as well as associated gluten-sensitive enteropathy (GSE).

System(s) affected: skin

Synonym(s): Duhring disease, Duhring-Brocq disease

EPIDEMIOLOGY

Occurs most frequently in those of Northern European origin

Rare in persons of Asian or African American origin

Predominant age: most common in 4th and 5th decades but may present at any age

Childhood DH is rare in most countries, although an Italian study showed 27% of patients were age of <10 years and 36% age of <20 years.

Predominant gender: adults: male > female (1.5:1 in the United States, 2:1 worldwide); children: female > male

Incidence

1/100,000 persons per year in the United States

Prevalence

11/100,000 persons in the U.S. population; as high as 39/100,000 persons worldwide

ETIOLOGYAND PATHOPHYSIOLOGY

mebooksfree.com

Evidence suggests that epidermal transglutaminase (eTG) 3, a keratinocyte enzyme involved in cell envelope formation and maintenance, is the autoantigen in DH.

eTG is highly homologous with tissue transglutaminase (tTG), which is the antigenic target in celiac disease and GSE.

The initiating event for DH is presumed to be the interaction of wheat peptides with tTGs, which results in the formation of an autoantigen with high affinity for particular class II major histocompatibility complex (MHC) molecules.

Presentation of the autoantigen leads to activation of T-cells and the humoral immune system.

IgAantibodies against tTG cross-react with eTG and result in IgA-eTG immune complexes that are deposited in the papillary dermis. Subsequent activation of complement and recruitment of neutrophils to the area result in inflammation and microabscesses.

Skin eruption may be delayed up to 5 to 6 weeks after exposure to gluten.

Gluten applied directly to the skin does not result in the eruption, whereas gluten taken by mouth or rectum does. This implies necessary processing by the GI system.

Thought to be immune complex–mediated disease

Genetics

High association with human leukocyte antigen DQ2 (95%), with remaining patients being positive for DQ8, DR4, or DR3

Strong association with combination of alleles DQA1*0501 and DQB1*0201/0202, DRB1*03 and DRB1*05/07, or DQA1*0301 and DQB1*0302

RISK FACTORS

GSE: >90% of those with DH will have GSE, which may be asymptomatic.

Family history of DH or celiac disease

GENERALPREVENTION

Gluten-free diet (GFD) results in improvement of DH and reduces dependence on medical therapy. GFD also may reduce the risk of lymphomas associated with DH.

COMMONLYASSOCIATED CONDITIONS

mebooksfree.com

Hypothyroidism is the most common condition associated with DH.

GSE, gluten ataxia

Gastric atrophy, hypochlorhydria, pernicious anemia

GI lymphoma, non-Hodgkin lymphoma

Hyperthyroidism, thyroid nodules, thyroid cancer

IgAnephropathy

Autoimmune disorders, including systemic lupus erythematosus, dermatomyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, Raynaud phenomenon, insulin-dependent diabetes mellitus, myasthenia gravis, Addison disease, vitiligo, alopecia areata, primary biliary cirrhosis, and psoriasis

DIAGNOSIS

Diagnosis of DH involves a clinicopathologic correlation among clinical presentation, histologic and direct immunofluorescence (DIF) evaluation, serology, and response to therapy or dietary restriction.

HISTORY

Waxing and waning, intensely pruritic eruption with papules and tiny vesicles

Eruption may worsen with gluten intake.

GI symptoms may be absent or may not be reported until prompted.

PHYSICALEXAM

The classic lesions of DH are described as symmetric, grouped, erythematous papules and vesicles.

More commonly presents with erosions, excoriations, lichenification, hypopigmentation, and/or hyperpigmentation secondary to scratching and healing of old lesions

Areas involved include extensor surfaces of elbows (90%), knees (30%), shoulders, buttocks, and sacrum. The scalp is also frequently affected. Oral lesions are rare.

In children, purpura may be visible on digits and palmoplantar surfaces.

Adults with associated enteropathy are most often asymptomatic, with about 20% experiencing steatorrhea and <10% with findings of bloating, diarrhea, or malabsorption.

Children with associated enteropathy may present with abdominal pain, diarrhea, iron deficiency, and reduced growth rate.

mebooksfree.com

DIFFERENTIALDIAGNOSIS

In adults

–Bullous pemphigoid: linear deposition of C3 and IgG at the basement membrane zone

–Linear IgAdisease: homogeneous and linear deposition of IgAat the basement membrane zone, absence of GSE

–Prurigo nodularis

–Urticaria: wheals, angioedema, dermal edema

–Erythema multiforme

In children

–Atopic dermatitis: face and flexural areas

–Scabies: interdigital areas, axillae, genital region

–Papular urticaria: dermal edema

–Impetigo

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Serum IgAtTG antibodies: Detection of tTG antibodies was noted to be up to 95% sensitive and >90% specific for DH in patients on unrestricted diets (1,2) [A].

Serum IgAeTG antibodies: Antibodies to eTG, the primary autoantigen in DH, were shown to be more sensitive than antibodies to tTG in the diagnosis of patients with DH on unrestricted diets (95% vs. 79%) but is not widely available in all labs (1,2)[A].

Serum IgAendomysial antibodies (EMA): Antibodies to EMAhave a sensitivity between 50% and 100% and a specificity close to 100% in patients on unrestricted diets but is more expensive, time-consuming, and operatordependent than tTG (2).

Follow-Up Tests & Special Considerations

Serologic assessment of anti-tTG and anti-eTG correlate with intestinal involvement of disease and in conjunction with anti-EMAmay be useful in monitoring major deviations from GFD (1,2).

Genetic testing for haplotypes HLA-DQ2 and HLA-DQ8 can also be offered to patients to determine genetic susceptibility, to screen patients with high risk of CD, or if the diagnosis is not clear (1).

mebooksfree.com

Diagnostic Procedures/Other

The gold standard test to establish a diagnosis DH is DIF of the perilesional skin that demonstrate characteristic granular IgAdeposits in dermal papillae and/or basement membrane (1,2)[A]. It is this key diagnostic feature that differentiates this blistering skin condition from all other dermatological diseases (3).

DIF has a sensitivity and specificity of close to 100% (1).

In patients with high suspicion for DH with a negative DIF, another perilesional skin biopsy should be obtained from a different site (1). Histopathology of these lesions with routine staining reveals neutrophilic microabscesses in the tips of the dermal papillae and may show subepidermal blistering (1,2).

TREATMENT

GENERALMEASURES

GFD is the mainstay of treatment in DH and can lead to complete resolution of symptoms (1,2)[A].

Typically requires 18 to 24 months of strict adherence to GFD prior to resolution of skin lesions without any additional treatment

Lesions can recur within 12 weeks of reintroduction of gluten.

MEDICATION

Despite being on GFD, the lesions of DH take several months to clear, and active lesions warrant additional treatment (3).

Medications are useful for immediate symptom management but should only be used as an adjunct to dietary modification (2).

First Line

Dapsone is approved by the FDAfor use in DH and is the most widely used medication (2,4)[A].

Initial dosing of 25 to 50 mg/day on a strict GFD typically results in improvement of symptoms within 24 to 48 hours (1,3)[C].

It is recommended to use minimum effective dose with slow titration based on patient response and tolerability. Average maintenance dose is 1 mg/kg/day (50 to 150 mg/day) and can be increased up to 200 mg to obtain better symptom control.

mebooksfree.com

Minor outbreaks on the face and scalp are common even with treatment; not ideal for long-term use in DH

Dapsone works by inhibiting neutrophil recruitment and IL-8 release, inhibiting the respiratory burst of neutrophils, and protecting cells from neutrophil-mediated injury, thereby suppressing the skin reaction. It has no role in preventing IgAdeposition or mitigating the immune reaction in the gut (2,4).

Precautions

–Common side effects include nausea, vomiting, headache, dizziness, weakness, and hemolysis.

–Adrop in hemoglobin of 1 to 2 g is characteristic with dapsone 100 mg/day.

–G6PD deficiency increases severity of hemolytic stress. Dapsone should be avoided, if possible, in those who are G6PD-deficient.

–Dose-related methemoglobinemia may occur with doses >100 mg/day. Cimetidine may reduce the severity of this side effect.

–Risk of distal motor neuropathy

ALERT

Monitor for potentially fatal dapsone-induced sulfone syndrome: fever, jaundice and hepatic necrosis, exfoliative dermatitis, lymphadenopathy, methemoglobinemia, and hemolytic anemia.

Can occur 48 hours or 6 months after treatment, most often 5 weeks after initiation

Pediatric Considerations

<2 years: Dosing is not established.

>2 years: 0.5 to 1.0 mg/kg/day

Pregnancy Considerations

Category C: Safety during pregnancy is not established.

Secreted in breast milk and will produce hemolytic anemia in infants

Adherence to a strict GFD 6 to 12 months before conception should be considered with the hope of eliminating need for dapsone during pregnancy.

Second Line

High-potency topical steroids can be used acutely to control symptoms until dapsone becomes effective (1)[C].

Sulfapyridine (1 to 2 g/day) is FDA-approved for use in DH and is thought to be the active metabolite in sulfasalazine (2 to 4 g/day) (2,5)[B]. Common side

mebooksfree.com

effects include nausea, vomiting, and anorexia. Enteric-coated form may reduce side effects. Other side effects include agranulocytosis, hypersensitivity reactions, hemolytic anemia, proteinuria, and crystalluria (2,5).

Topical steroids and 3rd-generation antihistamines can be used to provide relief from symptoms of pruritus and itching.

ISSUES FOR REFERRAL

Over time, the management of DH warrants an interdisciplinary treatment that includes providing a referral to dermatologist, gastroenterologist, and registered dietitian (1,2).

ADDITIONALTHERAPIES

Asingle case report described topical dapsone therapy as potential alternative treatment or as an adjunct to oral dapsone to decrease systemic exposure and risk of severe side effects. However, it has not been studied extensively (6)[C].

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Patient Monitoring

Every 6 to 12 months by physician and dietitian to evaluate GFD adherence and recurrence of symptoms

Adherence to GFD can be monitored with serologic levels of anti-tTG, antieTG, and EMAlevels (1).

Patients on dapsone require lab monitoring weekly for the 1st month, biweekly for 2 months, and then every 3 months for the duration of medication use (1,5).

DIET

Grains that should be avoided: wheat (includes spelt, kamut, semolina, and triticale), rye, and barley (including malt)

Safe grains (gluten-free): rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), and oats

Care should be taken to avoid gluten-free grains that are contaminated with sources of gluten during processing such as oats.

mebooksfree.com

Sources of gluten-free starches that can be used as flour alternatives

–Cereal grains: amaranth, buckwheat, corn, millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), and Montina

–Tubers: arrowroot, jicama, taro, potato, and tapioca

–Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, and soybeans

–Nuts: almonds, walnuts, pistachios, chestnuts, hazelnuts, and cashews

–Seeds: sunflower, flax, and pumpkin

PATIENT EDUCATION

Patients started on dapsone should be made aware of potential hemolytic anemia and the signs associated with methemoglobinemia.

American Academy of Dermatology, 930 N. Meacham Road, P.O. Box 4014, Schaumberg, IL60168-4014; (708) 330-0230

The University of Chicago Celiac Disease Center, 5841 S. Maryland Ave., Mail Code 4069, Chicago, IL60637; (773) 702-7593; www.celiacdisease.net or http://www.cureceliacdisease.org/

Gluten Intolerance Group of North America, 31214-124 Ave. SE, Auburn, WA98092; (206) 246-6652; fax (206) 246-6531; https://www.gluten.org/ The Celiac Disease Foundation, 13251 Ventura Blvd., #1, Studio City, CA

9160; (818) 990-2354; fax (818) 990-2379

PROGNOSIS

DH is a chronic disease with excellent prognosis, provided strict adherence to a GFD is maintained.

10to 15-year survival rates do not seem to differ from general population.

Remission in 10–15%

Skin disease responds readily to dapsone. Occasional new lesions (2 to 3 per week) are to be expected and are not an indication for altering daily dosage.

Strict adherence to a GFD improves clinical symptoms and decreases dapsone requirement. GFD is the only sustainable method of eliminating cutaneous and GI disease.

Risk of lymphoma may be decreased in those who maintain a GFD.

COMPLICATIONS

Majority of complications are associated with GSE.

Malnutrition, weight loss, nutritional deficiencies (folate, vitamin B12, iron) Abdominal pain, dyspepsia

mebooksfree.com

Osteoporosis, dental abnormalities

Autoimmune diseases

Lymphomas

REFERENCES

1.Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Investig Dermatol. 2015;8:257–265.

2.Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis. J Am Acad Dermatol. 2011;64(6):1027–1033.

3.Reunala T, Salmi TT, Hervonen K. Dermatitis herpetiformis: pathognomonic transglutaminase IgAdeposits in the skin and excellent prognosis on a glutenfree diet. Acta Derm Venereol. 2015;95(8):917–922.

4.Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103–124.

5.Willsteed E, Lee M, Wong LC, et al. Sulfasalazine and dermatitis herpetiformis. Australas J Dermatol. 2005;46(2):101–103.

6.Handler MZ, Chacon AH, Shiman MI, et al. Letter to the editor: application of dapsone 5% gel in a patient with dermatitis herpetiformis. J Dermatol Case Rep. 2012;6(4):132–133.

ADDITIONALREADING

Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol. 2011;64(6):1017–1024.

Cardones AR, Hall RPIII. Management of dermatitis herpetiformis. Immunol Allergy Clin North Am. 2012;32(2):275–281.

Cardones AR, Hall RPIII. Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation. Immunol Allergy Clin North Am. 2012;32(2):263–274.

Kárpáti S. An exception within the group of autoimmune blistering diseases: dermatitis herpetiformis, the gluten-sensitive dermopathy. Immunol Allergy Clin North Am. 2012;32(2):255–262.

Paek SY, Steinberg SM, Katz SI. Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol. 2011;147(3):301–305.

SEE ALSO

mebooksfree.com