Postać krwotoczna choroby Duhringa

Introduction

Dermatitis herpetiformis (DH; Duhring disease) belongs to IgA-dependent autoimmune blistering dermatoses. Dermatitis herpetiformis is most common in the North European population [1]. The disease usually surfaces in puberty, however, it may develop at every age. Dermatitis herpetiformis is also the most common blistering disease in children. The proportion of incidence in men and women equals 3 : 2. The course of the disease is chronic and with a tendency towards exacerbations and remissions [2, 3].
Dermatitis herpetiformis has a complex etiopathogenesis. Environmental, genetic, and immunological factors are taken into account in the development of the disease [3]. The most common cause of DH is gluten intolerance. Gluten is a mixture of plant proteins built from gliadin’s amino acids and glutenin that are found in cereal grains such as: wheat, barley, oats, rye, and in malt.
Examples of comestible products that contain gluten include: flour, ready-made foods, cold cuts, sweets, dairy, and alcohol [4]. Patients with DH suffer from gluten-dependent enteropathy [3]. All patients have anatomical changes in the small intestine that take the form of intestinal villi atrophy, however, gastroenterological symptoms are usually mild or completely absent [5]. Strict and long-term gluten-free diet allows for achieving disease remission. Unusually, some patients experience spontaneous improvement, however, this process has not been fully explained yet.
A strong connection between this disease entity and individuals with specific histocompatibility antigens, HLA, has been confirmed. HLA DR3 and HLA DQw2 predispose for the disease development and have been detected in 80–90% of cases; whereas HLA-B8 and HLA DQ8 are present in 10–20% of patients [3, 4].
Participation of the genetic factor is confirmed by the fact that in Japan, where the above-mentioned histocompatibility antigens are almost non-existent, DH is rare [2]. Additionally, it was showed that the risk of disease development in the first-degree relatives of patients might be 15 times higher as compared with the general population [6].
DH-patients have been proved to have an increased incidence of concomitant autoimmune disease. Those include thyroid diseases, type 1 diabetes, malignant anaemia, lupus erythematosus, Sjögren’s syndrome, and leucoderma [3].
Furthermore, it has been confirmed that iodine is a factor that induces and intensifies skin lesions. It is contained in drugs, comestible products, and seaside air. Concomitant infectious diseases and stress also contribute to lesion intensification in DH [7].

Objective

The aim of the article is to present an extremely rare case of haemorrhagic lesions in DH that developed unusually late in a 72-year-old patient, and to present a review of current literature.

Case report

A 72-year-old male reported to the Department of Dermatology and Venereology, Medical University of Lodz, due to polymorphic skin lesions that had been present for several months. Cutaneous lesions were accompanied by a burning sensation and intensified pruritus assessed by the patients as 7/10 points on the Visual Analogue Scale (VAS). The patient did not associate the appearance of lesions with any factors – he denied prior and concomitant infections, usage of new cosmetics, drugs, and contact with preparations that have toxic or allergic effects.
In the medical history the patients confirmed: stable coronary arterial disease, paroxysmal atrial fibrillation, arterial hypertensions, hyperlipidaemia, degenerative spine disease, and prostate gland hypertrophy. In the past, the patient experienced brain infarction and was treated due to duodenal ulcers. Moreover, the patient underwent the following procedures: coronary artery bypass graft, several percutaneous coronary interventions, appendectomy, and a surgery of inguinal hernia. The patient denied dermatological diseases in the family. Prior to being admitted to the Department, the patient was treated on an outpatient basis with antihistamine preparations and topical glucocorticosteroids without significant improvements.
Upon admission, erythematopapular lesions with a clear haemorrhagic component and erosions as well as scabs were confirmed on the smooth skin (figs. 1, 2). The lesions had an annular structure and symmetrical distribution with the greatest intensity at the elbows, knees, buttocks and thighs. Inconspicuous skin lesions were observed on the forearms and dorsal surfaces of palms. Some lesions merged to form bigger foci. Additionally, impetiginisation within some lesions was observed; it was associated with a secondary bacterial infection caused by a superinfection triggered by obstinate scratching. Those lesions took the form of honey- and yellow-coloured scabs (fig. 3). At the boarder of the smooth skin and the scalp, single erythematous papulae were observed.
Inconspicuous fine-flake desquamation of the epidermis was present on the scalp. Physical examination did not reveal significant abnormalities from the norm. The patient did not report any pain cause by the gastrointestinal tract.
Values of basic laboratory tests were within normal limits. Direct immunofluorescence test of the healthy skin sample taken from the lesion area on the buttock showed the presence of IgA (++) granular deposits at the tops of papillae (MP Biomedicals, USA) (fig. 4). Indirect immunofluorescence test results showed the serum presence of IgA antibodies directed towards the endomysium of smooth muscles (IgA EmA) with the 1/20 titre, and IgA antibodies directed towards gliadin with the 1/20 titre (Euroimmun, Germany). The examination utilizing the immunoblot method confirmed the presence of antibodies directed towards tissue transglutaminase IgA (anti-tTG), and antibodies directed towards gliadin IgA and IgG. The presence of other antibodies was not confirmed. Histopathological examination of a skin sample with a lesion showed smoothening of the epidermis with a crevicular exfoliation of all epidermal layers. Papillae skin was oedematous in places, with neutrophil infiltrations mostly in the crevasses and papillae (fig. 5). Acantholytic cells were not confirmed. According to the pathomorphologist’s assessment, the holistic image did not have the signs of pemphigus: it could suggest pemphigoid or DH.
On the basis of clinical presentation and results of additional test, DH was diagnosed. Other vesical and vascular diseases were excluded. Gluten-free diet was started; due to considerable severity of lesions, a decision was made to simultaneously administer dapsone in the dose of 100 mg/day, and then, 50 mg/day. In addition, intensive topical treatment with glucocorticosteroids was started together with application of combined drugs containing also antimicrobial substances – due to superinfection of the lesions.
During the subsequent days of the therapy, a gradual improvement in the skin condition was observed. Erythematopapular lesions began to absorb themselves, erosions started to be covered by the epidermis, and no new lesions were observed. Already after several days of taking dapsone, the patient noticed significant decrease in pruritus (VAS – 2/10 points). Due to an increased methemoglobin concentration in follow-up exams (3.2%), it was decided to decrease the Dapsone dose down to 25 mg/day. Complete remission of skin lesions with remaining post-inflammatory discolourations was observed after 2 months of the treatment.

Discussion

Skin lesions in the DH are most often polymorphous. They include: papulae, erythemas, blisters, urticarial eruptions, and numerous secondary lesions caused by persistent scratching. Haemorrhagic reactions, such as the ones in the presented case, are less commonly observed. A distribution of lesions DH is characteristic as they are found symmetrically and their distribution is festoon-like or herpetiform-like. Extensor surfaces of limb, knees, elbows, buttocks, and scalp are areas predisposed for the appearance of lesions [1]. Skin eruptions are accompanied by pruritus of a burning sensation. Intensity of reported pain is often incommensurable with intensity of skin lesions. Accompanying pruritus and consequent need to scratch oneself result in the absence of blistering as in the described case. Then, erosions and ulcers dominate the clinical presentation that may indicate a wrong diagnosis.
Mucous membranes are usually free from lesions. In the majority of cases there are also no gastrointestinal symptoms. If those appear, they mostly concern children and take the form of diarrhoea, stomachache, and bloating. The lack of extracutaneous symptoms makes it difficult to connect skin lesions with gluten intolerance.
Etiopathogenesis of eruptions in this disease is complex and not fully known. Immunological mechanisms leading to tissue lesions have not been described yet.
In DH, during a direct immunofluorescence test of a healthy skin sample presence of granular IgA deposits in the papillary dermis can be observed. Deposits are usually limited to the tops of papillae. In less than 5% of cases of DH-patients, a linear pattern of IgA antibodies is detected, what should be differentiated from a linear IgA bullous dermatosis [8]. IgA deposits may be accompanied by less numerous C3 deposits; IgG and IgM are less commonly detected. Antibody deposits have a tendency to persist despite successful treatment and gluten-free diet [2, 3].
IgA antibodies directed towards the endomysium of smooth muscles and tissue as well as epidermal transglutaminase are detected in the bloodstream of patients suffering from DH. Antibodies against the endomysium are highly specific and their appearance is induced by gluten [9].
The presence of autoantibodies against tissue transglutaminase is strictly connected with the activity of the disease. The level of anti-tTG may be measured by means of ELISA that is characterized by 90% of specificity and sensitivity within the range of 47–95% [4]. Levels of antibodies against tissue transglutaminase correlate with the level of intensity of histopathological lesions in the mucosa of the jejunum in biopsy samples taken from DH-patients, and with the level of antibodies against the endomysium of smooth muscles [10]. The titre decreased under the influence of effective treatment, and increased with subsequent gluten provocations, and thus, it may be used for assessing whether the patient observed dietary guidelines [11, 12]. Characteristic features of DH in the histopathological image include the presence of subcutaneous vesicae with micro-abscesses in the skin papillae. Dominating inflammatory cells include neutrophils; eosinophils are less popular. Leucocyte infiltrations are usually accompanied by fibrosis and dilation of capillaries [13].
The diagnosis is made on the basis of clinical presentation, and histopathological as well as immunological test results [14]. Differential diagnostics should take into account linear IgA bullous dermatosis, herpetiform pemphigus, erythema multiforme bullosum, prurigo, lichen planus annularis, bullous lichen planus, and more common disease entities such as eczematous lesions and scabies. Differentiation within autoimmune bullous diseases only on the basis of clinical symptoms is impossible. Immunopathological tests are of the essence.
Erythema multiforme, just like DH, is characterized by a symmetrical distribution of lesions; however, its most common locations are distal parts of upper and lower limbs. It appears suddenly, is usually associated with an infection or drugs taken, has an acute course, and is accompanied by usual general symptoms such as fever and joint pain. In case of prurigo there are no blisters, and erosions, hypertrophic papulae and scabs dominate the presentation. The disease is chronic with no tendencies to subside.
In cases of lichen planus annularis and bullous lichen planus, characteristic Wickham striae are observed within glistering multilateral papulae that may be distributed linearly. In about half of the cases, the mucosa is also involved; linear or tree-like whitening of the epidermis is confirmed on the mucosa.
Eczema is usually associated with specific allergic and non-allergic factors, and lesions within its course are usually disseminated and do not have a herpetiform pattern. Then, scabies is characterized by itch mite track-like burrows, papulae, and neurotic excoriations that are most often found within fingers, wrists, skin folds, genital areas, and buttocks. The lesions are accompanied by pruritus that intensifies at night and after the body is warmed up [2, 3].
In case of haemorrhagic lesions, lichen aureus and erythema elevatum diutinum should be excluded. Lichen aureus is counted among pigmented purpuric dermatoses, and its clinical presentation is dominated by ecchymoses, pigmented lesions, haemorrhagic well-defined elevated gold and brown papulae that are distributed linearly and mostly cover distal sections of limbs. Erythema elevatum diutinum is a disease associated with vasculitis characterized by symmetrical papulae, nodes, haemorrhagic lesions and ulcers found within knees, elbows, dorsal parts of palms, feet, and buttocks. Similarly to DH, the lesions are concomitant with pruritus [2, 3].
It should be noted that the clinical presentation in the described patient was atypical. In the presented case there were no blisters, and haemorrhagic skin lesions resembled eruptions present in erythema elevatum diutinum and lichen aureus, what caused diagnostics and outpatient treatment difficult. Furthermore, patient’s age at which the disease appeared was atypical.
Gluten-free diet is an important part of treatment in DH. Patients’ level of gluten intolerance is varied. Some of them require restrictive diet, whereas in others a diet with decreased gluten content is sufficient. After a couple of months of following the diet, skin lesions subside, serum antibody concentration lowers, and histopathological presentation of the jejunal mucosa improves. The diet alleviates disorders in the absorption of necessary nutrients, and hence, it prevents iron, folic acid and vitamin B12 insufficiencies. In case the observed elimination diet does not bring satisfactory therapeutic effects or when symptoms and signs are intensified, pharmacological treatment is commenced. Dapsone is the drug of choice.
A recommended dose is 0.5–2 mg/kg body weight. Prior to administration of dapsone, CBC should be performed and the level of liver enzymes should be assessed. The use of dapsone is associated with the risk of side effects that include: methemoglobinemia, haemolytic anaemia, agranulocytosis, kidney damage, and systemic neuropathy. Methemoglobinemia occurs most commonly in the clinical practice [15]. Dermatological care and close monitoring of the treatment are necessary to ensure safe and effective use of the drug. During the therapy, blood morphology, methemoglobin level and liver markers should be monitored twice a year [14].
In case of dapsone intolerance, alternative treatment may utilize sulfapyridine, a combination of tetracycline with nicotinamide or cyclosporine. It should be a lifelong treatment. Conducted studies showed that the majority of patients is unable to tolerate gluten after a long-term observance of the elimination diet. Consequently, lifelong gluten-free diet is justified in all patients affected by DH [16].

Conflict of interest

The authors declare no conflict of interest.

References/Piśmiennictwo

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