Ministry of Health Protection of the Ukraine Zaporozhye state medical university Department of skin and venereal diseases

LESNITSKY A.I., MAKURINA G.I.

Bullous and Vesicular Dermatoses

Manual book for the students

2007

Bullous and Vesicular Dermatoses

Theoretical part
The group of vesicular and pemphigus dermatoses includes different diseases on the basis of etiology and pathogenesis (pemphigus, Duhrings dermatosis, simple vesicular lichens, herpes zoster, exudative multimorphic erythema).

True (acantholytic) pemphigus

Pemphigus is a malignant, serious disease. Its clinical manifestation is the formation of vesicles on non-inflamed skin and mucous membranes. If not treated the vesicles soon appear on the whole skin. Patients should consult not only dermatologists but also other specialists (physicians, dentists, infectionists). Due to this, the knowledge of this pathology is necessary for all the clinicians to render qualified help to the patients.

Etiology and pathogenesis of pemphigus

There are different etiopathogenic theories, in particular, the viral theory but it is not completely proved. Recently autoimmune processes are considered to be of great importance in the pathogenesis: discovery of antibodies to intercellular substance in the skin, in liquid of the vesicles and in blood serum. In immunofluorescence, in intercellular space of stratum spinosum of epidermis immunoglobulin G is found only in the patients with pemphigus.

Peculiarities of the course of pemphigus

The morphologic basis of development of vesicles in this disease is acantholysis destruction of protoplasmic process of the cells of the epidermis stratum spinosum, weakness of intercellular contacts and accumulation of exudate in this layer, due to which inter epidermal vesicle is formed. Acantholysis underlies Nikolskys phenomenon: by pulling the covering of the vesicle, the epidermis exfoliates outside the boundary of the vesicle on the healthy skin. During severe scratching of the healthy skin between the vesicles the exfoliation of the epidermis takes place. Nikolskys symptom is more expressed in the stage of pemphigus exacerbation. The vesicles appear suddenly on the healthy skin or mucosa, then open and form erosions, or their exudate gets covered by crust. The disease has a chronic character, continuous progress and in the absence of treatment soon results in lethal outcome. Treatment with corticosteroids reduces highly the severity of the disease.

Clinical varieties
Four forms of true pemphigus are differentiated: pemphigus vulgaris (common), pemphigus vegetans, pemphigus foliaceus (exfoliative) and seborrheal pemphigus.

Pemphigus Vulgaris
This form of pemphigus accounts for approximately 75 per cent of the total number of all forms of pemphigus (Fig. 1). Usually dermatosis begins with affection of the oral and throat mucosa (Fig. 2), after which, as a rule, the skin of the trunk, limbs, inguinal region, axillae, face and external genitals is involved in the process. Typically the course is severe and chronic. Patients died within a few months to two years in the precorticosteroid era. The disease sets in suddenly with the abrupt appearance of bullae on an apparently healthy skin. The bullae are at first tense and then rapidly become flaccid. They range in size from a pea to a bean but may be larger, and are filled first with clear and later on with thick serous fluid.

Fig. 1. Pemphigus vulgaris Weeping, eroded surfaces with polycyclic contours are formed rapidly in the process of evolution. In regeneration of the epidermis, stratified brownish crusts are formed, after which brown pigmentation remains on the areas of the foci. In other cases (when the process tends to spontaneous remission or under the effect of steroid therapy), the tops of the bullae remain intact, because the exudate resolves, and they gradually collapse and turn into a thin crust, which then rub off. As a rule, spontaneous remissions alternate with recurrences. In a benign course of the process the patient's general condition hardly changes. In a malignant course, the organism becomes exhausted, septic fever sets in and is particularly severe if secondary infection develops; there are also eosinophilia, retention of sodium and chlorides in the tissues and a diminution in the protein content. There may be changes in the blood protein fractions and in the content of immunoglobulins A, G and M. Intercurrent] diseases of the liver, kidneys, lungs and heart may develop. Patients suffering from pemphigus usually experience no itching. Sometimes the numerous erosions cause severe pain, which intensifies when clothes are changed or when the patient alters position. The lesions are particularly painful when located in the mouth, on the lips, and the genitals.

Fig. 2. Pemphigus vulgaris located on the lips The degenerative changes in the Malpighian layer, which are embraced by the term 'acantholysis' are the morphological base of a significant clinical and diagnostic sign known as Nikolsky's sign (phenomenon). It may be described as follows: If one pulls the ruptured top of the vesicle, the epidermis on the apparently healthy skin is separated; when the apparently healthy skin area between the bullae or erosions is rubbed, the upper layers of the epidermis are also separated, and finally, when apparently healthy skin areas remote from the foci of affection are rubbed, the upper layers of the epidermis are easily injured. Besides, when an intact bulla is pressed with a finger one can see the fluid separating the adjacent epidermal areas and the bulla enlarging on the periphery. This last diagnostic test in pemphigus is called the Asboe-Hansen's sign. Despite the high diagnostic value of Nikolsky's sign, it cannot be regarded strictly pathognomonic for true pemphigus, because it also occurs in other dermatoses (particularly in congenital epidermolysis bullosa, Ritter's disease, Lyell's syndrome). It is positive in almost all pemphigus patients in the phase of exacerbation, but may be negative in other periods of the disease. Modern methods of treatment make it possible to delay considerably the onset of recurrences in many such patients, whereas the use of maintenance steroid therapy prolongs the patients' life for many years after the disease.

Pemphigus Vegetans
At the beginning of its development this form of pemphigus is clinically similar to pemphigus vulgaris and often starts with the appearance of lesions on the oral mucosa. From the very onset of the disease, however, attention is drawn to the tendency of the bullae to be localized around the natural orifices, the navel and in the region of the large skin folds (axillary, inguinofemoral, intergluteal, under the mammary glands, behind the ears). Papulomatous growths (Fig. 3) secreting a considerable amount of exudate are formed later in places of the ruptured bullae against the background of an eroded surface covered with a dirty film. The lesions tend to coalesce and form large vegetative surfaces at places with purulent necrotic disintegration. Nikolsky's sign is often positive. The dermatosis is accompanied with pain and a sensation of burning. Active movements are difficult because of sharp pain.

Fig. 3. Pemphigus vegetans

If treatment is successful, the vegetations become flatter and drier and the erosions epithelize. Marked pigmentation remains after the lesions. In some patients with pemphigus vegetans, cachexia grows and death may occur.

Pemphigus Foliaceus
The disease is characterized by drastic acantholysis leading to the formation of superficial fissures directly under the horny layer, which later turn into bullae. Pemphigus foliaceus is encountered more often than the vegetans form among adults and prevails over other variants of pemphigus vulgaris in children. At the beginning of the disease, flaccid bullae with a thin top and slightly elevated above the surface form on apparently healthy skin. They rupture rapidly with the formation of large erosions. More frequently the tops of the bullae dry up into thin stratified scaly crusts. Epithelization of erosions under the crusts is slow. New portions of the exudate cause the layering of these crusts, producing a scaly surface, hence there is a term 'exfoliative', by which the disease is also known. It is in this variant of pemphigus that the sign described by Nikolsky in 1896 is always sharply positive. A chronic course for many years with periods of spontaneous improvement is characteristic of pemphigus foliaceus. As it advances, dermatosis gradually occupies extensive areas of the skin, including the scalp (the hair often falls out), and often develops along the type of erythroderma (Fig. 22). The oral mucosa is very rarely involved in pemphigus foliaceus. The severity of disorders in the general condition is determined by the extent of the skin affections: when there are few foci the general condition is hardly disturbed, while in generalized lesions, including the erythrodermic type, it deteriorates (particularly in children) with a rise in body temperature (which is at first subfebrile and then febrile), disorders of water and salt metabolism, and advancement of anemia and eosinophilia. The patients gradually become weaker, lose weight and cachexia develops.

Pemphigus seborrhoicus, or erythematosus (Senear-Usher syndrome)

Pemphigus seborrhoicus belongs to the group of true pemphigus because the possibility of its development into the foliaceus or vulgaris variant has been authentically proved (Fig. 4). In most cases, however, the disease is benign, though of a long duration. The lesions usually first appear on the face and less frequently on the scalp, chest and back. Closely arranged greasy crusts are formed against an erythematous background and simulate the picture of cicatrizing erythematosis on the face. Moist eroded surfaces are exposed when the crusts are removed. Acantholytic cells are seen in impression smears from these surfaces. The bullae are often formed unnoticeably and the crusts seem to be primary lesions. In other cases vesicles covered with stratified yellowish crusts are formed on the trunk and limbs, in sites characteristic of seborrhea. Lesions rarely occur on the mucous membranes, but if this happens, they are a bad prognostic sign. In patients with pemphigus erythematosus, luminescence is seen both in the intercellular substance of the prickle-cell layer and in the basal membrane in the region of the dermoepidermal boundary.

Fig. 4. Senear-Usher Syndrome Histopathology. Acantholysis, disruption of the connections between the epidermal cells, is the fundamental histopathological change in all the forms of true pemphigus. Acantholysis creates grounds for the subsequent formation of bullae, which are always located between the cells of the prickle-cell layer. It is particularly sharply marked in pemphigus foliaceus and is revealed even on areas of seemingly healthy skin. Thus it becomes clear that in such patients Nikolsky's sign may be positive almost on any area of the skin. In other forms of pemphigus it is mainly positive in places where the bullae are formed, close to them and, less frequently, in places remote from the bullae. As a consequence of the destruction of the intercellular bridges in the lower parts of the Malpighian layer, first there develop fissures and then bullae whose cavity is penetrated by cells and groups of cells (neutrophils, eosinophiles and, to a smaller extent, lymphocytes and histiocytes). Some of the cells of the prickle-cell layer undergo degenerative changes; their nuclei are round, the cells themselves are swollen, hyperchromatic and are surrounded with a narrow, sharply outlined ring of homogeneous protoplasm. These cells are smaller than the normal cells of this layer and
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possess large darkly stained nuclei containing two or three large nucleoli. The cytoplasm has a light-blue zone around the nucleus while on the periphery it is stained an intensive blue colour. These are acantholytic Tzanck cells, which are of high diagnostic significance, particularly in differentiating the bullae in pemphigus from those in Duhring's disease. Pemphigus vegetans is also characterized by intraepidermal eosinophilic abscesses. The diagnosis of true pemphigus does not present much difficulty in classical cases. It is often easy to diagnose pemphigus vulgaris due to its frequent onset with involvement of the oral mucosa, monomorphic character of eruptions, positive Nikolsky's sign, relatively slow advancement of the disease, and the increasing deterioration of the general condition. The important tests for verifying the diagnosis are detection of acantholytic cells in impression smears or in Giemsa-stained smears (cytodiagnosis by Tzanck) and the demonstration of fluorescence in the region of the intercellular spaces of the prickle-cell layer in response to anti-IgG by means of immunofluorescence. All this allows pemphigus to be differentiated from abruptly developing bullous skin lesions (erythema exudativum multiforme, toxicoderma bullosa, Duhring's disease, congenital epidermolysis bullosa and the bullous form of lupus erythematosus). Treatment with steroid hormones envisages the prescription of maximum doses (40-60 mg of prednisolone or methylprednisolone, 32-48 mg of triamcinolone, 4-6 mg of dexamethasone daily). In children these doses are reduced according to age. For instance, for children whose ages range from 5 to 15 years the daily dose of prednisolone should not exceed 10-20 mg, that of triamcinolone should be no more than 8-12 mg, and the maximum dose of dexamethasone 2-3 mg. Children are sometimes prescribed ACTH in a daily dose of 10-20 U, to stimulate the adrenal cortex. When new eruptions cease to appear and exudative phenomena in the foci diminishes, the dose of corticosteroids may be reduced, but very slowly (to avoid exacerbation of the process and prevent the 'phenomenon of steroid drug discontinuation'). The task of the physician in management pemphigus consists in 'titrating' such a dose of the hormone which would be minimum for the given patient and would not give rise to a recurrence of the disease. These are called minimum maintenance doses and patients with pemphigus must continue to take them constantly after discharge from the clinic. In individual cases medication with corticosteroid hormones can be completely discontinued after minimum doses have been taken for several years. Sometimes, however, even large doses of steroids are insufficient to arrest the pemphigoid process. In such cases the doses of the drug are gradually increased until the desirable therapeutic result is obtained, although the number and severity of complications, which at times are even hazardous to the patient's life, increase sharply with the considerable increase of steroid doses. The prescription of large doses of corticosteroids, however, is necessary when there are vital indications. In order to reduce the dose of corticosteroid hormones and in this way to avoid the severe complications, which they may induce, the hormones have been recently successfully combined with the prescription of cytostatic drugs. The following cytostatics (immunosuppressants) are used: prospidium chloride, 100 mg infused intravenously every day, total treatment dosage 2000-2500 mg; methotrexate, 25 mg injected intramuscularly once in 5-7 days to a total of 4 or 5 injections or half a tablet is taken orally four times a day, i.e. 25 mg taken daily for 5 days followed by a 3-day
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interval (a total of 4 or 5 such courses are given). Azathioprinum (Imuran) is prescribed orally in a daily dose of 200 mg, taken for 3 to 4 weeks after which the daily dose is gradually reduced to 50 mg; treatment lasts 4 to 6 months. Senthol containing prednisolone with potassium, calcium, vitamins and methylandrostenediol may be prescribed. Patients with pemphigus must also be given anabolic hormones (methandrostenolone, syn. Metandienone, Nerobolil, methylandrostenediol, etc.), calcium and potassium preparations, agents stimulating phagocytosis (pentoxyl, methyluracil) and vitamins (ascorbic acid, rutin, ascorutin, riboflavin, calcium pantothenate, folic acid). Antibiotics are given (orally and in injections) if secondary infection develops. Symptomatic therapy is very important. Depending on the patient's condition it consists of blood transfusions (150-200 ml preferably by drip), infusions of native plasma (also 150-200 ml), injection of gamma-globulin, antianaemin (2-4 ml injected intramuscularly daily or every other day), administration of liver preparations (heparin, vitahepancreatine, hepavit tablets) and autohemotherapy. The diet of patients with pemphigus should contain a low amount of table salt and carbohydrates but must include high-calorie proteins, calcium and vitamins. Proper and thorough care of a patient is of paramount importance when the affection occupies extensive skin and mucosal areas. Secondary coccal infection is prevented by prescribing frequent warm baths with disinfectant solutions (e.g., potassium permanganate) followed by application of disinfectant agents (Castellani's paint, 1-2 per cent aqueous pyoktanin solution, syn. crystal violet, 5 per cent boric acidnaphthalan ointment, etc.). It is essential to wash the mouth thoroughly after every meal (a mouthwash with calendula or 1:5000 nitrofurazone solution). The affected skin areas may be smeared with corticosteroid ointments (Locacorten, Flucinar, Dermasolone, Oxycort, Hyoxisone, etc.) and irrigated with aerosols containing corticosteroid and antibacterial agents (Oxycyclosole, etc.). The physician and attendant personnel should constantly assure the patient of his imminent recovery, which actually takes place in most cases as a result of corticosteroid therapy.

Diagnosis and differential diagnosis

To make a diagnosis, the clinical signs (often starts on the mucous membrane of the mouth, monomorphic vesicles, positive Nikolskys symptom, progressive disease), laboratory findings (discovery of Tzanck acantholytic cells in the smear from the erosion, discovery of immunoglobulin G during immunofluorescence in the intercellular space of the stratum spinosum), examination of the blood and urine characterize the upset of water, salt and protein metabolism. Differential diagnosis is carried out with multiform exudative erythema, bullous toxicoderma (Lyells syndrome) and Duhrings dermatosis (Fig. 5).

Fig. 5. Dermatitis herpetiformis (Duhrings disease) Differential sign Primary elements Character of lesions Erosion Localization of the vesicle Character of the elements Localization of elements Infection of the mouth cavity Nicolskys symptom Itch Course Prognosis Acantholytic pemphigus Vesicles on the healthy skin Flaccid, thin cover soon opens Often extensive, without the tendency towards epithelization Intraepidermal Monomorphic Unsystematic In most patients the disease often starts in the mouth cavity Positive Rare Continuos course Serious, in severe cases may be lethal Dermatitis herpetiformis (Duhrings disease) Vesicles, bulla, macula, papule, pustule (polymorphism) The cover is dense, exists for 7-10 days Often less; soon heals Subepidermal Polymorphic Geometric, i.e. grouped Very rare; does not start in the mouth cavity. Negative Usually intense Relapsing More favourable, rare transformation into pemphigus Not discovered Causes intensification Frequent in blood (20-30%) Nearly always high in vesicle Marked in many cases

Tzanck acantholytic cells Discovered Reaction with iodine Absent Eosinophilia Not high in blood; rare in vesicles Therapeutic effect Absent

Practical part
1. Methods of examination of patients with vesicular dermatosis. a) History-taking. Complaints (intense pain in herpes zoster, itch in Duhrings dermatosis, etc.), time of the emergence of lesions and their development, treatment received and its effect. b) At the time of examination pay attention to the distribution of the dermatosis and its preferred localization, monomorphism or polymorphism of the lesions, character of vesicles. Check Nikolskys symptom. In the suspicion of Duhrings dermatosis test with iodine preparations (Ydasons test) is performed. c) Laboratory examination: in blood analysis pay attention to eosinophilia (Duhrings dermatosis). In suspicion of this disease smears from the exudate (vesicle fluid) are checked to reveal the increased quantity of eosinophiles. In suspicion of pemphigus smears from newly opened vesicle are checked for the presence of acantholytic cells. Additionally, immunofluorescence (presence of immunoglobulin G in the intracellular space of the stratum spinosum in pemphigus, presence of immunoglobulin A in the basal membrane in Duhrings dermatosis) can be carried out. 2. Differential diagnosis. The differential diagnosis is made for every patient taking into account the above mentioned signs (see theoretical part). The final diagnosis is made. 3. Treatment. General and external treatment of the patients is prescribed individually depending on the nosologic form of dermatosis, age of the patient, presence of accompanying diseases. The student should know the indications and contraindications of corticosteroids and other medicaments to be able to prescribe the drugs. Get acquainted with the methods of the treatment in the surgery.

Test questions.
1. Modern theories of etiopathogenesis of pemphigus. 2. List the basic primary and secondary lesions, their localization. Characterize the general progress of the disease, possible complications, and prognosis. 3. What is acantholysis? 4. The causes of the Nikolskys symptom, its diagnosis and the importance in vesicular dermatosis. 5. What do we call acantholytic cells? The method of preparation of the smears. 6. What are the clinical peculiarities of pemphigus vulgaris, vegetans, foliaceus and seborrheic? 7. What do the immunofluorescence and the shining of intracellular substance prove? 8. Why are cytostatics used in the treatment of pemphigus? 9. Why is the permanent treatment with corticosteroids given during pemphigus? 10.Why are drugs of potassium and anabolic hormones given with high doses of corticosteroids?
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11.List the possible complications of corticosteroid therapy. 12.Which etiopathologic theories of Duhrings dermatitis are known? 13.List the primary morphological lesions in this disease. 14.List the basic signs, which are of importance for diagnosis in Duhrings dermatitis. 15.Name the basic and most effective drugs in the treatment of patients with Duhrings dermatitis.

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