Lesson 4

1. BULLOUS DERMATOSIS

(PEMPHIGUS VULGARIS, HERPETIPHORMIC DURINGS DERMATITIS).

2. PRACTICAL SKILLS OF HISTORY TAKING OF DERMATOLOGY PATIENT.

3. ASSESSMENT – 1.

 

AUTOIMMUNE SKIN DISEASES

 

1. http://www.elaine-moore.com/Articles/AutoimmuneDiseases/BullousSkinDiseases/tabid/213/Default.aspx

2. http://www.ehow.com/video_5112638_autoimmune-skin-problems.html

 

Autoimmune skin conditions can be isolated problems just on the skin or it can be a symptom of a more all-encompassing autoimmune disease. When the immune system targets otherwise healthy tissue, when it is supposed to target diseases and unknown invaders, it is considered an autoimmune condition. They appear in several different varieties and are frequently misdiagnosed or left untreated because the initial impacts mimic more common skin diseases. As with any skin disease, it is critical to properly treat it because damaged skin can worsen the condition and lead to infections.

Autoimmune blistering conditions, or bullous skin diseases, are the most typical kind of autoimmune diseases that affect the skin. In these particular situations the proteins that hold an individual's skin cells together are attacked by the immune system. Lesions and blisters are the consequence. Although skin issues are commonly associated with lupus, only 5 percent of lupus patients suffer through bullous skin symptoms. Ladies between the ages of 20 and 40 are most in jeopardy for bullous disorders.

Fluid filled blisters on the body is a disorder known as bullous pemphigoid. Blisters usually occur on the arms, legs or torso and older adults are at the highest risk for the condition. This is a chronic condition meaning it persists for years, often with periods with no blisters followed by flair-ups when blisters appear. Medications to inhibit the immune system and therefore keeping it from leading to this skin disease are what most doctors will prescribe if the condition is serious enough. The side effects can be that your immune system becomes too weakened manage everyday threats like germs and bacteria. Corticosteroids are treatments that are also used which relieves inflammation.

Dermatitis herpetiformis is an autoimmune skin disease that targets those with gluten intolerance or celiac disease. People with celiac disease are unable to digest the gluten protein that is present in grains such as wheat, rye and barley. Itchy blisters and hives will form commonly on a person’s back or buttocks; this disorder is handled by removing all gluten containing products from a person's lifestyle. People with hypothyroidism, Sjogren’s disease or rheumatoid arthritis are also known to get this skin condition.

Lichen planus appears together with other autoimmune conditions. This skin condition can strike those with alopecia (hair loss), autoimmune hepatitis, lupus, scleroderma and any number of other conditions. This condition causes small erosive purple lesions. These lesions usually cluster together and often shows up on on the shins, heels or ankles or on the insides of the forearms and wrists. Oral lesions are diagnosed in about 75% of those with the disease.

Psoriasis is an autoimmune skin disorder indicated by the rapid increase in skin cell creation. This leaves what is referred to as “plaque” where patches of raised skin appear. The patches appear to be red skin with silvery white dead dry skin on top. These lesions tend to show up on the the scalp, elbows, lower back and knees. In the U.S., there are 4.5 million adults with psoriasis with the people of European ancestry being the ones most likely to be affected.

Autoimmune skin conditions can be treated with antibiotics, immune suppressants, anti-inflammitories and ointments. It is essential to get an accurate diagnosis with any skin disorder so be certain you tell your health practitioner everything about your health since your health history and other disorders that you may have will help with a correct diagnosis. In combination with taking the remedy a general practitioner prescribes for you, you will want to take extra good care of your skin. This calls for using mild soaps, hypoallergenic lotions and limiting UV ray exposure.



 

ORAL MANIFESTATIONS OF AUTOIMMUNE BLISTERING DISEASES

1. http://emedicine.medscape.com/article/1077969-clinical#a0217

 

Oral manifestations of autoimmune blistering diseases generally can affect any area of the oral cavity, including the gingiva, palate, buccal, tongue, floor of the mouth, and pharynx. Blisters are broken easily; therefore, they rarely are observed clinically. Instead, erosions and superficial ulcers more likely are observed. However, in pemphigoid, because the blisters are situated deeply, they are more likely to be observed intact clinically.

In pemphigus vulgaris, oral lesions occur in most patients. In most patients, the oral mucous membranes are affected within 6 months of disease onset. In some patients, it remains exclusively an oral disease for months or years before generalized skin disease develops. For pemphigus vulgaris, the oral lesions are usually first to surface and last to resolve in any given patient. Typically, small blisters rapidly evolve into erosions covered with white-yellow pseudomembranes. All areas of oral mucous membranes, gingiva, buccal, palate, tongue, and floor of the mouth can be affected (see the image below). A subgroup of patients with pemphigus vulgaris does not develop skin disease.

Oral manifestations, including blisters, hemorrhag

 

 

Oral manifestations, including blisters, hemorrhagic erosions, and crusts, are shown on a patient with pemphigus vulgaris.

Pemphigus foliaceus is predominantly a skin disease. Oral or other mucous membrane involvements are very rare. In skin, desmoglein-3 is present predominantly in the lower layers of epithelial cells. By contrast, the layers of desmoglein-3 are present throughout the upper and lower layers of epithelium in the oral mucous membrane. Thus, the autoantibodies of patients with pemphigus foliaceus, which exclusively target desmoglein-1, are unable to break down the adherence of the upper layers of epithelium of oral mucosa, which is protected by the presence of desmoglein-3.

In paraneoplastic pemphigus, oral lesions, which are invariably present in this disease, can precede, follow, or appear at the same time of neoplasm discovery. Severe mucositis with hemorrhagic blisters, erosion, or ulceration can be observed in various oral mucosae. Lesions at the vermilion border almost always are present, which often leads to misdiagnosis of paraneoplastic pemphigus as erythema multiforme. For paraneoplastic pemphigus, the intractable hemorrhagic stomatitis is extremely painful and could cause substantial morbidity for patients with this disease.

In patients with bullous pemphigoid, oral lesions rarely are observed. If present, they usually are mild and consist of small blisters or erosions. In one patient with bullous pemphigoid and hemophilia, extensive bullous lesions occurred in the mouth, along with substantial bleeding.

With linear IgA bullous dermatosis (of adult and children), the oral lesions, rarely present, are similar to that of bullous pemphigoid or can mimic aphthaelike ulcers.

Oral lesions in epidermolysis bullosa acquisita commonly are observed. The lesions are deep-seated blisters, erosions, and ulcers, sometimes hemorrhagic. Milia are clinically observed.

Regarding mucous membrane pemphigoid, the oral mucous membrane is the most frequently affected site in this heterogeneous group of diseases, followed by ocular, skin, nasal, genital, pharyngeal, esophageal, laryngeal, and anal mucous membranes.Over 90% of patients with mucous membrane pemphigoid have oral mucosal lesions, as shown in the image below.

Oral manifestations of mucous membrane pemphigoid

 

Oral manifestations of mucous membrane pemphigoid (also known as cicatricial pemphigoid). Inflammatory gingival changes are characteristic of the disease.

Causes

Autoimmune blistering diseases generally are caused by autoantibodies targeting the skin components of the epithelial cell surfaces or basement membrane zone. Certain human leukocyte antigen (HLA) alleles have been reported to be associated with autoimmune blistering diseases. For example, HLA-DQB1*0301 is associated strongly with bullous pemphigoid and mucous membrane pemphigoid.

1.Pemphigus group

Pemphigus is derived from the Greek word pemphix meaning bubble or blister. Pemphigus describes a group of chronic bullous diseases, originally named by Wichman in 1791. The term pemphigus once included most bullous eruptions of the skin, but diagnostic tests have improved, and bullous diseases have been reclassified.

The term pemphigus refers to a group of autoimmune blistering diseases of the skin and mucous membranes characterized histologically by intraepidermal blister and immunopathologically by the finding of in vivo bound and circulating immunoglobulin G (IgG) antibody directed against the cell surface of keratinocytes.

The 3 primary subsets of pemphigus include pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Each type of pemphigus has distinct clinical and immunopathologic features. Pemphigus vulgaris accounts for approximately 70% of pemphigus cases.

Pathophysiology

Pemphigus vulgaris is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes and is mediated by circulating autoantibodies directed against keratinocyte cell surfaces. In 1964, autoantibodies against keratinocyte surfaces were described in patients with pemphigus. Clinical and experimental observations indicate that the circulating autoantibodies are pathogenic. An immunogenetic predisposition is well established.

Blisters in pemphigus vulgaris are associated with the binding of IgG autoantibodies to keratinocyte cell surface molecules. These intercellular or pemphigus vulgaris antibodies bind to keratinocyte desmosomes and to desmosome-free areas of the keratinocyte cell membrane. The binding of autoantibodies results in a loss of cell-to-cell adhesion, a process termed acantholysis. The antibody alone is capable of causing blistering without complement or inflammatory cells.

 

 

 

 

 

 

Cell adhesion in desmosomes

 

Pemphigus vulgaris antigen

Intercellular adhesion in the epidermis involves several keratinocyte cell surface molecules. Pemphigus antibody binds to keratinocyte cell surface the molecules desmoglein 1 and desmoglein 3. The binding of antibody to desmoglein may have a direct effect on desmosomal adherens or may trigger a cellular process that results in acantholysis. Antibodies specific for nondesmosomal antigens also have been described in the sera of patients with pemphigus vulgaris; however, the role of these antigens in the pathogenesis of pemphigus vulgaris is not known.

Antibodies

Patients with the mucocutaneous form of pemphigus vulgaris have pathogenic antidesmoglein 1 and antidesmoglein 3 autoantibodies. Patients with the mucosal form of pemphigus vulgaris have only antidesmoglein 3 autoantibodies. Patients with active disease have circulating and tissue-bound autoantibodies of both the immunoglobulin G1 (IgG1) and immunoglobulin G4 (IgG4) subclasses.

More than 80% of the patients with active disease produce autoantibodies to the desmosomal protein desmoglein. Disease activity correlates with antibody titers in most patients.In patients with pemphigus vulgaris, the presence of antidesmoglein 1 autoantibodies, as determined by enzyme-linked immunosorbent assay (ELISA), is more closely correlated with the course of the disease compared with antidesmoglein 3 autoantibodies. Lack of in vivo antibody binding (reversion to a negative result on direct immunofluorescence) is the best indicator of remission and can help predict a lack of flaring when therapy is tapered.

Complement

Pemphigus antibody fixes components of complement to the surface of epidermal cells. Antibody binding may activate complement with the release of inflammatory mediators and recruitment of activated T cells. T cells are clearly required for the production of the autoantibodies, but their role in the pathogenesis of pemphigus vulgaris remains poorly understood. Interleukin 2 is the main activator of T lymphocytes, and increased soluble receptors have been detected in patients with active pemphigus vulgaris.

 

1. PEMPHIGUS VULGARIS

 

1. http://www.patient.co.uk/doctor/Bullous-Dermatoses-%28Blisters-and-Bullae%29.htm

2. http://www.youtube.com/watch?v=GMyN0BTSFN8

 

 

 

*    Autoimmune disease characterised by large flaccid blisters; primarily in older individuals .

*    Scalp, face, flexures, groin and pressure points.

*    Lesions characteristically involves the oral mucosa.

*    It is important that early blisters preferably smaller ones are selected for biopsy.

*    Greek pemphix-blister or bubble

*    Disruption of intercelular cementing substance

*    Most common 80%

*    Fourth to sixth decade

*    50-70% mucosal lesions

*    Bullae rupture spontaneously, no tendency to heal spontaneously

*    Nikolsky’s sign (Asboe-Hansen sign)

 

 

 

Drug-induced pemphigus vulgaris : Drugs reported most significantly in association with pemphigus vulgaris include penicillamine,captopril, cephalosporin, pyrazolones, nonsteroidal anti-inflammatory drugs (NSAIDs), and other thiol-containing compounds. Rifampin, emotional stress, thermal burns, ultraviolet rays, and infections (eg, coxsackievirus, Herpesviridae family) have also been reported as triggers for pemphigus vulgaris.

Mucous membranes typically are affected first in pemphigus vulgaris. Mucosal lesions may precede cutaneous lesions by weeks or months. Patients with mucosal lesions may present to dentists, oral surgeons, or gynecologists.

Mucous membranes

o                                            Intact bullae are rare in the mouth. More commonly, patients have ill-defined, irregularly shaped, gingival, buccal, or palatine erosions, which are painful and slow to heal. The erosions extend peripherally with shedding of the epithelium.

o                                            The mucous membranes most often affected in pemphigus vulgaris are those of the oral cavity, which is involved in almost all patients with pemphigus vulgaris and sometimes is the only area involved. Erosions may be seen on any part of the oral cavity. Erosions can be scattered and often are extensive. Erosions may spread to involve the larynx, with subsequent hoarseness. The patient often is unable to eat or drink adequately because the erosions are so uncomfortable.

o                                            In juvenile pemphigus vulgaris, stomatitis is the presenting complaint in more than 50% of the cases.

o                                            Other mucosal surfaces may be involved, including the conjunctiva, esophagus (causes odynophagia and/or dysphagia), labia, vagina, cervix, vulva,penis, urethra, nasal mucosa, and anus.

 

 

Skin

The primary lesion of pemphigus vulgaris is a flaccid blister filled with clear fluid that arises on healthy skin or on an erythematous base, as shown in the images below.

 

Early, small blister filled with clear fluid arise

Early, small blister filled with clear fluid arises on healthy skin.

Flaccid blister filled with clear fluid arises on healthy skin.

The blisters are fragile; therefore, intact blisters may be sparse. The contents soon become turbid, or the blisters rupture, producing painful erosions, which is the most common skin presentation and is shown in the image below. Erosions often are large because of their tendency to extend peripherally with the shedding of the epithelium. An erosion.

An erosion.

 

·                     Vegetating pemphigus vulgaris: Ordinary pemphigus vulgaris erosions may develop vegetation. Lesions in skin folds readily form vegetating granulations. In some patients, erosions tend to develop excessive granulation tissue and crusting, and these patients display more vegetating lesions. This type of lesion tends to occur more frequently in intertriginous areas and on the scalp or face. The vegetating type of response can be more resistant to therapy and can remain in one place for long periods.

·                     Nails: Acute or chronic paronychia, subungual hematomas, and nail dystrophies affecting one or several fingers or toes have been reported with pemphigus vulgaris. Patients with paronychial pemphigus usually also have oral involvement.

·                     Pemphigus in pregnancy: Pemphigus vulgaris occurring in pregnancy is rare. When present, maternal autoantibodies may cross the placenta, resulting in neonatal pemphigus. Neonatal pemphigus is transient and improves with clearance of maternal autoantibodies.Treatment of pemphigus vulgaris in pregnancy is with oral corticosteroids; however, prednisone and its metabolites cross the placenta and have been associated with low birth weight, prematurity, infection, and adrenal insufficiency.

·                     Nikolsky sign: In patients with active blistering, firm sliding pressure with a finger separates normal-appearing epidermis, producing an erosion. This sign is not specific for pemphigus vulgaris and is found in other active blistering diseases.

·                     Asboe-Hansen sign: Lateral pressure on the edge of a blister may spread the blister into clinically unaffected skin.

 

HISTOPATHOLOGY

 

*                Target antigen is desmoglein 3 which is 130 kD localised in spinous layer and in mucus membrane.Early blisters; smaller in size selected.

*                Earliest change – spongiosis in lower epidermis. Acantholysis is suprabasal ,may extend into the adenexa.

*                Basal keratinocytes though seperated from one another remain attached to the basement membrane ;”Row of tombstones appearance”.

 

IMMUNOFLOURESCENCE

 

DIF

 

*                Direct immunofluorescence shows immunoglobulin G (IgG) on the keratinocyte cell surface of the patient's skin

*                Direct detection of tissue-bound antikeratinocyte (desmoglein) antibodies on perilesional skin of the patient

*                Antihuman IgG and C3 binding detected at epidermal cell surfaces; no deposition along basement membrane

 

 

 

 

 

 

IIF

 

*                Indirect immunofluorescence shows IgG in patient's serum that binds the cell surface of normal keratinocytes.

*                Autoantigens are desmogleins (transmembrane desmosomal adhesion molecules)

 

 

 

 

Medical Care

The aim of treatment in pemphigus vulgaris is the same as in other autoimmune bullous diseases, which is to decrease blister formation, promote healing of blisters and erosions, and determine the minimal dose of medication necessary to control the disease process. Note the images below. Therapy must be tailored for each patient, taking into account preexisting and coexisting conditions. Patients may continue to experience mild disease activity while under optimal treatment.

 

Erosions and healing areas on the back.

 

Erosions and healing areas on the back. Healing areas on the chest and abdomen.

Healing areas on the chest and abdomen.

Corticosteroids have improved overall mortality, but now much of the mortality and morbidity in these patients relates to the adverse effects of therapy. Whether massive doses of steroids have any advantage over doses of 1 mg/kg/d is unclear.

Immunosuppressive drugs are steroid sparing and should be considered early in the course of the disease. Epidermal growth factor may speed healing of localized lesions.Many authorities now use rituximab as first- or second-line therapy.The antitumor necrosis factor drugs sulfasalazine and pentoxifylline have been reported as effective adjunctive treatments, reducing the serum level of tumor necrosis factor and resulting in rapid clinical improvement. Dapsone has been suggested as a steroid-sparing agent in the maintenance phase of pemphigus vulgaris treatment ; dapsone has also been suggested as a first-line agent.

Intravenous immunoglobulin therapy has been suggested as efficacious in pemphigus vulgaris treatment. Amagai et al reported on the successful use of intravenous immunoglobulin in pemphigus patients who did not fully respond to systemic steroids, and Asarch et al reported its use in pediatric patients.[45]

Photodynamic therapy has been suggested as a possible adjunctive treatment for recalcitrant ulceration.

Medication Summary

The aim of treatment is to reduce the inflammatory response and autoantibody production. While target-specific therapy is not available, non–target-specific treatments currently are used. The most commonly used medications are corticosteroids.

The introduction of corticosteroids has reduced mortality greatly, but significant morbidity remains. Immunosuppressants should be considered early in the course of disease, as steroid-sparing agents. Mycophenolate mofetil and azathioprine are the usual agents considered as initial choices.Only one placebo-controlled blinded study of mycophenolate has demonstrated more rapid improvement in the short run but no significant steroid-sparing effects in the long term. A retrospective chart review has suggested a therapeutic ladder for patients with pemphigus vulgaris, but these authors' approach has not been validated. Rituximab and intravenous immunoglobulin have also proven useful alone or in combination and some authorities are now using rituximab as first-line therapy for severe disease.

A small case control trial showed improved laboratory and clinical outcomes in patients with pemphigus vulgaris treated with a combination of cytotoxic agents plus intravenous immunoglobulin (IVIG)compared with those treated with just IVIG.

Cyclophosphamide is used for refractory disease. The role of biologic agents is being investigated. Each of these agents should be prescribed and monitored by physicians familiar with them. Wound care for erosions includes daily gentle cleaning, application of topical agents to promote wound healing, and use of nonadhesive dressings. The goal of wound care is to promote healing, minimize trauma to the surrounding skin, and diminish scarring.

Anti-inflammatory agents

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

 

Immunosuppressive agents

Azathioprine (Imuran)

 

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. In conjunction with prednisone, more effective than prednisone alone. May be an effective monotherapy in mild cases, although therapeutic effect is delayed 3-5 wk.

Consider withdrawal if no improvement within 3 mo.

Complications

*                   Secondary infection, which may be either systemic or localized to the skin, may occur because of the use of immunosuppressants and the presence of multiple erosions. Cutaneous infection delays wound healing and increases the risk of scarring.

*                   Long-term immunosuppressant therapy may result in infections and secondary malignancies (eg, Kaposi sarcoma), owing to impaired immune surveillance.

*                   Growth retardation has been reported in children taking systemic corticosteroids and immunosuppressants.

*                   Bone marrow suppression has been reported in patients receiving immunosuppressants. An increased incidence of leukemia and lymphoma is reported in patients receiving prolonged immunosuppression.

*                   Impaired immune responsiveness caused by corticosteroids and other immunosuppressive drugs may result in the rapid spread of infection. Corticosteroids suppress clinical signs of infection and may allow diseases such as septicemia or tuberculosis to reach an advanced stage before diagnosis.

*                   Osteoporosis may occur following the use of systemic corticosteroids.

*                   Adrenal insufficiency has been reported following prolonged use of glucocorticoids.

 

2. PEMPHIGUS VEGETANS

 

1. http://www.fpnotebook.com/DER/Blister/PmphgsVgtns.htm

2. http://www.youtube.com/watch?v=kqT-Q20-Dok

 

 

n     Rare variant of pemphigus vulgaris.

n     Vegetating lesions in flexures.

n     Initially bullae or pustule

n     Two types – Neumann and Hallopeau.

n     Antibodies against Pemphigus vulgaris antigens – 130 KDa.

 

Symptom

 

n     Painful blisters in the mouth appear first, and may lead to weight loss

n     Blisters occur on the skin and mucosal areas, especially where trauma and pressure applied

n     Large areas of affected skin seep and crustation

n     Fever and malaise

n     Pruritus normally absent

n     Skin or mucosae can just shear off leaving widespread painful erosions

n     Nikolsky's sign - epidermis is easily detached from underlying skin

 

 

 

 

 

 

 

HISTOPATHOLOGY

 

n     Vegetating lesions are acanthotic, hyperkeratotic and papillomatous.

n     Suprabasal clefts contain acantholytic cells and eosinophils. Intraepidermal eosinophilic abscesses seen in older lesions.

n     Hallopeau lesions – pustules on normal skin with acantholysis and small suprabasal clefts.

n     Dermis – heavy infiltrate of lymphocytes and eosinophils with few neutrophils.

 

 

 

 

 

Tzanck test

 

n     Acantholytic cells

n     Cause of abnormal result

n     Pemphigus vulgaris

n     Other bullous skin diseases

 

Skin biopsy

 

n     Intraepidermal separation of keratinocytes, forming a split between lower and upper portions of epidermis

n     Acantholysis - separation of individual epidermal cells from surrounding cells

n     Mild or absent inflammatory infiltrate

 

Nikolsky’s sign:

 

*                A positive Nikolsky's sign signifies a separation of epithelial cells either from one another or from the basement membrane, which is a layer of connective tissue to which epithelium usually adhered.

*                 In these diseases, there are defects in the cell-to-cell attachement mechanisms, and even minute amounts of trauma can elicit a clinical response of a blister formation when the cells are manually detached with the forceful turn of the pencil eraser on the skin. In the case of pemphigus, the pencil twist easily rips the spinous cells apart because they possess defective desmosomes, and in the case of pemphigoid, the hemidesmosomes are defective. Within minutes, a blister will form, and this is pathognomonic, or absolutely indicative, of a vesicular/bullous disease

 

 

3. PEMPHIGUS FOLIACEOUS

 

1. http://emedicine.medscape.com/article/1064019-overview

2. http://www.youtube.com/watch?v=KZWWVVm60w4

 

Background

Pemphigus foliaceus (PF) is generally a benign variety of pemphigus. It is an autoimmune skin disorder characterized by the loss of intercellular adhesion of keratinocytes in the upper parts of the epidermis (acantholysis), resulting in the formation of superficial blisters. It is typified by clinical involvement of healthy-appearing skin that blisters when rubbed (the Nikolsky sign; commonly but incorrectly spelled Nicholsky), a finding named after Dr Piotr Nikolsky, who first described this sign in 1896.[1] Pemphigus foliaceus is characterized by a chronic course, with little or no involvement of the mucous membranes.

Pierre Louis Alphee Cazenave, founder of the first journal dedicated entirely to dermatology, documented the first description of pemphigus foliaceus in 1844 in this journal. The description was of a 47-year-old woman who consulted him at l'Hopital Saint Louis in Paris for a generalized eruption of several years' duration. Nikolsky described lateral extension of the preexisting erosion due to lifting up the collarette (and when applying a lateral pressure to the clinically intact skin), whereas Asboe-Hansen described extension of the intact blister due to pressure that is applied to its roof.

Pemphigus foliaceus has the following 6 subtypes: pemphigus erythematosus (PE), pemphigus herpetiformis (PH), endemic pemphigus foliaceus, endemic pemphigus foliaceus with antigenic reactivity characteristic of paraneoplastic pemphigus (but with no neoplasm), immunoglobulin A (IgA) pemphigus foliaceus, and drug-induced pemphigus foliaceus. See Pemphigus Erythematosus; Pemphigus Herpetiformis; Pemphigus, Paraneoplastic; and Pemphigus, IgA for more information.

Senear and Usher originally described PE in 1926 as an unusual type of pemphigus with features of lupus erythematosus. PE (also known as Senear-Usher syndrome) is best viewed as a localized form of pemphigus foliaceus. Chorzelski et al determined its immunopathology in 1968.

Another pemphigus foliaceus variant with pruritic, flaccid vesicles in an annular pattern has been characterized as IgA pemphigus foliaceus, with antibodies of IgA class providing the basis for diagnosis.

Jablonska and associates coined the term pemphigus herpetiformis for the pemphigus foliaceus variant that often begins as small clusters of pruritic papules and vesicles mimicking dermatitis herpetiformis.

Endemic pemphigus foliaceus, or fogo selvagem (formerly known as Brazilian pemphigus foliaceus because it is evident mainly in the river valleys of rural Brazil), has also been described in Columbia, El Salvador, Paraguay, Peru, and recently in Tunisia. Fogo selvagem (Portuguese for wild fire) displays immunopathologic findings of pemphigus and a distinctive epidemiology suggestive of a disorder triggered by an infectious insect-borne agent (see Fogo Selvagem). A focus of endemic pemphigus foliaceus also exists in El Bagre, Columbia and shares features with Senear-Usher syndrome but occurs in an endemic fashion. Heterogeneous antigenic reactivity was observed as in paraneoplastic pemphigus but with no evidence of association with neoplasia. This endemic pemphigus disease in El Bagre had immunologic features similar to pemphigus foliaceus or erythematosus.

Chorzelski et al in 1999 described paraneoplastic pemphigus with cutaneous and serologic features of pemphigus foliaceus in a patient with an underlying lymphoma. The authors are not aware of any similar patients with these highly unusual findings.

Drug-induced pemphigus foliaceus is mostly associated with penicillamine, nifedipine, or captopril, medications with a cysteinelike chemical structure.

A transition from pemphigus vulgaris (PV) to pemphigus foliaceus, or vice versa, is not likely. However, in the experience at the Medical University of Warsaw, PV in the remission period may resemble pemphigus foliaceus. About 7% of patients with pemphigus foliaceus may have the initial features of PH. This figure was 35% in patients with endemic pemphigus foliaceus in Tunisia (see Pemphigus Vulgaris). The pivotal contributions of Jean-Claude Bystryn have been summarized.

Pathophysiology

Superficial blisters in pemphigus foliaceus are induced by immunoglobulin G (IgG) (mainly IgG4 subclass) autoantibodies directed against a cell adhesion molecule, desmoglein 1 (160 kd), expressed mainly in the granular layer of the epidermis. Desmoglein 1 is also a major autoantigen in cases of PH, suggesting that most cases of both PE and PH are clinical variants of pemphigus foliaceus. The mechanism of acantholysis induction by specific autoantibodies may involve phosphorylation of intracellular proteins associated with desmosomes. Complement activation does not play a pathogenic role in pemphigus foliaceus.

Antibodies against desmoglein 3 are also present in patients with paraneoplastic pemphigus (PNP), a severe condition associated with various antibodies against different components of the cell adhesion complex. Other target antigens, including the acetylcholine receptor, have also been postulated to be relevant in the pathogenesis of pemphigus foliaceus.

Cholinergic control of epidermal cohesion may be important.The regulation of keratinocyte cell-to-cell and cell-matrix adhesion is an important biological function of cutaneous acetylcholine. Recent progress in therapy of pemphigus using cholinergic drugs supports this concept.

Precipitating factors include medications and ultraviolet light radiation. It was recently suggested that both enhanced autoantibody epidermal binding and preferential neutrophil adhesion to UV-irradiated epidermis contribute to acantholysis development in photo-induced pemphigus foliaceus.

Endemic pemphigus foliaceus seems to have an environmental cause. The prevalence of antibodies against desmoglein 1 is high in people residing in endemic areas of Brazil, with disease onset preceded by a sustained antibody response due to an as yet unknown environmental factor.

The role of genetic factors is evident in fogo selvagem in which a strong association exists with some human leukocyte antigen DRB1 (HLA-DRB1) haplotypes, including DRB1*0404, 1402, 1406, and 1401. In France, persons with DRB1*0102 and 0404 are at an increased risk of pemphigus foliaceus.

Pemphigus trigger factors have been meticulously analyzed by Ruocco and Ruocco, who have delineated an exhaustive list and stressed the need to detect environmental provoking or precipitating factors. As a superb memory device to facilitate thorough patient evaluation, Ruoccohas cleverly observed that PEMPHIGUS should encourage the physician to consider pesticides (PE), malignancy (M), pharmaceuticals (P), hormones (H), infectious agents (I), gastronomy (G), ultraviolet light (U), and stress (S).

Rarely, a change in pemphigus subtype may occur, accompanied by qualitative and quantitative changes in the anti-Dsg autoantibody profile as detected using antigen-specific enzyme-linked immunosorbent assays (ELISAs). Thus, the antibody profile defines the clinical phenotypes of pemphigus, and that intermolecular "epitope spreading" may be the immunological mechanism underlying a shift between pemphigus foliaceus and PV.

It has been suggested that polymorphisms in the 2q33 and 3q21 chromosomal regions influence susceptibility to pemphigus foliaceus.

Scientific evidence links interactions between thymoma function, thymoma, and pemphigus, often associating loss of self-tolerance and the presence of autoimmunity. The association of pemphigus foliaceus and thymoma is noteworthy.

Clinical Presentation

 

The bullae usually start on the trunk. The course of the disease is long-term, with the patient's general health being satisfactory. Spontaneous remission sometimes occurs, but the lesions can persist for several years. A unique clinical pattern may occur in children, with individual lesions appearing as arcuate, circinate, or polycyclic.Eyelid skin involvement without conjunctival changes occurs occasionally in patients with pemphigus foliaceus.

 

Physical

The primary lesions are small, superficial blisters; however, these flaccid bullae are difficult to find because they are transient and transform into erosions. Typical pemphigus foliaceus has scaly, crusted erosions on an erythematosus base confined mainly to so-called seborrhoic areas (eg, face, scalp, upper part of the trunk).

The Nikolsky sign is the finding that physical trauma can shear the pathologic epidermis of the skin of patients with pemphigus foliaceus, resulting in clinical lesions. The Nikolsky sign should probably be regarded as a moderately sensitive but highly specific tool for the diagnosis of pemphigus.

The erosions can become numerous, showing a tendency to generalize. Occasionally, erythrodermia develops. Thus, pemphigus foliaceus may be evident as a an erythroderma or a psoriasiform erythroderma.Atrophic changes of the nails and the hair are sometimes evident. The erosions may be accompanied by a burning sensation and local pain. In contrast to PV, in pemphigus foliaceus, little or no involvement of the mucous membranes occurs. Note the images below.

 

Middle-aged American woman of Mexican lineage with

 

Middle-aged American woman of Mexican lineage with superficial bullae characteristic of pemphigus foliaceus.

 

 

Pemphigus foliaceus. Middle-aged American woman of

 

Pemphigus foliaceus. Middle-aged American woman of Mexican lineage with superficial bullae formation.

 

A 41-year-old woman of Puerto Rican origin with a

 

A 41-year-old woman of Puerto Rican origin with a 9-year history of pemphigus foliaceus, often with erythroderma flares. A 41-year-old woman of Puerto Rican origin with a 9-year history of pemphigus foliaceus, often with erythroderma flares.

 

A 41-year-old woman of Puerto Rican origin with a

IgA pemphigus foliaceus begins as pruritic, flaccid vesicles in an annular pattern.

PH commences as intensely pruritic, grouped papules and vesicles suggestive of dermatitis herpetiformis. Erythematous patches with peripheral vesicles may be present. Sometimes, oral erosions are seen.

PE starts as erythematous patches with border vesiculation, often in a butterfly distribution on the cheeks and the forehead, with similar patches on the sternal and interscapular skin. Crusted plaques may appear in the healing phase.

PNP is a subset of pemphigus combining the clinical features of PV variably associated with those of erythema multiforme, bullous pemphigoid, and lichen planus. Chorzelski and associates in 1999 described a most unusual case of PNP with the immunopathologic findings of pemphigus foliaceus. The clinical pattern appears to be correlated with that of the antibody profile; therefore, patients with antibodies directed against desmoglein 1 tend to have the clinical features of pemphigus foliaceus.

Differential Diagnoses

*       Contact Dermatitis, Allergic

*       Contact Dermatitis, Irritant

*       Drug-Induced Bullous Disorders

*       Drug-Induced Photosensitivity

*       Epidermolysis Bullosa

*       Epidermolysis Bullosa Acquisita

*       Erysipelas

*       Erythema Multiforme

*       Erythroderma (Generalized Exfoliative Dermatitis)

*       Fogo Selvagem

*       Glucagonoma Syndrome

*       Herpes Simplex

*       Impetigo

*       Insect Bites

*       Linear IgA Dermatosis

*       Lupus Erythematosus, Bullous

*       Lupus Erythematosus, Drug-Induced

*       Lupus Erythematosus, Subacute Cutaneous

*       Papular Urticaria

*       Pemphigus Erythematosus

*       Pemphigus Herpetiformis

*       Pemphigus Vulgaris

*       Pemphigus, Drug-Induced

*       Pemphigus, IgA

*       Pemphigus, Paraneoplastic

*       Pseudoporphyria

*       Subcorneal Pustular Dermatosis

Laboratory Studies

Immunofluorescence using both direct techniques and indirect techniques is the most reliable method to diagnosis pemphigus.Because of the rare occurrence of pemphiguslike antibodies, pemphigus cannot be diagnosed by indirect immunofluorescence (IIF) alone and must be confirmed by direct immunofluorescence (DIF). With the use of 2 appropriate substrates (ie, monkey esophagus [or human skin] and guinea pig esophagus and standardized conjugates), in IIF, PV and pemphigus foliaceus patterns are different; PV stains throughout the epidermis, and pemphigus foliaceus stains only in the upper epidermis, whereas, with DIF, the patterns are similar. With a DIF study, cell surface immune deposits are often present throughout the entire epidermis in both pemphigus foliaceus and PV. Using DIF on telogen hair outer root sheath may be beneficial for diagnosis and follow-up, irrespective of the presence of scalp lesions.

8uImmunologic examination with DIF testing shows IgG in the intercellular space, mainly in the upper parts of the epidermis; an IIF study documents the presence of circulating pemphigus antibodies, especially with a guinea pig esophagus used as a substrate. One IIF study suggested that using both a monkey esophagus and the human skin increases the sensitivity and aids in distinguishing pemphigus foliaceus from PV. In PH, IgG deposits are evident in the upper epidermis, with circulating IgG to the epidermal cell surface. The subcorneal pustular dermatosis type of IgA pemphigus foliaceus has IgA deposition on the upper epidermal cell surfaces and circulating IgA antibodies to the epidermal cell surfaces. Desmogleins 1 and 3 are the major cell surface target molecules in patients with PH. In the unusual instance when PV becomes pemphigus foliaceus, or vice versa, the clinical alteration is associated with a shift in the antidesmoglein autoantibody profile.

Other methods, such as ELISA and immunoblot assays, can be used, but they require highly purified antigens to give similar results. The sensitivity for PV and pemphigus foliaceus antibodies is more than 98% in at least the renowned laboratory of Jarzabek-Chorzelska and associates,with their many decades of experience. Histologic examination is useful, but it is not the preferred method for diagnosing pemphigus foliaceus because it cannot replace a highly reliable DIF method.

Another less experienced laboratory found ELISA to be superior to an IIF study for serodiagnosis of pemphigus foliaceus at various stages of disease activity.

Pemphigus foliaceus arising during the administration of D-penicillamine was described in an elderly patient in whom withdrawal of D-penicillamine resulted in improvement of the skin lesions and ELISA scores for anti–desmoglein 1 antibodies revealed a rapid decline.

Histologic Findings

Pemphigus foliaceus begins as acantholysis of the upper epidermis, often resulting in a subcorneal cleft. It usually enlarges and detaches without bullae formation, though a bulla may form showing acantholysis at both the roof and the floor. More established lesions may have acanthosis and mild-to-moderate papillomatosis. Hyperkeratosis and parakeratosis may also be evident, with dyskeratotic cells within the granular layer. These features may be particularly pronounced in long-standing PE. A mild dermal lymphocytic infiltrate occurs, often with the presence of eosinophils. Eosinophilic spongiosis may also be noted, especially in PH.

Histologic view shows the typical pattern of a det

 

 

Histologic view shows the typical pattern of a detached stratum corneum without bullae formation. Pigmentary incontinence is prominent in the dermis, reflecting the patient's 9-year history of recurrent superficial bullae.

Medical Care

Present information is probably inadequate to ascertain the optimal therapy for pemphigus foliaceus (PF), including the optimal glucocorticoid dose, the role of adjuvant immunosuppressive medications, and long-term adverse events to improve the risk-to-benefit ratio.Therapy for pemphigus foliaceus is usually less aggressive than that of PV because of lower morbidity and mortality rates.

First results indicate that nonsteroidal treatment of pemphigus is possible. Mestinon may be used to slow down progression of the disease and to treat mild cases with chronic lesions on limited areas. Antimalarial therapy may be effective monotherapy in some patients. However, a major obstacle in comparing therapeutic outcomes is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus.Common terms and endpoints of pemphigus are needed to accurately measure and assess disease extent, activity, severity, and therapeutic response.

Topical glucocorticosteroids may be sufficient in cases of limited involvement.

In more extensive cases (similar to PV), adjuvant immunosuppressants, including systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclophosphamide, and cyclosporin A, may be necessary.

In some cases, such as PE, combined therapy is beneficial with the use of corticosteroids and sulfones or antimalarial agents.

Topical treatment with antibiotics and corticosteroids, such as topical clobetasol cream or ointment 0.05% twice a day, is helpful. Other vehicles that may be useful are creams, foams, liquids (for scalp lesions), and aerosols. Antibiotics, such as minocycline 50 mg daily, may be effective. Nicotinamide 1.5 g/d and tetracycline 2 g/d have also been reported to be beneficial in a small number of patients. Antibiotics and nicotinamide are purported to have anti-inflammatory effects.

Photoprotection is appropriate for some patients because UV-B may trigger acantholysis and cause a flare-up of the disease.

Successful anti-CD20 antibody treatment has also been described.

Plasmapheresis is another therapeutic option in patients with recalcitrant disease. It may decrease autoantibody titers in some patients and favorably influence the clinical outcome, especially in patients with otherwise therapy-resistant pemphigus foliaceus. It is often used in conjunction with cytostatic agents, such as cyclophosphamide or azathioprine, to reduce a predictable rebound increase in autoantibody synthesis. Potential complications, including the need for maintaining venous access, a bleeding tendency, electrolyte shifts, pulmonary edema, fever, chills, hypotension, and septicemia, should be considered.

Amagai et al reported that a single cycle of intravenous immunoglobulin at 400 mg/kg/d for 5 days is effective and safe for patients with pemphigus that is relatively resistant to systemic steroid therapy.Toth and Jonkman also reported on successful therapy with intravenous immunoglobulin (low dose).

Corticosteroid agents

Prednisone (Deltasone, Orasone)

 

1. Antibiotic agents

*    Minocycline (Dynacin, Minocin)

*       Dapsone (Avlosulfon)

 

2. Antimalarial agents

Hydroxychloroquine (Plaquenil)

 

3. Immunomodulatory agents

 

*    Azathioprine (Imuran)

*     Cyclophosphamide (Cytoxan, Neosar)

 

Complications

Monitor pemphigus foliaceus (PF) patients for other autoimmune disorders, particularly thymoma and myasthenia gravis.

New cutaneous pain or new constitutional symptoms, change in primary morphology, rapid disease progression, or failure to respond to appropriate therapies may suggest a concurrent cutaneous viral infection such as by herpes simplex or cytomegalovirus.

 

PEMPHIGUS  ERYTHEMATOSUS

http://emedicine.medscape.com/article/1063881-overview

 

 

Background

The various types of pemphigus include pemphigus erythematosus, pemphigoid, pemphigus vegetans, pemphigus vulgaris, and pemphigus foliaceus.

Pemphigus erythematosus, also known as Senear-Usher syndrome, is an overlap syndrome with features of lupus erythematosus (LE) and pemphigus foliaceus. Pemphigus is demonstrated by acantholysis and immunoglobulin deposits in the interkeratinocyte substance (see the image below).

Direct immunofluorescence microscopy performed on

 

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

The lupus component of pemphigus erythematosus is demonstrated by circulating antinuclear antibodies (ANA) and sometimes by immunoglobulin and complement deposits at the dermoepidermal junction

Pathophysiology

Patients with pemphigus erythematosus present with vesiculobullae or superficially eroded lesions, which may ooze and crust, particularly in sun-exposed areas, such as the face, the upper part of the chest, and the back.

Clinical Presentation

History

Onset and progression of pemphigus erythematosus are typically slow. Although the distribution of the pemphigus erythematosus lesions should suggest induction by sunlight, the patient may be completely unaware of the photosensitive nature of the disorder.

Physical

Pemphigus erythematosus lesions typically involve the scalp, the face, the upper part of the chest, and the back. Patients with classic pemphigus erythematosus present with small, flaccid bullae with scaling and crusting. Occasionally, the appearance may suggest a papulosquamous disorder. On the face, pemphigus erythematosus presents on the bridge of the nose and on the malar areas as in the butterfly distribution seen in LE.

 

Secondary infection may occur, resulting in impetiginization, in healing with pigment changes, and in scarring.

With extensive involvement, pemphigus erythematosus patients may present with an exfoliative erythroderma. The skin may be tender. Patients with pemphigus erythematosus do not typically develop mucous membrane involvement. Electrolyte imbalance and loss of temperature control can occur with extensive skin involvement.

Causes

Patients with pemphigus develop an autoimmune response directed against desmosomes. In patients with pemphigus foliaceus and its variant, pemphigus erythematosus, the target antigen is desmoglein 1. Desmogleins are desmosomal proteins important in keratinocyte adhesion. The binding of autoantibodies is postulated to result in a cascade of biochemical intracellular events that eventuates in the loss of desmosome function. Additionally, certain HLA haplotypes (A10 or A26, DRW6) are thought to be associated, suggesting a genetic predisposition.

Differential Diagnoses

*       Atopic Dermatitis

*       Lupus Erythematosus, Acute

*       Lupus Erythematosus, Discoid

*       Lupus Erythematosus, Subacute Cutaneous

*       Pemphigus Foliaceus

*       Pemphigus, Paraneoplastic

*       Seborrheic Dermatitis

Laboratory Studies

With direct immunofluorescence (see the image below) in pemphigus erythematosus, linear deposits of immunoglobulin G (IgG) and C3 are present in the intercellular space of the epidermis. Granular deposits of C3 and IgG at the dermoepidermal junction are present in 80% of patients, particularly in biopsy specimens from the face or other sun-exposed areas.[4]

Direct immunofluorescence microscopy performed on

 

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

With immunoelectron microscopy in pemphigus erythematosus, IgG and C3 deposits are localized to the epidermal cell membranes and the upper dermis.

Patients with pemphigus erythematosus may have other laboratory abnormalities suggestive of systemic lupus erythematosus (SLE); these include anemia, lymphopenia, thrombocytopenia, renal abnormalities, proteinuria, or a positive rheumatoid factor.

Histologic Findings

Intraepidermal superficial bullae are usually within the granular layer or just below it. Acantholysis may occur in the blister floor or roof. Old lesions may have follicular hyperkeratosis with acantholysis and dyskeratosis of the granular layer. See the images below.

Biopsy shows moderate epithelial hyperplasia with

 

Biopsy shows moderate epithelial hyperplasia with a suprabasal cleft that shows suprabasal acantholysis. The rest of the epithelium shows spongiosis with neutrophils. The submucosa has a moderately dense mixed perivascular infiltrate of lymphocytes and neutrophils. At places, the epithelium is missing, and the surface is covered by fibrin and necrotic inflammatory cells. Photo courtesy of Dr. Uday Khopkar.

 

Biopsy shows upper epidermal acantholytic blisteri

 

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer. The blister contains plasma, RBCs, and few acute inflammatory cells. The epidermis at the periphery of the blister shows mild spongiosis with neutrophils. In the roof of the blister, a few elongated acantholytic cells can be seen. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

 

Biopsy shows upper epidermal acantholytic blisteri

 

Biopsy shows upper epidermal acantholytic blistering dermatitis involving the granular and upper spinous layer with absence of roof of blister. The epidermis shows mild spongiosis with neutrophils. Underlying dermis shows superficial and mid perivascular mixed infiltrate of neutrophils and lymphocytes. Photo courtesy of Dr. Uday Khopkar.

 

Biopsy shows sparse superficial and deep perivascu

 

Biopsy shows sparse superficial and deep perivascular infiltrate of lymphocytes. The papillary dermis is edematous and there is extravasation of RBCs. Basal layer shows vacuolization and interface infiltration by lymphocytes. Reticular dermis shows small amount of mucin. Photo courtesy of Dr. Uday Khopkar.

Medical Care

Topical therapy

Topical corticosteroids are useful for pemphigus erythematosus patients with limited disease or as an adjunct to systemic therapy. Selection of the appropriate topical steroid strength and vehicle depends on the body site, the age of the patient, and the potential for steroid adverse effects. Use of daily sunscreen and sun protection is necessary. Griffies et al reported promising results in treating discoid lupus and pemphigus erythematosus in dogs with topical application of 0.1% tacrolimus, an immunomodulator produced by a fungus. Remission with tacrolimus occurred alone in some dogs, whereas steroid use was decreased or discontinued in other dogs.

Systemic therapy

Systemic steroids have been the mainstay of therapy for widespread pemphigus since their first use in 1950. Prednisone at 1-2 mg/kg/d as a single morning dose or as intravenous pulses may control the disease. Appropriate monitoring is critical.

Dapsone is effective in some patients with pemphigus erythematosus.Patients tend to respond relatively quickly, with improvement within several weeks. It can be a steroid-sparing drug. The possible mode of action is stabilization of lysosomal membranes and inhibition of polymorphonuclear leukocyte (PMN) toxicity. The recommended dose is 100-200 mg/d. Hemolytic jaundice may result in people with G-6-PD deficiency. Other adverse effects include agranulocytosis, leading to death, headaches, malaise, hepatitis, hypersensitivity reactions, and neuropathy. Caution is required.

Azathioprine is a potent immunosuppressive agent that has been used as a steroid-sparing agent. The usual doses are 0.5 -2.5 mg/kg/d, based on results of thiopurine methyltransferase activity. Those who are deficient are at an increased risk of bone marrow toxicity with this agent, as are patients who are taking allopurinol.

Other useful drugs in pemphigus erythematosus treatment are as follows:

*       Tetracycline and niacinamide

*       Cyclophosphamide

*       Methotrexate

*       Parenteral gold

*       Hydroxychloroquine

*       Plasmapheresis

*       Mycophenolate mofetil

*       Extracorporeal photochemotherapy

*       Rituximab

*       Dexamethasone-cyclophosphamide combination

 

Dexamethasone-cyclophosphamide combination therapy has recently been studied. In 2009, Kandan and Thappa reported good outcomes in 65 cases of pemphigus treated with dexamethasone-cyclophosphamide pulse therapy.

Pasricha and Poonam reported the effects of a few modifications in the regimen in 123 patients treated with the dexamethasone-cyclophosphamide pulse/dexamethasone pulse (DCP/DP) regimen over a period of 5 years (1998-2002). The 3 modifications introduced into the regimen were: (1) an additional daily dose of oral betamethasone sufficient to control the disease activity during phase I, which was progressively tapered completely as the patient recovered; (2) use of systemic antibiotics, if the patient had skin lesions, and oral anticandidal drugs, if the patient had oral ulcers, until complete healing; and (3) insistence on thorough cleaning of the skin and scalp, with a normal soap and shampoo, and proper maintenance of oral hygiene in spite of skin/mucosal lesions. The regimen consisted of DCP/DP repeated in exactly 28-day cycles, along with cyclophosphamide at 50 mg/d, insistence on completing treatment, and avoidance of irregular pulses in all patients.

Cyclophosphamide is contraindicated in patients who wish to have children.

Medication Summary

The goal of pharmacotherapy in pemphigus erythematosus is to reduce morbidity and to prevent complications.

Plasmapheresis and immunoadsorption have been shown to be effective in the treatment of pemphigus erythematosus. Plasmapheresis and, more recently, immunoadsorption, are extracorporeal treatments that act rapidly on disease activity by lowering the load of the causative autoantibodies in the patient's circulation, causing a rebound of the plasma cell clone. During rebound, the plasma cells are more sensitive to chemotherapy.

In immunoadsorption, the immunoglobulins are selectively removed from the patient's plasma by adsorbing the antibodies to the matrix in a column of the immunoadsorption apparatus, after which the "cleansed" plasma is returned to the patient. Reportedly, immunoadsorption has higher efficacy and fewer adverse effects compared with plasmapheresis. In one German study, immunoadsorption was effective and safe in treating resistant and severe pemphigus. However, more studies are needed to support these data.

Corticosteroids

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

 

Antineoplastic agents

Cyclophosphamide (Cytoxan, Neosar)

 

Sulfone antibiotics

*                Dapsone (Avlosulfon)

*                 Azathioprine (Imuran)

*                 Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin)

 

Anti-inflammatory agents

Rituximab (Rituxan)

2. Paraneoplastic pemphigus

No true cause has been firmly established. Some patients have autoantibodies against desmoglein-3, and these autoantibodies can induce blisters in newborn mice.The possible link between the underlying neoplasm and autoimmunity may be due to an immune dysregulation secondary to the presence of neoplasm. In addition to autoantibodies to desmoglein-3, most patients develop autoantibodies to many intracellular epithelial components, desmoplakins I and II, periplakin, envoplakin, BP230 (BPAg1), and a 170-kd membrane protein. Several other smaller proteins are involved.

Autoantibodies to these intracellular components probably develop as a secondary autoimmune response rather than a primary cause. Neoplasms are clearly associated with paraneoplastic pemphigus. The most common associated benign tumor is thymoma, followed by Castleman tumor, a rare and complex lymphoproliferative disease. The most common associated malignant tumor is non-Hodgkin lymphoma, followed by chronic lymphocytic leukemia.

3. Pemphigoid group

Autoantibodies to BP180 are the likely inducing autoantigen. Passive transfer experiments using rabbit antimouse BP180 antibodies induce blisters in newborn mice, and the blister induction apparently is complement dependent. The target antigen for linear IgA bullous dermatosis (childhood and adult) is a truncated BP180 protein. The target antigen for epidermolysis bullosa acquisita is type VII collagen, particularly the noncollagenous (NC1) domain.

4. Mucous membrane pemphigoid

Multiple target antigens have been identified, including BP180, laminin-5, laminin-6, type VII collagen, and beta-4 integrin, but no clinical hallmark distinguishes subsets of patients with regard to the target antigen. Rabbit antibodies generated against laminin-5 can induce blisters in newborn mice. Presently, the link between the autoantibodies and the scarring process that characterizes this group of diseases is missing.

Differential Diagnoses

*       Aphthous Stomatitis

*       Behcet Disease

*       Erythema Multiforme

*       Herpes Simplex

*       Herpes Zoster

*       Lichen Planus

*       Oral Lichen Planus

*       Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

1. Direct immunofluorescence microscopy

Direct immunofluorescence microscopy (DIF) determines the types and locations of immune deposits within patients' epithelial tissues. DIF detects deposits at the epithelial cell surfaces and at the epithelial basement membrane zone of the perilesional skin biopsy specimens obtained from patients with the diseases of the pemphigus and pemphigoid groups, respectively. Note the images below.

Direct immunofluorescence microscopy performed on

 

Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.

 

Direct immunofluorescence microscopy performed on

 

Direct immunofluorescence microscopy performed on biopsy specimen obtained from a patient with mucous membrane pemphigoid detects linear immunoglobulin G deposits at the epithelial basement membrane zone.

In paraneoplastic pemphigus, DIF usually reveals deposits at both the epithelial cell surfaces and the epithelial basement membrane zone.

In a study of the sensitivity of DIF on oral mucosal tissues for oral diseases, it was found that positive DIF findings were detected in 100% of pemphigus vulgaris cases, 67% of cicatricial pemphigoid cases, and 56% of bullous pemphigoid cases. Interestingly, biopsy specimens taken from oral tissue location distant to the actual lesion provide essentially the same positive rate as those taken perilesionally. In addition, punch biopsies yielded significantly better positive rates than shave biopsies.

2. Indirect immunofluorescence microscopy

Indirect immunofluorescence microscopy (IIF) determines the patterns of patients' circulating autoantibodies that bind the epithelial components.

IIF detects epithelial cell surface-binding and epithelial basement membrane zone-binding autoantibodies in patients with diseases of the pemphigus and pemphigoid groups, respectively. The titer of the circulating autoantibodies corresponds to the severity of disease in pemphigus.

In addition to binding to squamous epithelial cell surfaces (eg, skin, esophagus substrates), circulating autoantibodies from patients with paraneoplastic pemphigus also label transitional epithelium (eg, lumen of rat bladder).

Indirect immunofluorescence on salt-split substrate

Indirect immunofluorescence on salt-split substrate (ssIIF) uses epithelial substrates in which the lamina lucida of the basement membrane zone has been split at the middle, leaving the target antigens for the autoantibodies of bullous pemphigoid and epidermolysis bullosa acquisita to the roof and the base of the split substrate, respectively.

Using salt-split epithelial substrates, ssIIF detects the circulating autoantibodies from patients with bullous pemphigoid and epidermolysis bullosa acquisita binding respectively to the roof and the base of the substrates, thus distinguishing these 2 diseases.

In patients with mucous membrane pemphigoid, their circulating autoantibodies can bind to the roof, the base, or both, corresponding to the heterogeneity of the target antigens recognized by these autoantibodies.

3. Other Tests

Immunoelectron microscopy

Two methods of immunoelectron microscopy (IEM) can be used to delineate the ultrastructural location of the target antigens, direct method of IEM (DIEM) and indirect method of IEM (IIEM).Whereas DIEM uses patients' epithelial tissues, IIEM uses patients' circulating autoantibodies (serum study). IEM tests are used primarily to study the various autoantigens in the epithelial basement membrane zone.

IEM detects the target antigens (BP180) for bullous pemphigoid, linear IgA bullous dermatosis, and a certain subset of mucous membrane pemphigoid at the upper lamina lucida/hemidesmosome areas; detects the target antigens laminin-5 and laminin-6 for a certain subset of mucous membrane pemphigoid at the lower lamina lucida; and detects the target antigen, type VII collagen, for epidermolysis bullosa acquisita at the lamina densa and sublaminar densa areas.

Immunoblotting

Immunoblotting (IB) test delineates the molecular sizes of the target antigens that are immunolabeled by patients' autoantibodies.

IB test is able to detect that the autoantibodies from patients with bullous pemphigoid and certain subsets of mucous membrane pemphigoid recognize a 230-kd (BPAg1) and/or a 180-kd (BPAg2) epithelial proteins; that the autoantibodies from patients with certain subset of mucous membrane pemphigoid recognize one or all of the 3 protein subunits, 200-kd/165-kd (alpha chain), 140-kd (beta chain), and 155-kd/105-kd (gamma chain) of laminin-5; and that the autoantibodies from patients with epidermolysis bullosa acquisita recognize the 290-kd type VII collagen.

Enzyme-linked immunosorbent assay

Enzyme-linked immunosorbent assay (ELISA) test detects the target antigens of circulating autoantibodies from patients using the known recombinant proteins.[ELISA test detects autoantibodies that recognize their autoantigens in nondenatured form; therefore, it is a more sensitive detection method than IB test. ELISA test also can be a quantitative method.

Immunoprecipitation

Immunoprecipitation (IP) test detects the target antigens of circulating autoantibodies from patients. IP test detects autoantibodies that recognize their autoantigens in native form; therefore, it is a more sensitive detection method than IB test but is more difficult to perform.

MEDICAL CARE

Patients with oral manifestations of autoimmune blistering diseases should be treated conjointly with an oral medicine specialist. Furthermore, patients should have an oral prophylaxis performed by a dental hygienist or dentist prior to initiation of systemic or topical therapy. During the course of therapy, patients should have oral prophylaxis (oral hygiene) performed every 3-4 months. Additionally, they should be monitored for oral candidiasis, especially once on immunosuppressive therapy.

For patients who are treated with systemic corticosteroids, calcium and vitamin D blood levels should be monitored and supplements given if needed to reduce steroid-induced osteoporosis. Furthermore, and especially in patients with pemphigus vulgaris, a baseline bone density test should be performed.

For patients with severe disease who are treated with systemic corticosteroids, steroid-induced osteoporosis should be prevented or reduced by taking an osteoclast-mediated bone resorption inhibitor-bisphosphonate (eg, Fosamax).

For patients who do not respond to more conventional therapies, intravenous infusion of humanized monoclonal antibodies to B cells (anti-CD20, rituximab) should be discussed with the patient's primary physician, after the precaution to assess for serious infections is taken into account.

Elderly patients who have other significant health problems (eg, diabetes mellitus, hypertension, heart diseases) may require treatment with a more conservative approach (eg, topical corticosteroids, tetracycline). The goal of treatment is to achieve disease control with low doses of medications and minimal adverse effects.

Consultations

Examination by pulmonary specialists is recommended for patients with severe oral lesions, especially those patients with paraneoplastic pemphigus if the patients have symptoms or signs suggestive of respiratory difficulty. Respiratory failure and death have been reported in these patients.

Examination by gastroenterologists is recommended for some patients with severe oral lesions to detect possible involvement of the esophagus. Dysphagia can be an associated symptom.

Examination by ophthalmologists experienced in external eye diseases is recommended for those patients with oral lesions and symptoms or signs of ocular inflammation.

Thorough examination by consulting physicians experienced in mucous membrane pemphigoid (cicatricial pemphigoid) is recommended for some patients with oral lesions that also can have genital mucosal involvement.

Care provided by oral medicine specialists or physicians experienced in the field of oral medicine is recommended for patients with severe oral disease.

 

References

1. Werth VP, Fivenson D, Pandya AG, et al. Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch Dermatol. Jan 2008;144(1):25-32. [Medline].

2. Green MG, Bystryn JC. Effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antidesmoglein 1 and antidesmoglein 3 antibodies in pemphigus vulgaris. Arch Dermatol. Dec 2008;144(12):1621-4. [Medline].

3.Masmoudi A, Baricault S, Chikrouhou H, et al. [Tunisian pemphigus foliaceus with antidesmoglein 3 antibody]. Ann Dermatol Venereol. Jan 2008;135(1):69-70. [Medline].

 

4. Pigozzi B, Peserico A, Schiesari L, Alaibac M. Pemphigus foliaceus evolving into pemphigus vulgaris: a probable example of 'intermolecular epitope spreading' confirmed by enzyme-linked immunosorbent assay study. J Eur Acad Dermatol Venereol. Feb 2008;22(2):242-4. [Medline].

5. Martin LK, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. Jan 21 2009;CD006263. [Medline].

5. el-Darouti M, Marzouk S, Abdel Hay R, et al. The use of sulfasalazine and pentoxifylline (low-cost antitumour necrosis factor drugs) as adjuvant therapy for the treatment of pemphigus vulgaris: a comparative study. Br J Dermatol. Aug 2009;161(2):313-9. [Medline].

6. [Best Evidence] Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. Apr 2009;60(4):595-603. [Medline].

7. Asarch A, Razzaque Ahmed A. Treatment of juvenile pemphigus vulgaris with intravenous immunoglobulin therapy. Pediatr Dermatol. Mar-Apr 2009;26(2):197-202. [Medline].

8. Bakos L, Zoratto G, Brunetto L, Mazzotti N, Cartell A. Photodynamic therapy: a useful adjunct therapy for recalcitrant ulceration in pemphigus vulgaris. J Eur Acad Dermatol Venereol. May 2009;23(5):599-600. [Medline].

9. Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J Invest Dermatol. Aug 2010;130(8):2041-8. [Medline].

10. Dalla-Costa R, Pincerati MR, Beltrame MH, Malheiros D, Petzl-Erler ML. Polymorphisms In the 2q33 and 3q21 Chromosome Regions Including T Cell Coreceptor and Ligand Genes May Influence Susceptibility to Pemphigus Foliaceus. Hum Immunol. Apr 27 2010;[Medline].

11. Kumaresan M, Rai R, Sandhya V. Immunofluorescence of the outer root sheath: an aid to diagnosis in pemphigus. Clin Exp Dermatol. Dec 24 2010;[Medline].

12. Daniel BS, Murrell DF. The actual management of pemphigus. G Ital Dermatol Venereol. Oct 2010;145(5):689-702. [Medline].

13. Shelly S, Agmon-Levin N, Altman A, Shoenfeld Y. Thymoma and autoimmunity. Cell Mol Immunol. Feb 14 2011;[Medline].

14. Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. Feb 24 2011;[Medline].

15. Strowd LC, Taylor SL, Jorizzo JL, Namazi MR. Therapeutic ladder for pemphigus vulgaris: emphasis on achieving complete remission. J Am Acad Dermatol. Mar 2011;64(3):490-4. [Medline].

16. Lolis M, Toosi S, Czernik A, Bystryn JC. Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies. J Am Acad Dermatol. Mar 2011;64(3):484-9. [Medline].

17. Leshem YA, Katzenelson V, Yosipovitch G, David M, Mimouni D. Autoimmune diseases in patients with pemphigus and their first-degree relatives. Int J Dermatol. Jul 2011;50(7):827-31. [Medline].

18. Lolis M, Toosi S, Czernik A, Bystryn JC. Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies. J Am Acad Dermatol. Mar 2011;64(3):484-9. [Medline].

19. Anuradha Ch, Malathi N, Anandan S, Magesh K. Current concepts of immunofluorescence in oral mucocutaneous diseases. J Oral Maxillofac Pathol. Sep 2011;15(3):261-6. [Medline]. [Full Text].

20. Singh S. Evidence-based treatments for pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid: a systematic review. Indian J Dermatol Venereol Leprol. Jul-Aug 2011;77(4):456-69. [Medline].

21. Fariba G, Ayatollahi A, Hejazi S. Pemphigus foliaceus. Indian Pediatr. Mar 8 2012;49(3):240-1. [Medline].

 

22. Grekin SJ, Fox MC, Gudjonsson JE, Fullen DR. Psoriasiform pemphigus foliaceus: a report of two cases. J Cutan Pathol. Jan 10 2012;[Medline].

23. Gee SN, Velez NF, Sepehr A, Burgin S. Two distinct viral infections complicating pemphigus foliaceus. Dermatol Online J. Jan 15 2012;18(1):3. [Medline].

24. Oktarina DA, Poot AM, Kramer D, Diercks GF, Jonkman MF, Pas HH. The IgG "Lupus-Band" Deposition Pattern of Pemphigus Erythematosus: Association With the Desmoglein 1 Ectodomain as Revealed by 3 Cases. Arch Dermatol. Jul 16 2012;1-6. [Medline].

 

 

DERMATITIS HERPETIFORMIS

 

1. http://emedicine.medscape.com/article/1062640-overview

 

2. http://www.youtube.com/watch?v=ToCi8rmmanU

 

Background

Dermatitis herpetiformis (DH) is an autoimmune blistering disorder associated with a gluten-sensitive enteropathy (GSE). The disease was described and named in 1884 by Dr. Louis Duhring at the University of Pennsylvania.[1] Dermatitis herpetiformis is characterized by grouped excoriations; erythematous, urticarial plaques; and papules with vesicles. The classic location for dermatitis herpetiformis lesions is on the extensor surfaces of the elbows, knees, buttocks, and back. Dermatitis herpetiformis is exquisitely pruritic, and the vesicles are often excoriated to erosions by the time of physical examination, as shown in the image below.

 

 

 

 dermatitis_herpetiformis_38.jpg

 

 

Classic vesicles of dermatitis herpetiformis.

Diagnosis requires direct immunofluorescence of a skin biopsy specimen showing deposition of immunoglobulin A (IgA) in a granular pattern in the upper papillary dermis. Although most patients are asymptomatic, greater than 90% have an associated gluten-sensitive enteropathy upon endoscopic examination. Among patients with celiac disease, 15-25% develop dermatitis herpetiformis. The mainstays of treatment are dapsone and a gluten-free diet.

Pathophysiology

Dermatitis herpetiformis is a disease of the skin caused by the deposition of IgA in the papillary dermis, which triggers an immunologic cascade, resulting in neutrophil recruitment and complement activation. Dermatitis herpetiformis is the result of an immunologic response to chronic stimulation of the gut mucosa by dietary gluten.

An underlying genetic predisposition to the development of dermatitis herpetiformis has been demonstrated. Both dermatitis herpetiformis and celiac disease (CD) are associated with an increased expression of HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2 haplotypes. Environmental factors are also important; monozygotic twins may have dermatitis herpetiformis, celiac disease, and/or gluten-sensitive enteropathy with variable symptomatology.

The leading theory for dermatitis herpetiformis is that a genetic predisposition for gluten sensitivity, coupled with a diet high in gluten, leads to the formation of IgA antibodies to gluten-tissue transglutaminase (t-TG), which is found in the gut. These antibodies cross-react with epidermal transglutaminase (e-TG).eTG is highly homologous with tTG. Serum from patients with gluten-sensitive enteropathy, with or without skin disease, contains IgA antibodies to both skin and gut types.Deposition of IgA and epidermal TG complexes in the papillary dermis cause the lesions of dermatitis herpetiformis.

In patients with gluten-sensitive enteropathy, levels of circulating antibodies to tissue and epidermal transglutaminase have been found to correlate with each other, and both appear to correlate with the extent of enteropathy.

Co-localized IgA and eTG deposits have been demonstrated in the papillary dermis in patients with dermatitis herpetiformis and, to lesser extent, in healthy skin of gluten-sensitive enteropathy patients.eTG has not been demonstrated in normal papillary dermis, suggesting it is part of the circulating complex that is deposited in the papillary dermis, rather than originating from the papillary dermis.

Cutaneous IgA deposits in dermatitis herpetiformis have been shown to function in vitro as a ligand for neutrophil migration and attachment. Although IgA deposition is pivotal for disease, an increased serum IgA is not necessary for pathogenesis; in fact, case reports describe dermatitis herpetiformis in patients with a partial IgA deficiency.When the disease is active, circulating neutrophils have a higher level of CD11b and an increased ability to bind IgA. The characteristic histologic finding of dermatitis herpetiformis is neutrophil accumulation at the dermoepidermal junction, frequently localizing to the papillary tips of the basement membrane zone.

Collagenase and stromelysin 1 may be induced in basal keratinocytes either by cytokines released from neutrophils or by contact with keratin from damaged basement membrane matrix. Stromelysin 1 may contribute to blister formation.

One study found levels of E-selectin mRNA expression in normal-appearing skin of patients with dermatitis herpetiformis to be 1271 times greater that that of controls.Additionally, the same study observed increased soluble E-selectin, IgA antitissue transglutaminase antibodies, tumor necrosis factor-alpha, and serum interleukin 8 (IL-8) levels in patients with dermatitis herpetiformis, providing further evidence of endothelial cell activation and a systemic inflammatory response as part of the pathogenic mechanism of the disease. Mild local trauma may also induce the release of cytokines and attract the partially primed or activated neutrophils, which is consistent with the typical location of dermatitis herpetiformis lesions on frequently traumatized areas, such as the knees and elbows.

Deposits of C3 also may be present in a similar pattern at the dermoepidermal junction. The membrane attack complex, C5-C9, also has been identified in perilesional skin, although it may be inactive and not contribute to cell lysis.

A recent study showed an increased expression of disintegrin and metalloproteinase (ADAMs) 8, 10, 15, and 17 in lesional skin of patients with dermatitis herpetiformis compared with controls. The high affinity of ADAMs for the basement membrane led the authors to hypothesize a role in blister formation in dermatitis herpetiformis.

Hormonal factors may also play a role in the pathogenesis of dermatitis herpetiformis, and reports describe dermatitis herpetiformis induced by treatment with leuprolide acetate, a gonadotropin-releasing hormone analog.Androgens have a suppressive effect on immune activity, including decreased autoimmunity, and androgen deficient states may be a potential trigger for dermatitis herpetiformis exacerbation. Exacerbation of dermatitis herpetiformis by oral contraceptives has also been reported.

Apoptosis may contribute to the pathogenesis of epidermal changes in dermatitis herpetiformis, and research demonstrates a markedly increased apoptotic rate within the epidermal compartment in dermatitis herpetiformis.In addition, Bax and Bcl-2 proteins are increased in the dermal perivascular compartment and Fas proteins showed epidermal staining in dermatitis herpetiformis lesions.

Most patients with dermatitis herpetiformis have histologic evidence of enteropathy, even in the absence of symptoms of malabsorption. In one study, all dermatitis herpetiformis patients had increased intestinal permeability (as measured by the lactulose/mannitol ratio) and up-regulation of zonulin, a regulator of tight junctions.Thus, increased expression of zonulin may be involved in the pathogenesis of enteropathy in patients with dermatitis herpetiformis.

Clinical Presentation

 

History

Patients typically present with a waxing and waning, pruritic eruption on the extensor surfaces of the arms, knees, and buttocks. It may become generalized. Small vesicles may have been noted but have often been excoriated by the time of presentation to the physician. They may have associated worsening of disease with dietary intake of gluten. Many do not report any GI symptoms, even when prompted.

Physical

The diagnosis is suspected based on the distribution of the eruption.

Flesh-colored–to–erythematous excoriated papules or plaques with herpetiform (ie, small, clustered) vesicles are symmetrically distributed over extensor surfaces, including the elbows, knees, buttocks, and shoulders.

Dermatitis herpetiformis rarely occurs on the posterior (nuchal) scalp and face. Lesions occur infrequently on the oral mucosa, but males are more likely than females to have involvement of the oral and genital membranes. Palms and soles are spared. Digital purpura resembling vasculitis can occur. Erythematous papules and urticarialike plaques occur less frequently; bullae are rare.

The eruption is intensely pruritic; patients often present with erosions and crusts in the absence of vesicles, which have ruptured due to excoriation.

Typical symptoms include burning, stinging, and intense itching. Rarely, if ever, are patients totally asymptomatic, although the degree of itching varies.

Dermatitis herpetiformis is a lifelong disease, although periods of exacerbation and remission are common.

Polymorphic lesions on extensor surface of arm.

 

Polymorphic lesions on extensor surface of arm.

 

Causes

Dermatitis herpetiformis is generally accepted as a cutaneous manifestation of celiac disease. The genetic predisposition to the development of gluten sensitivity underlies the disease.

Gluten is a protein present in grasses of the species Triticeae, which includes barley, rye, and wheat. Rice and oats belong to different species and are generally well tolerated.Strict compliance with a gluten-free diet results in normalization of the small bowel mucosal changes and control of the cutaneous manifestations of dermatitis herpetiformis in most patients. Levels of circulating antibodies also tend to normalize.

Although cornstarch does not contain gluten, 2 case reports describe patients with well-controlled dermatitis herpetiformis who had disease flares after ingesting cornstarch.

The gluten-sensitive enteropathy does not cause symptoms in most dermatitis herpetiformis patients. Less than 10% exhibit symptoms of bloating, diarrhea, or malabsorption. However, greater than 90% show abnormalities upon endoscopic examination. Two thirds have villous atrophy detected on intestinal biopsy specimens. The other third shows elevated intraepithelial lymphocyte counts, increased T-cell receptor gamma/delta intraepithelial lymphocyte counts, or both.

The critical role of associated gluten-sensitive enteropathy in the pathogenesis of dermatitis herpetiformis is confirmed by the fact that resumption of a gluten-containing diet in patients with dermatitis herpetiformis results in a return of the characteristic skin disease.

Mild steatorrhea or other signs of mild malabsorption (eg, altered D-xylose absorption, iron or folate deficiency) can be demonstrated in 20-30% of patients with dermatitis herpetiformis.

Patients with dermatitis herpetiformis and no apparent GI disease can be induced into developing dermatitis herpetiformis by increasing gluten intake, which is often termed latent gluten-sensitive enteropathy.

IgA circulating immune complexes are present in 25-35% of patients with dermatitis herpetiformis, although no association with disease severity has been noted. These immune complexes also have been noted in patients with isolated gluten-sensitive enteropathy and are believed to be related to the presence of the gut disease.

IgA antibodies to gliadin (a portion of wheat protein), reticulum, and smooth muscle endomysium have also been noted in patients with dermatitis herpetiformis and in those with isolated gluten-sensitive enteropathy.

IgA endomysial antibodies are most specific for gluten sensitivity and are found in 80% of patients with dermatitis herpetiformis and greater than 95% of patients with celiac disease. The presence of IgA antiendomysial antibodies correlates with the extent of the gut disease; however, some dermatitis herpetiformis patients do not have detectable IgA antiendomysial antibodies, even during episodes of active skin disease.

The criterion standard for the diagnosis of dermatitis herpetiformis remains the presence of granular deposits of IgA in normal-appearing perilesional skin. It is positive in 92.4% of patients.

Patients with bullous pemphigoid, cicatricial pemphigoid, Henoch-Schönlein purpura, and alcoholic liver disease also may have IgA deposits in normal skin; however, the pattern of IgA deposits is different from that seen in patients with dermatitis herpetiformis.

In patients with dermatitis herpetiformis, 10-15% of their first-degree relatives have dermatitis herpetiformis or celiac disease. HLA studies have conclusively established the presence of a genetic predisposition for dermatitis herpetiformis. Patients with dermatitis herpetiformis have an increased expression of the HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2 haplotypes. This is identical to the HLA association found in patients with isolated gluten-sensitive enteropathy. Most persons with these HLA types do not have dermatitis herpetiformis or gluten-sensitive enteropathy. Associations of HLA and dermatitis herpetiformis are as follows:

·         For HLA-B8, the association with dermatitis herpetiformis is 58-87%, versus 20-30% for control patients.

·         For HLA-DR3, the association with dermatitis herpetiformis is 90-95%, versus 23% for control patients.

·         For HLA-DQ2, the association with dermatitis herpetiformis is 95-100%, versus 40% for control patients.

Other associations include the following:

·                     Associated GI conditions include gluten enteropathy, gastric atrophy, gastric hypochlorhydria, and pernicious anemia.

·                     Associated autoimmune diseases include dermatomyositis, type 1 diabetes mellitus, myasthenia gravis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, and thyroid abnormalities. Thyroid abnormalities are present in as many as 50% of dermatitis herpetiformis patients and include hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer.

·                     Neurologic manifestations such as ataxia have been rarely described.

·                     Associated neoplastic conditions include GI lymphomas and non-Hodgkin lymphoma; patients are at increased risk of developing these cancers.A gluten-free diet may reduce the incidence of dermatitis herpetiformis–associated lymphomas.

·                     Celiac disease usually involves more severe and widespread intestinal involvement. Celiac disease has been associated with genetic abnormalities, including Down syndrome, Turner syndrome, and William syndrome. Liver disease, neurologic disorders, and other skin diseases are also increased in celiac disease, possibly due to common HLA regions on chromosome 6 or immune molecule cross-reactivity.

·                     Gastric manipulation (surgery) may induce dermatitis herpetiformis.

·                     Several chemicals have been associated with induction of dermatitis herpetiformis, including potassium iodide and cleaning solutions.

·                     Case reports have described dermatitis herpetiformis induced by medications. Leuprolide acetate, inhibitors of tumor necrosis factor-alpha, anti-influenza medications, and progesterone-containing contraceptives have been reported in association with development of dermatitis herpetiformis.

Diagnostic Considerations

Eczema

Papular urticaria

Differential Diagnoses

*       Bullous Pemphigoid

*       Erythema Multiforme

*       Linear IgA Dermatosis

*       Neurotic Excoriations

*       Scabies

*       Transient Acantholytic Dermatosis

Laboratory Studies

The diagnosis of dermatitis herpetiformis (DH) is made on the basis of skin biopsy results. However, other tests should be performed depending on the presence of symptoms of associated syndromes. Serum markers, such as IgA endomysial antibodies, are negative in as many as 10-37% of patients with dermatitis herpetiformis.Arguments have been made in favor of testing for tissue transglutaminase for diagnosis,but tissue transglutaminase enzyme-linked immunosorbent assay positivity can occur in many autoimmune diseases because of impurities and cross-reactivity.

 

Anti-endomysial Antibody in Dermatitis Herpetiformis

Procedures

The diagnosis is made after observing characteristic findings from skin biopsy specimens. The biopsy sample should be taken from the edge of a lesion for hematoxylin and eosin staining and from normal-appearing perilesional skin for direct immunofluorescence staining.

Results of direct immunofluorescence of lesional skin are often falsely negative. The vigorous immune response degrades the IgA antibody at the site. Therefore, biopsy specimens for the direct immunofluorescence studies should be taken from healthy-appearing skin.

Immunofluorescence showing immunoglobulin A at the

 

Immunofluorescence showing immunoglobulin A at the dermoepidermal junction (direct immunofluorescence stain).

 

Histologic Findings

Biopsy specimens of lesional skin reveal neutrophils in the dermal papillae, with fibrin deposition, neutrophil fragments, and edema. Eosinophils may be present. Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation. Vesicles form in the lamina lucida, the weakest portion of the dermoepidermal junction, due to neutrophil lysosomal enzymes.

Papillary microabscesses form and progress to sube

 

Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation in the lamina lucida, the weakest portion of the dermoepidermal junction (hematoxylin and eosin stain).

The histologic differential diagnosis of early skin lesions includes bullous lupus erythematosus, bullous pemphigoid, epidermolysis bullosa acquisita, and linear IgA disease.The histologic differential diagnosis of late skin lesions includes bullous drug eruption, bullous pemphigoid, erythema multiforme, and herpes gestationis.

Granular IgA deposits in dermal papillae of perilesional skin observed by direct immunofluorescence is the criterion standard of diagnosis. However, the presence of both granular and linear IgA deposits has been reported on direct immunofluorescence testing in a patient with dermatitis herpetiformis.

Inflammation in lesional skin degrades the immunoreactants and is usually negative for the diagnostic granular pattern. Because deposits are found more reliably in the surrounding normal-appearing skin, the standard practice is to obtain biopsy specimens from normal-appearing perilesional skin for direct immunofluorescent staining.

Medical Care

Treatment of dermatitis herpetiformis (DH) include avoidance of gluten by consuming a gluten-free diet and pharmacotherapy.

A gluten-free diet is a lifelong commitment, and adherence to a strict diet is difficult to achieve. Improvement of skin disease with a gluten free diet takes several months. Gluten is present in various foods that are consumed on an everyday basis, most importantly wheat, barley, and rye. Concern has surrounded oats containing gluten, but studies have shown that consumption of a moderate amount of oats does not worsen dermatitis herpetiformis or celiac disease. Contamination of gluten-free products with gluten remains a potential problem. Nutritional supplementation with multivitamins and iron may be prudent in patients on a strict gluten-free diet.

Dapsone (diaminodiphenyl sulfone) and sulfapyridine are the primary medications used to treat dermatitis herpetiformis. The exact mechanism of action is unknown but is thought to be related to inhibition of neutrophil migration and function. Patients report a symptomatic improvement within hours after initiation of dapsone therapy. Patients should be monitored for the adverse effects of dapsone, primarily hemolytic anemia, methemoglobinemia, agranulocytosis, and neuropathy. For patients unable to tolerate dapsone, particularly those who develop hemolysis, sulfapyridine may be substituted. New lesion formation is suppressed for up to 2 days after a dose of dapsone; however, dapsone does not improve GI mucosal pathology.

A retrospective study has shown remission, defined as 2 years with no symptoms, in 12% of patients.When dermatitis herpetiformis is well-controlled, attempts can be made to taper off dapsone and perhaps attempt a diet with gluten.

Other, less effective treatments for dermatitis herpetiformis include colchicine, cyclosporine, azathioprine, and prednisone. Ultraviolet light may provide some symptomatic relief. Cyclosporine should be used with caution in patients with dermatitis herpetiformis because of a potential increase in the risk of developing intestinal lymphomas.

One case report described resolution of dermatitis herpetiformis after initiation of the Atkins diet.

Nonsteroidal anti-inflammatory drugs may exacerbate dermatitis herpetiformis; however, ibuprofen appears to be safe.

Iodides may elicit or exacerbate dermatitis herpetiformis.

Diet

Dietary intake of gluten causes the disease, and elimination of gluten from the diet improves it.

·                     A position statement by the American Gastroenterological Association (AGA) Institute advises that treatment for patients with dermatitis herpetiformis, like that of all patients with celiac disease, requires a strict, lifelong adherence to a gluten-free diet. The AGA stresses the importance of patient education, motivation, and support in maintaining adherence, and recommends consultation with an experienced dietician, referral to a support group, and clinical follow up for compliance, as well as treatment of nutritional deficiency states.[42] See the guideline summary, AGA Institute medical position statement on the diagnosis and management of celiac disease.

·                     Most patients (as many as 80%) who can maintain a gluten-free diet respond with control of their skin disease. Some patients are able to discontinue dapsone therapy. Compliance with a gluten-free diet is difficult and requires a motivated patient, and the best treatment response occurs with absolute gluten restriction in the diet.

·                     Strict dietary vigilance may be required for 5-12 months before the dapsone dose can be reduced.

·                     Maintaining a gluten-free diet is the only sustainable method of eliminating the disease, not only from the skin, but also from the GI mucosa.

·                     Patients on a gluten-reduced diet may experience a decrease in symptoms; therefore, such a diet can reduce the dosage of dapsone required for disease control.

·                     Neither IgA deposition nor circulating antibodies correlate with gluten intake in short-duration studies; however, some studies have suggested a correlation with complement deposition. Avoidance of dietary gluten for 10 years or more has resulted in loss of cutaneous IgA deposits, which then return upon reinstitution of gluten in the diet.

·                     Elemental diets may improve the disease within weeks.These diets consist of free amino acids, small amounts of triglycerides, and short-chain polysaccharides; they are marketed by pharmaceutical companies. One report has suggested that this improvement may be independent of gluten ingestion; however, this finding has not been confirmed.

 

References:

1. Hull CM, Liddle M, Hansen N, et al. Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis. Br J Dermatol. Jul 2008;159(1):120-4. [Medline].

2. Marietta EV, Camilleri MJ, Castro LA, Krause PK, Pittelkow MR, Murray JA. Transglutaminase autoantibodies in dermatitis herpetiformis and celiac sprue. J Invest Dermatol. Feb 2008;128(2):332-5. [Medline].

3. Zebrowska A, Wagrowska-Danilewicz M, et al. Expression of selected ADAMs in bullous pemphigoid and dermatitis herpetiformis. Journal of Dermatological Science. 2009;56:58-73.

 

4. Madan V, Jamieson LA, Bhogal BS, Wong CS. Inflammatory epidermolysis bullosa acquisita mimicking toxic epidermal necrolysis and dermatitis herpetiformis. Clin Exp Dermatol. Jul 29 2009;[Medline].

 

5. Al-Niaimi F,Cox NH,Lewis-Jones S. Dermatitis herpetiformis exacerbated by cornstarch. JAAD. 2010;62:510-511.

 

6. Ko CJ, Colegio OR, Moss JE, McNiff JM. Fibrillar IgA deposition in dermatitis herpetiformis-an underreported pattern with potential clinical significance. Journal of cutaneous pathology. 2010;37:475-477.

 

7. Paek SY, Steinberg SM, Katz SI. Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol. Mar 2011;147(3):301-5. [Medline].

 

 

 

Case history

 

 

 

The diagnostic process classically involves the following step:

 

1- History taking.

2- Clinical examination.

3- Investigation.

4- Professional diagnosis.

5- Definitive diagnosis.

6- Treatment plane.

7- Follow up.

 

1- History taking

 

The art of taking an accurate case history is probably the most important step in the diagnosis of the medical and surgical

Condition, history taking must systematic Using special set or sequence.

 

Objective of taking history:

 

1-To provide dentist with information that may be necessary for making diagnosis.

2- To establish good or positive provisional relationship with patient who affects cooperation and confidence.

3- To provide dentist with information concerning patient past and present medical dental and personal history.

4- To provide information about patient systemic health which may be greatly affect the treatment plain and prognosis and disease that could be transmitted to dentist, his staff or other patient.

5- It serves as legal document.

 

Component of pt. history:

 

1-Personal history.

2-Chief complaint .

3-History of chief complaint.

4-Past history.

5-Medical history and systemic review.

6-Familial history.

7-Personal and social habit.

 

1-personal history :

 

Include the full name of the pt. age ,sex,address,telephon number ,occupation this information may aid or contribute in diagnosis since some medical problem have tendency to occur in particular age group , sex , or race .some time occupation may be associated with particular disease or may influence the type of therapy.

 

2-chief compliant –c c-:

 

Is usually the reason of pt. visit, the chief complaint is the best stated in the pt, own words in brief the summary of the problem {e.g. pain ,swelling , ulcer ,parasthesia ,numbness, clicking ,halitosis, bleeding trismus}if pt. complaint of several symptom should be listed.

 

3-History of present illness:

 

The pt, tell the story in his fashion never ask pt, leads question and you have to see if the pt in condition able to give you history which reliable and his statement, can be relied upon,

Ask the pt, about:

1.Duration ( length of the complain ).

2.Onset date of onset, manner of the onset.

3.precipitating, predisposing factor  ,hot, cold, sweet.

 

4. Characteristic includes:

 

A-nature (continuous intermitted, stapping.

B-severity mild, sever, very sever.

C-location .

D-Radiation felling of pain in site other causative lesion this called refers pain.

E-temporal feature .

F-aggravating factor.

G-relieving factor.

H-associated constitutional symptom and signs.

 

5-therapy:

A- Type of therapy.

B- Dose.

C- Provider.

D- Effect of therapy.

E- Date of therapy.

 

If the pt, comes with chief complaint (pain) very detail history should be taken particularly attention paid to

 

5- Medical history and systemic review (M, H):

 

http://www.mergeleftmarketing.com/vsImages/Information/Images%20for%20Consultation/Search.jpg

 

It includes review the past and present illness or disease because:

A. these information may add in diagnosis of various condition occur or has oral manifestation that related to specific systemic disease aids, leukemia.

B. the presence of many disease may lead or need modification for the treatment plane and affect the manner in therapy is provide C. Drugs used in treatment some systemic disease can also have effect on the mouth (oral manifestation ) or dictate some modification to dental or surgical  treatment e.g. anticoagulant drugs chemotherapy.

 

The past medical history includes:

 

1-Previous serious illness or disease.

2-Childhood diseases.

3-Hospitalization.

4-Operations.

5-Injuries to the head and neck.

6-Allergy to drugs or general allergy.

7-Listing of modification taken in the last six months.

 

 

How to take medical history:

         

Any patient come should be asked certain concise questions:

 

1-If he is currently receiving any medical care or under supervision of any clinician.

2-whether he has been hospitalized and why?

3-if you have any serious illness remembered by the patient?

4-if you have any surgical operation before?

5- If the patient takes any type of drugs before in the past or present time.

 

6- Family history F. H.

 

Details of family history may reveal   valuable information about diseases that are occurring in families e.g. Tuberculosis, hemophilia psychiatric or neoteric disorders, breast cancer. Congenital anomalies such as cleft lip, cleft palate.

 

7- Personal or social habits, smoking cigarettes or pipe addiction.