Lesson 8

June 27, 2024
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LESSON 2

THEMES:

1. BULLOUS DERMATOSIS. PEMPHIGUS, ITS VARIETIES. HERPETIFORMIC DERMATITIS. VIRUS DERMATOSIS. HERPES SIMPLEX. HERPES ZOSTER. WARTS (HUMAN PAPILLOMAVIRUS INFECTIONS): COMMON WARTS, FLAT WARTS, PLANTAR WARTS. MOLLUSCUM CONTAGIOSUM.

2. URTICARIA AND ERYTHEMA. ALLERGIC, IDIOPATHIC, THERMOGRAPHIC, CHOLINERGIC URTICARIA. ANGIOEDEMA.bULLOUS AND NONBULLOUS ERYTHEMA MULTIFORM. VASCULITIS ALLERGIC, URTICARIAL, NODULE. HENOCHSCHONLEIN PURPURA

 

AUTOIMMUNE SKIN DISEASES

 1. http://www.elaineoore.com/Articles/AutoimmuneDiseases/BullousSkinDiseases/tabid/213/Default.aspx

2. http://www.ehow.com/video_5112638_autoimmuneskinproblems.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, 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 (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.

 

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 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.

 

 

 ·                     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.

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 medicatioecessary 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. 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

   

 

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. 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 superficial bullae characteristic of pemphigus foliaceus.

  

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

 

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.

 

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.

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).

1. Corticosteroid agents

Prednisone (Deltasone, Orasone)

 

2. Antibiotic agents

*        Minocycline (Dynacin, Minocin)

*           Dapsone (Avlosulfon)

 

3. Antimalarial agents

Hydroxychloroquine (Plaquenil)

 

4. 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).

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.

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.

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 iewborn 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 iewborn 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

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 ofintermolecular epitope spreadingconfirmed by enzymelinked 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. DallaCosta R, Pincerati MR, Beltrame MH, Malheiros D, PetzlErler 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.

 

 

 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 ieutrophil 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 iormal 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 beeoted 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.

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 iormalization 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 beeoted. These immune complexes also have beeoted 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 beeoted 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 iormal 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

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. 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 depositioor 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].

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MOLLUSCUM CONTAGIOSUM

http://emedicine.medscape.com/article/910570-overview

http://www.youtube.com/watch?v=fZ6E4DYXQkI

 

Background

Molluscum contagiosum virus causes a benign viral infection that is largely (if not exclusively) a disease of humans. Molluscum contagiosum virus causes characteristic skin lesions consisting of single or, more often, multiple, rounded, dome-shaped, pink, waxy papules that are 2-5 mm (rarely up to 1.5 cm in the case of a giant molluscus) in diameter. The papules are umbilicated and contain a caseous plug. See the images below for examples.

Note the central umbilication in these classic les

Note the central umbilication in these classic lesions of molluscum contagiosum.

 

 

 Approximately 10% of patients develop eczema aroun

Approximately 10% of patients develop eczema around lesions. Eczema associated with molluscum lesions spontaneously subsides following removal.

 Larger lesions may have several clumps of molluscu

Larger lesions may have several clumps of molluscum bodies rather than the more common single central umbilication. This may make them difficult to recognize as molluscum contagiosum.

 

 

 

Molluscum contagiosum on the right axilla.

Molluscum contagiosum on the right axilla.

Molluscum contagiosum virus is an unclassified member of the Poxviridae family. It cannot be grown in tissue culture or eggs; it has been grown in human foreskin grafted to athymic mice but has not been transmitted to other laboratory animals. Through restrictive endonuclease analysis of the genomes of isolates, molluscum contagiosum virus types I-IV have been identified. In a study of 147 patients, molluscum contagiosum virus I caused 96.6% of infections, and molluscum contagiosum virus II caused 3.4%; however, no relationship was observed between virus type and lesional morphology or anatomical distribution.[1] Molluscum contagiosum viruses III and IV are rare. In patients with human immunodeficiency virus (HIV) infection, molluscum contagiosum virus II causes most infections (60%).

Bateman first described the disease in 1817, and Paterson demonstrated its infectious nature in 1841. In 1905, Juliusburg proved its viral nature. Infection follows contact with infected persons or contaminated objects, but the extent of epidermal injury necessary is unknown. Lesions may spread by autoinoculation.

Complications

Complications of molluscum contagiosum include irritation, inflammation, and secondary infections. Lesions on eyelids may be associated with follicular or papillary conjunctivitis. Bacterial superinfection may occur but is seldom of clinical significance. Cellulitis is an unusual complication of molluscum contagiosum in patients who are HIV infected.Secondary infection with Staphylococcus aureus has resulted in abscess formation, whereas Pseudomonas aeruginosa can cause necrotizing cellulitis.

Etiology

Transmission

The molluscum contagiosum virus may be inoculated along a line of minor skin trauma (eg, from shaving), resulting in lesions arranged in a linear pattern (see the image below). This process, termed autoinoculation, can also result from manipulation of lesions by the patient. Autoinoculation is different from the Koebner phenomenon, which is also called an isomorphic response. In the Koebner phenomenon, new lesions develop along a line of trauma and the etiology of the underlying condition is unknown. Psoriasis and lichen planus are examples of skin conditions that commonly koebnerize.

In a patient who had preexisting molluscum contagi

In a patient who had preexisting molluscum contagiosum, the virus was inoculated along a line of minor skin trauma, resulting in the development of the 3 new lesions.

Molluscum contagiosum virus transmission through direct skin contact between children sharing a bath and between athletes sharing gymnasium equipment and benches has been reported. An association between school swimming pool use and molluscum contagiosum infection has also been reported.

Three distinct disease patterns are observed in 3 different patient populations: children, adults who are immunocompetent, and patients who are immunocompromised (children or adults). The prognosis and therapy are different for each of these groups.

Molluscum contagiosum is most common in children who become infected through direct skin-to-skin contact or indirect skin contact with fomites, such as bath towels, sponges, and gymnasium equipment. Lesions typically occur on the chest, arms, trunk, legs, and face. Hundreds of lesions may develop in intertriginous areas, such as the axillae and intercrural region (see the image below). Lesions may rarely occur on the mucous membranes of the lip, tongue, and buccal mucosa. The palms are spared. Patients with atopic dermatitis may develop large numbers of lesions.

Molluscum lesions may become quite numerous in int

Molluscum lesions may become quite numerous in intertriginous areas. This child has autoinoculated lesions to both inner thighs.

In adults, molluscum contagiosum most commonly is a sexually transmitted disease (STD). Healthy adults tend to have few lesions, which are limited to the perineum, genitalia, lower abdomen, or buttocks. Molluscum contagiosum in healthy children and adults is usually a self-limited disease.

Widespread, persistent, and atypical molluscum contagiosum may occur in patients who are significantly immunocompromised or have acquired immunodeficiency syndrome (AIDS) with low CD4 T-lymphocyte counts (see the images below). Molluscum contagiosum may be the presenting complaint in patients with AIDS. Molluscum contagiosum virus infection in immunocompromised patients may be particularly resistant to therapy. Other opportunistic infections in these patients may closely resemble molluscum contagiosum.

Molluscum contagiosum rarely occurs on the face in

Molluscum contagiosum rarely occurs on the face in an adult unless the patient is infected with HIV. When molluscum contagiosum occurs in individuals infected with HIV, facial lesions are common and frequently numerous.

 

Molluscum contagiosum lesions in individuals infec

 

Molluscum contagiosum lesions in individuals infected with HIV may number in the hundreds. In addition, they may become quite large and prominent. Multiple papules on the face of a man with HIV.

 

Multiple papules on the face of a man with HIV.

Case reports have detailed molluscum contagiosum eruptions in areas that were treated with tacrolimus 0.1% (Protopic).

Infection

The molluscum contagiosum virus replicates in the cytoplasm of epithelial cells, producing cytoplasmic inclusions and enlargement of infected cells. This virus infects only the epidermis. Infection follows contact with infected persons or contaminated objects, but the extent of necessary epidermal injury is unknown. The initial infection seems to occur in the basal layer, and the incubation period is usually 2-7 weeks. This is suggested by the fact that, although viral particles are noted in the basal layer, viral deoxyribonucleic acid (DNA) replication and the formation of new viral particles do not occur until the spindle and granular layers of the epidermis are involved. Infection may be accompanied by a latent period of as long as 6 months.

Following infection, cellular proliferation produces lobulated epidermal growths that compress epidermal papillae, while fibrous septa between the lobules produce pear-shaped clumps with the apex upwards. The basal layer remains intact.

Cells at the core of the lesion show the greatest distortion and are ultimately destroyed, resulting in large hyaline bodies (ie, molluscum bodies, Henderson-Paterson bodies) containing cytoplasmic masses of virus material. These bodies are present in large numbers and appear as a white depression at the center of fully developed lesions. Occasionally, the lesions can progress beyond local cellular proliferation and become inflamed with attendant edema, increased vascularity, and infiltration by neutrophils, lymphocytes, and monocytes.

As with other poxviruses, molluscum contagiosum virus does not appear to develop latency but evades the immune system through the production of virus-specific proteins. Cell-mediated immunity is most important in modulating and controlling the infection. Children and patients with HIV infection generally have more widespread lesions. Prevalence of molluscum contagiosum virus in patients with HIV may be as high as 5-18%, and the severity of infection is inversely related to the CD4 T-lymphocyte count. More extensive and resistant infections also are noted in patients receiving prednisone and methotrexate.

The virus is not strongly immunogenic, as it infrequently induces antibody formation. Specific antibodies have been found in approximately 80% of patients and in about 15% of control subjects. A role for humoral immunity in regression of lesions is not established. Reinfection is common.

Viral characteristics

Molluscum contagiosum is a viral disease caused by a DNA poxvirus and is largely, if not exclusively, a disease of humans. It is an unclassified member of the Poxviridae family (ie, poxviruses).

The poxviruses are a large group of viruses with a high molecular weight. They are the largest animal viruses, only slightly smaller than the smallest bacteria, and are just visible using light microscopy. They are complex DNA viruses that replicate in the cytoplasm and are especially adapted to epidermal cells. They cannot be grown in tissue culture or eggs. Molluscum contagiosum virus has been grown in human foreskin grafted to athymic mice but not in other laboratory animals.

Humans are the host for the following 3 types of molluscum contagiosum virus:

  • Orthopoxvirus – This resembles variola (smallpox) and vaccinia, which are ovoid (300 x 250 nm)
  • Parapoxvirus – These are orf and milker’s nodule viruses, which are cylindrical (260 x 160 nm)
  • Unclassified (with features that are intermediate between those of the orthopox and parapox groups) – These are intermediate in structure (275 X 200 nm); they include molluscum contagiosum virus and tanapox

The primary structure and coding capacity of molluscum contagiosum virus was determined by Senkevich et al.Analysis of the molluscum contagiosum virus genome has revealed that it encodes approximately 182 proteins, 105 of which have direct counterparts in orthopoxviruses.

Restriction endonuclease analysis of the genomes has identified 4 types. Molluscum contagiosum virus I and molluscum contagiosum virus II have genomes of 185 kilobases (kb) and 195 kb, respectively. Molluscum contagiosum virus III and IV are very rare.

No relationship between virus type and lesional morphology or anatomical distribution is known. Molluscum contagiosum virus encodes an antioxidant protein (MC066L), selenoprotein, which functions as a scavenger of reactive oxygen metabolites and protects cells from damage from ultraviolet (UV) light and peroxide. The particular role of this protein is not known.

In one study, type I caused 96.6% and type II caused 3.4% of infections in 147 patients, but no relationship was observed between virus type and lesional morphology or anatomic distribution.

Disfiguring lesions may occur in patients with the following conditions:

*       AIDS – Facial and perioral molluscum contagiosum are most commonly observed as a manifestation of HIV infection, particularly in homosexual men with HIV; at the time of molluscum contagiosum diagnosis, the CD4 count is low

*       Immunocompromise – Lesions are especially common and extensive on the face and neck

*       Sarcoidosis

*       Lymphocytic leukemia

*       Congenital immunodeficiency

*       Selective immunoglobulin M (IgM) deficiency

*       Thymoma

*       Treatment with prednisone and methotrexate

*       Disseminated malignancy

*       Refractory atopic dermatitis

Diagnostic Considerations

The cutaneous manifestations of other opportunistic infections, such as cutaneous cryptococcosis, histoplasmosis, and aspergillosis, may mimic molluscum contagiosum and must be ruled out in immunocompromised hosts. (See the images below.)

 

This lesion of cutaneous coccidioidomycosis could

This lesion of cutaneous coccidioidomycosis could be included among the differential diagnoses of molluscum contagiosum.

 

This keratoacanthoma could be included among the d

 

This keratoacanthoma could be included among the differential diagnoses of molluscum contagiosum.

Molluscum contagiosum may be randomly associated with other lesions, such as epidermal cysts, nevocellular nevi, sebaceous hyperplasias, and Kaposi sarcoma. Pseudocystic molluscum contagiosum, giant molluscum contagiosum, and molluscum contagiosum associated with other lesions are responsible for frequent clinical misdiagnoses.

Infection of children through sexual abuse is possible; however, to a greater extent than warts, molluscum contagiosum virus is quite common on the genital, perineal, and surrounding skin of children.Regard abuse as unlikely, unless other suspicious features are present.

Histologic or microscopic confirmation of molluscum contagiosum is indicated in patients who are immunocompromised because several life-threatening opportunistic infections may clinically mimic molluscum contagiosum.

Conditions to consider in the differential diagnosis of molluscum contagiosum include the following:

  • Keratoacanthoma
  • Verruca vulgaris (warts)
  • Eccrine poroma
  • Epidermal cyst
  • Foreign body granuloma
  • Lichen planus
  • Flat warts (verruca plana)
  • Pyoderma

Perforating disorders (all very rare in children) to consider in the differential diagnosis of molluscum contagiosum include the following:

  • Acquired reactive perforating dermatosis of renal failure
  • Kyrle disease
  • Perforating serpiginous elastoma
  • Perforating folliculitis
  • Verrucous perforating collagenoma
  • Perforating granuloma annulare

Differential diagnoses to consider in patients with AIDS include the following:

  • Cutaneous Cryptococcus. Cutaneous cryptococcus presents as molluscumlike eruptions (on the face, it often has a very dramatic appearance); the patient may have few or no other symptoms associated with cryptococcal meningitis
  • Cutaneous coccidioidomycosis
  • Cutaneous histoplasmosis
  • Cutaneous aspergillosis

Differential Diagnoses

*       Basal Cell Carcinoma

*       Condyloma Acuminatum

*       Cryptococcosis

*       Keratosis Pilaris

*       Milia

*       Pearly Penile Papules

*       Pyogenic Granuloma

*       Surgical Treatment of Basal Cell Carcinoma

*       Varicella-Zoster Virus

References:

1. FeryBlanco C, Pelletier F, Humbert P, Aubin F. [Disseminated molluscum contagiosum during topical treatment of atopic dermatitis with tacrolimus: efficacy of cidofovir]. Ann Dermatol Venereol. May 2007;134(5 Pt 1):457-9. [Medline].

2. Connell CO, Oranje A, Van Gysel D, Silverberg NB. Congenital molluscum contagiosum: report of four cases and review of the literature. Pediatr Dermatol. Sep-Oct 2008;25(5):553-6. [Medline].

3. Reynolds MG, Holman RC, Yorita Christensen KL, Cheek JE, Damon IK. The Incidence of Molluscum contagiosum among American Indians and Alaska Natives. PLoS One. 2009;4(4):e5255. [Medline]. [Full Text].

4. Mathes EF, Frieden IJ. Treatment of molluscum contagiosum with cantharidin: a practical approach. Pediatr Ann. Mar 2010;39(3):124-8, 130. [Medline].

5. Veregen (sinecatechins) Ointment, 15% [package insert]. Planegg/Martinsried, Germany: MediGene AG; 2011.

 

HUMAN  PAPILLOMAVIRUS

 

http://emedicine.medscape.com/article/219110-overview#aw2aab6b2b3

http://www.youtube.com/watch?v=4oEyOZwS1ds

 

 

Etiology

The definitive cause of anogenital warts is HPV infection.The HPV capsid lacks an envelope, which makes the organism very stable and resistant to various treatments. No serologic typing is available, because of the lack of consistent in vitro culture methods. Typing of HPV is based on genotype, which generally is determined by molecular hybridization using molecularly cloned HPV DNA of known type as the standard. Two HPV are of different types when their DNA hybridize (bind) less than 50% as efficiently to each other as to themselves.

The nearly 40 types of HPV that have been found in genital warts are highly host-specific. These viruses do not infect laboratory animals and are not susceptible to acyclovir. In addition, HPV types demonstrate a high degree of site specificity, with some types only found on certain parts of the skin or mucous membranes. As a rule, HPV types causing common warts of the skin do not infect moist epithelium, and vice versa.

Multiple clinical associations with unique genotypes of HPV have been documented. Some of these associations are listed in the Table below.

Diseases Associated With Specific HPV Types

Nongenital Cutaneous Disease

HPV Type

Common warts (verrucae vulgaris)

1, 2, 4, 26, 27, 29, 41, 57, 65, 75-78

Plantar warts (myrmecias)

1, 2, 4, 60, 63

Flat warts (verrucae planae)

3, 10, 27, 28, 38, 41, 49

Butcher’s warts (common warts of people who handle meat, poultry, and fish)

1-4, 7, 10, 28

Mosaic warts

2, 27, 57

Ungual squamous cell carcinoma

16

Epidermodysplasia verruciformis (benign)

2, 3, 10, 12, 15, 19, 36, 46, 47, 50

Epidermodysplasia verruciformis (malignant or benign)

5, 8-10, 14, 17, 20-25, 37, 38

Nonwarty skin lesions

37, 38

Nongenital Mucosal Disease

HPV Type

Respiratory papillomatosis

6, 11

Squamous cell carcinoma of the lung

6, 11, 16, 18

Laryngeal papilloma (recurrent respiratory papillomatosis)[14]

2, 6, 11, 16, 30, 40, 57

Laryngeal carcinoma

6, 11

Maxillary sinus papilloma

57

Squamous cell carcinoma of the sinuses

16, 18

Conjunctival papillomas

6, 11

Conjunctival carcinoma

16

Oral focal epithelial hyperplasia (Heck disease)

13, 32

Oral carcinoma

16, 18

Oral leukoplakia

16, 18

Squamous cell carcinoma of the esophagus

16, 18

Anogenital Disease

HPV Type

Condylomata acuminata

1-6, 10, 11, 16, 18, 30, 31, 33, 35, 39-45, 51-59, 70, 83

Bowenoid papulosis

16, 18, 34, 39, 40, 42, 45

Bowen disease

16, 18, 31, 34

Giant condylomata (Buschke-Löwenstein tumors)

6, 11, 57, 72, 73

Unspecified intraepithelial neoplasia

30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66-69

Low-grade squamous intraepithelial lesions (LGSIL)

6, 11, 16, 18, 26, 27, 30, 31, 33-35, 40, 42-45, 51-58, 61, 62, 67-69, 71-74, 79, 81-84

High-grade squamous intraepithelial lesions (HGSIL)

6, 11, 16, 18, 31, 33, 35, 39, 42, 44, 45, 51, 52, 56, 58, 59, 61, 64, 66, 68, 82

Carcinoma of vulva

6, 11, 16, 18

Carcinoma of vagina

16

Carcinoma of cervix[15, 16]

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82

Carcinoma of anus

16, 31, 32, 33

Carcinoma in situ of penis (erythroplasia of Queyrat)

16

Carcinoma of penis

16, 18

Risk factors

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process, particularly in the anogenital-mucosal category. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV, are especially susceptible to HPV infections.

Sexual activity

A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

Women with a history of high-grade squamous intraepithelial lesions (HGSIL) of the cervix or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital-mucosal category, particularly vaginal and anal carcinoma (relative risks, 5.6 and 4, respectively).

Anal cancer has been strongly associated with male homosexuality and with specific male practices, such as engaging in receptive anal intercourse; relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

Tobacco smoking

Women who smoke tobacco have an increased risk of developing cervical neoplasia. Measurable amounts of a potent carcinogen, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents are likely to play a role in the increased prevalence of HPV malignant transformation observed in patients who smoke tobacco.

Oral contraceptive use

Women who take oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma. This risk declines after oral contraceptive use is stopped, and no risk is demonstrated in women who took these agents for less than 5 years.

Chewing Indian betel quid

A high incidence of oral cancer associated with HPV infection has been demonstrated in India among patients who chew betel quid. This stimulant is made from the leaves of the betel plant and is used in a manner similar to chewing tobacco.

Ultraviolet and x-ray irradiation

EV is particularly susceptible to ultraviolet (UV) and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.

Clinical Presentation

Anogenital warts

Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.

Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.

Flat condylomata (squamous intraepithelial neoplasia) are the most common lesions of the cervix but may also develop on the vulva, anus, and male genitalia. They appear as white plaquelike growths.

An additional malignant variant is the giant condyloma, or Buschke-Löwenstein tumor, generally regarded as a verrucous carcinoma. These most often involve the glans penis, perianal area, and foreskin. In addition to their large cauliflower shape, they tend to form abscesses and fistulas and tend to invade locally.

Genital warts generally do not become clinically apparent until several months after inoculation with HPV. They follow a slow and indolent course and may develop by inoculation from opposing surfaces.

Condylomata acuminata are often asymptomatic. These lesions are generally not painful, but they can be associated with pruritus; bleeding may be observed if the lesions become confluent and are irritated by clothing. Most patients seek medical care when they notice lumps on the vulva, perianal area, or periclitoral area, or because they experience pruritus or occasional bleeding.

Cervical disease

Most cervical infections are either latent or subclinical and therefore asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of HPV-triggered dysplasia.

Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.

Anal cancer

The most common presenting symptoms of squamous cell carcinoma (SCC) of the anus are rectal bleeding and sensation of a mass. These symptoms may be attributed mistakenly to hemorrhoids.

Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.

Nonanogenital mucosal disease

Oral warts represent infection of the oral mucosa. Although they are subtle and easily missed, they are fairly common. HPV types 6 and 11 have been isolated from nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.

HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas most frequently present with hoarseness at an average age of 3 years.

Focal epithelial hyperplasia (Heck disease) is a disseminated HPV infection of the oral mucosa most commonly associated with HPV 32 and HPV 13. This condition may have a family predilection.

Nongenital cutaneous HPV

Common cutaneous warts (verruca vulgaris) generally appear on keratinized skin, presumably at the site of inoculation. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface (so-called kissing warts).

Common cutaneous warts appear as circumscribed, rough, hyperkeratotic papulonodules or plaques with irregular scaly surfaces and develop most often on the hands, fingers, feet, and knees. Such warts are frequently discovered when the patient notices changes in the skin. In general, they are asymptomatic, but they may be painful with application of pressure. Typically, they are benign and self-limited.

Palmoplantar warts appear on the acral surfaces of the feet and hands. They are notable for their thickness, which complicates treatment. Deep plantar warts occur most commonly as solitary lesions that may become black and painful before spontaneously regressing. They may contain small black “seeds,” which are thrombosed capillaries.

Plantar warts.

Plantar warts.

Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.

Flat warts (verruca plana) most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. They often are not obvious but may induce significant disturbances of pigmentation. Regression usually occurs spontaneously after several years, and pruritus or erythema occurs several weeks before their disappearance.

Flat wart.

Flat wart.

Lloyd described Bowenoid papulosis as multicentric pigmented Bowen disease of the groin. It manifests as multiple, warty, red-brown papules in the anogenital region. These papules may coalesce.

Malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually arise first on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.

Verrucous warts in patient with HIV infection.

Epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is an autosomal recessive familial trait that increases susceptibility to a subset of wart generally not observed in populations without EV. HPV genotypes associated with EV have been observed in patients who are immunosuppressed for organ transplantation or in patients with HIV infection. These individuals are at increased risk for skin cancer if not recognized and treated.

EV generally begins in childhood and can affect almost any area of the body. The warts are generally subtle and flat and may initially be mistaken for tinea versicolor. EV tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.

References:

1.  Lee LA, Cheng AJ, Fang TJ, Huang CG, Liao CT, Chang JT, et al. High incidence of malignant transformation of laryngeal papilloma in Taiwan. Laryngoscope. Jan 2008;118(1):50-5. [Medline].

2.[Best Evidence] Kliewer EV, Demers AA, Elliott L, Lotocki R, Butler JR, Brisson M. Twenty-year trends in the incidence and prevalence of diagnosed anogenital warts in Canada. Sex Transm Dis. Jun 2009;36(6):380-6. [Medline].

3. [Best Evidence] Hoy T, Singhal PK, Willey VJ, Insinga RP. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. Oct 2009;25(10):2343-51. [Medline].

4. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis. Jul 29 2009;9:119. [Medline]. [Full Text].

5. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen Hz, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. May 25 2010;401(1):70-9. [Medline]. [Full Text].

6. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. Nov 2010;11(11):1048-56. [Medline].

7. ánchez-Alemán MA, Uribe-Salas FJ, Lazcano-Ponce EC, Conde-Glez CJ. Human papillomavirus incidence and risk factors among Mexican female college students. Sex Transm Dis. Apr 2011;38(4):275-8. [Medline].

8. Castle PE, Rodríguez AC, Burk RD, Herrero R, Wacholder S, Hildesheim A, et al. Long-term persistence of prevalently detected human papillomavirus infections in the absence of detectable cervical precancer and cancer. J Infect Dis. Mar 15 2011;203(6):814-22. [Medline]. [Full Text].

9. Giuliano AR, Lee JH, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet. Mar 12 2011;377(9769):932-40. [Medline]. [Full Text].

10. Chaturvedi AK, Katki HA, Hildesheim A, Rodríguez AC, Quint W, Schiffman M, et al. Human papillomavirus infection with multiple types: pattern of coinfection and risk of cervical disease. J Infect Dis. Apr 1 2011;203(7):910-20. [Medline]. [Full Text].

Urticaria

http://emedicine.medscape.com/article/762917-overview

http://tu.tv/videos/treatmentforurticariachronicurtic

 

Background

Urticaria, commonly referred to as hives, is the most frequent dermatologic disorder seen in the ED. It appears as raised, well-circumscribed areas of erythema and edema involving the dermis and epidermis that are very pruritic. Urticaria may be acute (lasting less than 6 wk) or chronic (lasting more than 6 wk). A large variety of urticaria variants exist, including acute immunoglobulin E (IgE)–mediated urticaria, chemical-induced urticaria (non-IgE-mediated), urticarial vasculitis, autoimmune urticaria, cholinergic urticaria, cold urticaria, mastocytosis, Muckle-Wells syndrome, and many others.

Urticaria may be confused with a variety of other dermatologic diseases that are similar in appearance and are pruritic including atopic dermatitis (eczema), maculopapular drug eruptions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, and others. Usually, however, the experienced clinician is able to distinguish these from urticaria because of its distinctive appearance (see the images below), the fact that it is intensely pruritic, and because it blanches completely with pressure.

Urticaria developed after bites from an imported f

Urticaria developed after bites from an imported fire ant.

 

Urticaria associated with a drug reaction.

Urticaria associated with a drug reaction.

Acute IgE-mediated urticaria is the most benign form of anaphylaxis. It usually occurs independently, but it may be accompanied by the more serious clinical manifestations of anaphylaxis: angioedema and anaphylactic shock. The etiologies of both acute and chronic urticaria are numerous (see Causes below). The etiologic agent is more likely to be identified in acute urticaria (40-60%) than in chronic urticaria (10-20%). The lesions of IgE-mediated urticaria usually last less than 24 hours and are often migratory, leaving no residual skin abnormalities. The lesions of urticarial vasculitis usually last longer than 24 hours, are both painful and pruritic, and often leave purpuric and hyperpigmented lesions.

Clinical Presentation

Information regarding history of previous urticaria and duration of rash and itching is useful for categorizing urticaria as acute, recurrent, or chronic.

  • For chronic or recurrent urticaria, important considerations include previous causative factors and the effectiveness of various treatments.
  • Ask about precipitants, such as heat, cold, pressure, exercise, sunlight, emotional stress, or chronic medical conditions (eg, hyperthyroidism, systemic lupus erythematosus [SLE], rheumatoid arthritis, polymyositis, amyloidosis, polycythemia vera, lymphoma and other malignant neoplasms).
  • Ask about other medical conditions that can cause pruritus (usually without rash), such as diabetes mellitus, chronic renal insufficiency, primary biliary cirrhosis, or other nonurticarial dermatologic disorders (eg, eczema, contact dermatitis).
  • Ask about family and personal medical history of angioedema, which is urticaria of the deeper tissues and can be life threatening if it involves the larynx and vocal cords. Causes specific to angioedema include hereditary angioedema (a deficiency in C1-inhibitors) and acquired angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers (ARBs). Characteristics of angioedema include the following:
    • Vasodilation and exudation of plasma into deeper tissues than is seen in simple urticaria
    • Swelling that is generally nonpitting and nonpruritic and usually occurs on the mucosal surfaces of the respiratory tract (lips, tongue, uvula, soft palate, and larynx) and GI tract (swelling of the intestine leading to severe abdominal pain)
    • Hoarseness, the earliest sign of laryngeal edema (Ask the patient if he or she has had a voice change.)
  • For acute urticaria, ask about possible precipitants, such as the following:
    • Recent illness (eg, fever, sore throat, cough, rhinorrhea, vomiting, diarrhea, headache)
    • Medication use including penicillins, cephalosporins, sulfas, diuretics, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), iodides, bromides, quinidine, chloroquine, vancomycin, isoniazid, antiepileptic agents, and other agents
    • Intravenous radiocontrast media
    • Travel (amebiasis, ascariasis, strongyloidiasis, trichinosis, malaria)
    • Foods (eg, shellfish, fish, eggs, cheese, chocolate, nuts, berries, tomatoes)
    • New perfumes, hair dyes, detergents, lotions, creams, or clothes
    • Exposure to new pets (dander), dust, mold, chemicals, or plants
    • Pregnancy (usually occurs in last trimester and typically resolves spontaneously soon after delivery)
    • Contact with nickel (eg, jewelry, jeans stud buttons), rubber (eg, gloves, elastic bands), latex, industrial chemicals, and nail polish
    • Sun or cold exposure
    • Exercise

rticaria is characterized by blanching, raised, palpable wheals, which can be linear, annular (circular), or arcuate (serpiginous). These lesions occur on any skin area and are usually transient and migratory. These lesions are often separated by normal skin, but may coalesce rapidly to form large areas of erythematous, raised lesions that blanch with pressure.

  • Dermographism may occur (urticarial lesions resulting from light scratching).
  • The physical examination should focus on conditions that might precipitate urticaria or could be potentially life threatening.
    • Angioedema of the lips, tongue, or larynx
    • Individual urticarial lesions that are painful, long lasting (longer than 36-48 h), or are ecchymotic; also, urticarial lesions that leave residual hyperpigmentation or ecchymosis upon resolution (suggesting urticarial vasculitis)
    • The presence of systemic signs or symptoms, particularly fever, arthralgias, arthritis, weight changes, bone pain, or lymphadenopathy
    • Scleral icterus, hepatic enlargement, or tenderness that suggests hepatitis or cholestatic liver disease
    • Thyromegaly suggesting autoimmune thyroid disease; joint examination for any evidence of connective tissue disease, rheumatoid arthritis, or systemic lupus erythematosus (SLE)
    • Lungs for pneumonia or bronchospasm (asthma)
    • Skin for evidence of bacterial or fungal infection
  •   Pregnancy (ie, pruritic urticarial papules and plaques of pregnancy [PUPPP])

  Chronic urticaria can be related to all of the above as well as to the following:

  • Autoimmune disorders (SLE, rheumatoid arthritis, polymyositis, thyroid autoimmunity, and other connective tissue diseases); probably up to 50% of chronic urticaria is autoimmune
  • Cholinergic urticaria induced by emotional stress, heat, or exercise; examine for other signs of cholinergic stimulation including lacrimation, salivation, and diarrhea.

http://emedicine.medscape.com/article/1049978-clinical

Close-up view shows small urticarial wheals within

Close-up view shows small urticarial wheals within large erythematous flares.

 

  Urticaria pigmentosa is a familial dermatologic disorder characterized by hyperpigmented (yellow, tan, or brown) papules or plaques that may be associated with lymphoproliferative disorders. These lesions are composed of mast cells. When the skin overlying an individual lesion of urticaria pigmentosa is stroked, a linear wheal is formed; this characteristic and diagnostic sign is known as the Darier sign.

  Recurrent urticaria can be related to the following:

  • Sun exposure –solar urticaria, occurring only on skin exposed to the sun
  • Exercise (cholinergic urticaria)
  • Emotional or physical stress
  • Water (aquagenic urticaria)

 

References:

1. Shimauchi T, Kabashima K, Tokura Y. Solar urticaria as a manifestation of ChurgStrauss syndrome. Clin Exp Dermatol. Mar 2007;32(2):209-10. [Medline].

2. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. Sep 10 2009;4:19. [Medline].

3. Hughes R, Cusack C, Murphy GM, Kirby B. Solar urticaria successfully treated with intravenous immunoglobulin. Clin Exp Dermatol. Jun 17 2009;[Medline].

4. Maksimovic L, Fremont G, Jeanmougin M, Dubertret L, Viguier M. Solar urticaria successfully treated with intravenous immunoglobulins. Dermatology. 2009;218(3):252-4. [Medline].

5. Adamski H, Bedane C, Bonnevalle A, Thomas P, Peyron JL, Rouchouse B, et al. Solar urticaria treated with intravenous immunoglobulins. J Am Acad Dermatol. Aug 2011;65(2):336-40. [Medline].

6. Calzavara-Pinton P, Zane C, Rossi M, Sala R, Venturini M. Narrowband ultraviolet B phototherapy is a suitable treatment option for solar urticaria. J Am Acad Dermatol. May 25 2011;[Medline].

 

Pediatric Henoch-Schonlein Purpura

http://emedicine.medscape.com/article/984105-overview

 

Background

Willan and Heberden appeared to have first noted Henoch-Schoenlein (or Henoch-Schönlein) purpura (HSP) in the early 1800s. However, Schönlein first described the combination of acute purpura and arthritis in children in 1837, and Henoch reported the manifestations of abdominal pain and nephritis in 1874.

Henoch-Schoenlein purpura is an acute immunoglobulin A (IgA)–mediated leukocytoclastic vasculitis that primarily affects children. The dominant clinical features of Henoch-Schoenlein purpura include cutaneous purpura, arthritis, abdominal pain, GI bleeding, orchitis, and nephritis.

The prevalence of Henoch-Schoenlein purpura peaks in children aged 3-10 years. In the Northern hemisphere, the disease occurs mostly from November to January. The male-to-female ratio is 1.5-2:1. In one half to two thirds of children, an upper respiratory tract infection precedes the clinical onset of Henoch-Schoenlein purpura by 1-3 weeks. In general, patients with Henoch-Schoenlein purpura appear mildly ill. They often have a fever, with a temperature usually not higher than 38°C (100.4°F). Henoch-Schoenlein purpura is typically an acute, self-limited illness; however, one third of patients have one or more recurrences.

Purpuric papules and plaques of the lower extremit

Purpuric papules and plaques of the lower extremity characteristic of Henoch-Schönlein purpura.

 

Hemorrhagic macules, papules, and patches on the a

Hemorrhagic macules, papules, and patches on the ankle and foot of a child with Henoch-Schönlein purpura.

Causes

The conditions below may precede Henoch-Schoenlein purpura.

Infections include the following:

Vaccinations include the following:

  • Typhoid
  • Measles
  • Cholera
  • Yellow fever

Environmental exposure to allergens include the following:

  • Drugs (eg, ampicillin, erythromycin, penicillin, quinidine, quinine, cytarabine)
  • Foods
  • Horse serum
  • Cold exposure
  • Insect bites

Glomerulocystic kidney disease has also beeoted.

Differential Diagnoses

*       Child Abuse & Neglect: Physical Abuse

*       Endocarditis, Bacterial

*       IgA Nephropathy

*       Meningococcal Infections

*       Rheumatic Fever

*       Rocky Mountain Spotted Fever

*       Systemic Lupus Erythematosus

Consultations

Because Henoch-Schoenlein purpura is a multisystem disease, consultations with the following specialists can be helpful in diagnosis and treatment.

*       Dermatologist

*       Gastroenterologist

*       Nephrologist

*       Rheumatologist

 

Reference:

1. Prais D, Amir J, Nussinovitch M. Recurrent Henoch-Schonlein purpura in children. J Clin Rheumatol. Feb 2007;13(1):25-8. [Medline].

2. Ha TS, Lee JS. Scrotal involvement in childhood Henoch-Schonlein purpura. Acta Paediatr. Apr 2007;96(4):552-5. [Medline].

3. Ozkaya O, Bek K, Alaca N, et al. Cerebral vasculitis in a child with Henoch-Schonlein purpura and familial Mediterranean fever. Clin Rheumatol. Oct 2007;26(10):1729-32. [Medline].

4. Chan KH, Tang WY, Lo KK. Bullous lesions in Henoch-Schonlein purpura. Pediatr Dermatol. May-Jun 2007;24(3):325-6. [Medline].

5. Anil M, Aksu N, Kara OD, et al. Henoch-Schonlein purpura in children from western Turkey: a retrospective analysis of 430 cases. Turk J Pediat. 51;2009:429-36. [Medline].

6. Al Sufyani MA. Acute hemorrhagic edema of infancy: unusual scarring and review of the English language literature. Int J Dermatol. Jun 2009;6:617-22. [Medline].

7. Nikibakhsh AA, Mahmoodzadeh H, Karamyyar M, et al. Treatment of complicated henoch-schonlein purpura with mycophenolate mofetil: a retrospective case series report. Int J Rheumatol. Jun 2010;[Medline].

 

Dermatologic Manifestations of Urticarial Vasculitis 

http://emedicine.medscape.com/article/1085087-overview

http://www.dailymotion.com/video/xl9ibq_autoimmune-chronic-urticaria-urticarial-vasculitis-treatment-urticarial-vasculitis-symptoms_lifestyle#.UQ2ayvLE2H4

 

Background

Urticarial vasculitis is an eruption of erythematous wheals that clinically resemble urticaria but histologically show changes of leukocytoclastic vasculitis.[1, 2] Urticarial vasculitis may be divided into normocomplementemic and hypocomplementemic variants. Both subsets can be associated with systemic symptoms (eg, angioedema, arthralgias, abdominal or chest pain, fever, pulmonary disease, renal disease, episcleritis, uveitis, and Raynaud phenomenon). The hypocomplementemic form more often is associated with systemic symptoms and has been linked to connective-tissue disease (ie, systemic lupus erythematosus [SLE]).

Clinical Presentation

Patients with urticarial vasculitis present with an urticarial eruption, often accompanied by a painful or burning sensation. Lesions are generalized wheals or erythematous plaques, occasionally with central clearing, lasting for more than 24 hours in a fixed location (in contrast to urticaria, which resolves in minutes to hours or migrates continually). Petechiae may be noted within the lesions, and they may resolve with ecchymoses or postinflammatory hyperpigmentation. Patients may have photosensitivity, lymphadenopathy, arthralgia, angioedema (40%), fever, abdominal pain, dyspnea, and pleural and pericardial effusions.Most cases of urticarial vasculitis are idiopathic.

The primary causes of urticarial vasculitis are as follows:

  • Drug induced, such as ACE inhibitors, penicillin, sulfonamides, fluoxetine, cimetidine, diltiazem, thiazides, potassium iodide, non-steroid inflammatory drugs, and glatiramer acetate.
  • Rheumatic disease, such as SLE and Sjögren syndrome: Urticarial vasculitis has also been reported with immunoglobulin A and immunoglobulin M monoclonal gammopathies, mixed cryoglobulins, and hematologic and solid malignancies
  • Viral disease, such as hepatitis B, hepatitis C,and infectious mononucleosis

Urticarial vasculitis is divided into hypocomplementemic and normocomplementemic categories, as follows:

  • Hypocomplementemia often is associated with a systemic condition, such as SLE (in which >50% of patients have hypocomplementemia).In addition, as many as 71% of patients with hypocomplementemic urticarial vasculitis have a positive antinuclear antibody titer but do not fulfill the American Rheumatism Association criteria for SLE. Some authors have suggested evaluation of hypocomplementemic urticarial vasculitis for immunoglobulin G antibodies to C1q. Individuals with these antibodies have a higher incidence of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease.
  • Normocomplementemic vasculitis can be associated with connective-tissue disease but at a much lower rate.

Lesions of urticarial vasculitis initially appear as erythematous wheals (see image below). As the lesions progress, purpura may develop. Often, the urticarial vasculitis lesions resolve with postinflammatory pigmentation. Annular or targetoid lesions may be observed.

Raised erythematous wheals with postinflammatory h

Raised erythematous wheals with postinflammatory hyperpigmentations suggest urticarial vasculitis.

Laboratory Studies

Check CH50, C3, C4, Clq, and antibodies to Clq in urticarial vasculitis patients. If these test results are positive, evaluate renal function and urinalysis to check for the effects of vasculitis on the kidneys.

If the history suggests viral infections, obtain hepatitis B, hepatitis C, and heterophile antibody serologies.

Direct immunofluorescence may show deposition of vascular C3, fibrin, and immunoglobulins. A lupus band may be detected in patients with underlying lupus erythematosus.

If warranted, obtain antinuclear antibody and lupus serologies. Anti-SSA and anti-SSB may be seen in patients with Sjögren syndrome. Test results for antineutrophilic cytoplasmic antibodies are generally negative, and, if they are positive, the possibility of Wegener granulomatosis or microscopic polyangiitis should be considered.

Medical Care

Urticarial vasculitis tends to run a chronic course. Mortality is low, unless renal or pulmonary disease occurs. The goal of treatment is to achieve long-term control with the least amount of toxicity.

A complete patient history is the basis for treatment. In the history, ask for time of onset of the lesions; duration of the lesions (eg, >24 h); whether lesions are painful or burning, rather than pruritic; and the history of resolution with purpura or hyperpigmentation. Inquire about the patient’s medications, fever, arthralgia, dyspnea, abdominal pain, and symptoms of angioedema.

Consultations

Consultation with the following specialists may be needed:

Antihistamines

Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

 Colchicine

 

Sulfone antibiotics

Dapsone (Avlosulfon)

 

Antimalarials

Hydroxychloroquine (Plaquenil)

 

Nonsteroidal anti-inflammatory agents

 

Indomethacin (Indocin)

 

Cytotoxic agents

 

Azathioprine (Imuran)

 

Glucocorticoids

Prednisone (Deltasone)

 

References:

1. Kallenberg CG. Anti-C1q autoantibodies. Autoimmun Rev. Sep 2008;7(8):612-5. [Medline].

2. Cicek D, Kandi B, Oguz S, Cobanoglu B, Bulut S, Saral Y. An urticarial vasculitis case induced by glatiramer acetate. J Dermatolog Treat. 2008;19(5):305-7. [Medline].

3. Jara LJ, Navarro C, Medina G, Vera-Lastra O, Saavedra MA. Hypocomplementemic urticarial vasculitis syndrome. Curr Rheumatol Rep. Dec 2009;11(6):410-5. [Medline].

 4. Buck A, Christensen J, McCarty M. Hypocomplementemic urticarial vasculitis syndrome: a case report and literature review. J Clin Aesthet Dermatol. Jan 2012;5(1):36-46. [Medline].

 

 

 

 

 

 

 

 

 

 

 

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