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Skin Diseases

Paraneoplastic pemphigus without antidesmoglein 3 or antidesmoglein 1 autoantibodies

British Journal of Dermatology, Mar 1, 2001

Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous blistering disease characterized by... more Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous blistering disease characterized by IgG autoantibodies that bind to various epithelia and immunoprecipitate a complex of 250, 230, 210, 190 and 170 kDa proteins. A recent study has suggested that PNP patients have antidesmoglein (Dsg) 3 autoantibody and that the antibody plays a pathogenic role in PNP. We report a 72-year-old woman with PNP associated with thymoma and adenocarcinoma of the lung. Diagnosis of PNP was made by the characteristic clinical, histological and immunopathological findings, as well as immunoprecipitation of characteristic 230, 210 and 190 kDa proteins. Using enzyme-linked immunosorbent assay with baculovirus-expressed recombinant proteins, the patient&#39;s serum was negative against both Dsg 3 and Dsg 1. This finding is unusual, and it suggests that the target antigen, which is involved in acantholysis, may be other than Dsg 3 in this case.

Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice

Journal of Clinical Investigation, Aug 15, 1998

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association wit... more Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. Patients with PNP develop characteristic IgG autoantibodies directed against multiple antigens, most of which have been identified as cytoplasmic proteins of the plakin family (desmoplakin I, II, BPAG1, envoplakin, and periplakin). This study identified cell surface target antigens of PNP. We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus. ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1. All of 12 PNP sera tested immunoprecipitated Dsg3. Removal of anti-Dsg3 autoantibodies by immunoadsorption was sufficient to eliminate the ability of PNP sera to induce cutaneous blisters in neonatal mice in vivo. Furthermore, anti-Dsg3-specific antibodies that were affinity purified from PNP sera were proven to be pathogenic and caused blisters in neonatal mice. These findings indicate that Dsg3 and Dsg1 are the cell surface target antigens in PNP and that IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation. (

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Paraneoplastic pemphigus with cutaneous and serological features of pemphigus foliaceus

British Journal of Dermatology, Aug 1, 1999

specimens with microwave irradiation (Fig. 2b). In contrast, all of the specimens from three pati... more specimens with microwave irradiation (Fig. 2b). In contrast, all of the specimens from three patients in the negative control showed no staining (Fig. 2d). However, the specimens from the other two patients in the negative control showed discontinuous or weak linear staining, which was clearly different from those irradiated with microwave (Fig. 2c). Our study has been shown that we are able to make a diagnosis of autoimmune bullous disease using microwave irradiation. The staining intensity in the microwave-irradiated sections was comparable with that obtained by the conventional method. The incubation time in the conventional method is usually 40 min to 1 h. However, microwave irradiation required only 5 min. In addition to the staining of known antigens it may be possible that microwave irradiation would retrieve unknown antigens. The mechanism of antigen retrieval by microwave remains unclear. Microwave energy is a non-ionizing electromagnetic wave and microwave itself increases the molecular movement of dipolar molecules such as H2O. Microwaves generate heat rapidly and facilitate the formation of antigen± antibody complexes. However, if microwaves are too strong, it might cause overheating, resulting in the loss of antigenicity. Therefore, the time and strength of irradiation should be adjusted carefully. The disadvantage of this method is the dif®culty of determining the optimal staining condition. With further modi®cation, this method may be widely used for other immuno ̄uorescence stainings.

Chronic idiopathic acrocyanosis

Journal of The American Academy of Dermatology, Dec 1, 2001

Acrocyanosis is an uncommon condition characterized by symmetric coolness and violaceous discolor... more Acrocyanosis is an uncommon condition characterized by symmetric coolness and violaceous discoloration of the hands and feet. The nose, ears, lips, and nipples are also often affected. The disease is temperature dependent and generally worsens with cold exposure. Acrocyanosis is often secondary to a variety of underlying causes. We present a very interesting case of a 44-year-old woman with almost lifelong idiopathic acrocyanosis. Differential diagnoses are discussed in this article.

Evaluating the role of immunoablative high-dose cyclophosphamide therapy in pemphigus vulgaris

Journal of the American Academy of Dermatology, 2003

Basic pharmacologic approach to immunosuppressive therapy for autoimmune blistering diseases

Dermatologic Therapy, 2002

The pathophysiology of the most important bullous skin diseases, pemphigus and bullous pemphigoid... more The pathophysiology of the most important bullous skin diseases, pemphigus and bullous pemphigoid, has been carefully defined by the use of experimental animal models of the diseases. This has shown that to successfully treat pemphigus, one must reduce autoantibody production, while in contrast, bullous pemphigoid can be treated by blocking any of several steps in an inflammatory cascade. This knowledge has led to rational therapeutic approaches to both disorders. This approach can be applied to other autoimmune bullous skin diseases, with an expected increase in efficacy of therapy and decreased morbidities from immunosuppressive drugs.

Elevated Serum Levels of Interleukin-6 in Paraneoplastic Pemphigus

Journal of Investigative Dermatology, Mar 1, 1999

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Paraneoplastic pemphigus in children and adolescents

British Journal of Dermatology, Oct 1, 2002

Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease associated with specific B-... more Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease associated with specific B-cell lymphoproliferative neoplasms. There has been an increasing number of individual reports in the childhood and adolescent population. To examine the clinical and immunopathological features of PNP occurring in children and adolescents. We analysed the clinical and immunopathological findings of 14 patients under the age of 18 years with a confirmed diagnosis of PNP. Sera from all patients were analysed by indirect immunofluorescence (IF) and immunoprecipitation for plakin autoantibodies, immunoblotting for detection of plectin autoantibodies, and enzyme-linked immunosorbent assay (ELISA) for the detection of desmoglein (Dsg) 1 and Dsg3 autoantibodies. Severe oral mucositis was observed in all patients, and lichenoid cutaneous lesions in eight of 14 patients. The average age at presentation was 13 years. Striking findings included: pulmonary destruction leading to bronchiolitis obliterans in 10 patients, association with Castleman&amp;amp;amp;amp;amp;amp;#39;s disease in 12 patients, and a fatal outcome in 10 patients. The underlying neoplasm was occult in 10 patients. Histological findings include lichenoid and interface dermatitis with variable intraepithelial acantholysis. Deposition of IgG and C3 in the mouth and skin by direct IF was not found in some cases, but indirect IF detected IgG autoantibodies in all cases. Immunoprecipitation revealed IgG autoantibodies against desmoplakin I, envoplakin and periplakin in all cases, and against desmoplakin II and the 170-kDa antigen in 13 and 10 patients, respectively. Dsg3 and Dsg1 autoantibodies were present in 10 and three patients, respectively, and plectin autoantibodies in 13 patients. PNP in children and adolescents is most often a presenting sign of occult Castleman&amp;amp;amp;amp;amp;amp;#39;s disease. It presents with severe oral mucositis and cutaneous lichenoid lesions. Serum autoantibodies against plakin proteins were the most constant diagnostic markers. Pulmonary injury appears to account for the very high mortality rates observed.

Clinical phenotype and anti-desmoglein autoantibody profile in paraneoplastic pemphigus

Journal of The American Academy of Dermatology, Apr 1, 2001

Paraneoplastic pemphigus (PNP) has similar features to pemphigus vulgaris (PV), including circula... more Paraneoplastic pemphigus (PNP) has similar features to pemphigus vulgaris (PV), including circulating anti-desmoglein (Dsg) IgG as pathogenic autoantibodies. When PV is divided into mucosal dominant type and mucocutaneous type, mucosal dominant type has only anti-Dsg3 IgG, whereas the mucocutaneous type has both anti-Dsg3 and anti-Dsg1 IgG. The purpose of this study was to determine whether there is a difference in anti-Dsg autoantibody profile between mucosal dominant PNP and mucocutaneous PNP. Twenty-one patients with PNP were categorized as mucosal dominant and mucocutaneous types based on clinical information. Antibody titers against Dsg3 and Dsg1 were measured by enzyme-linked immunosorbent assay by means of recombinant Dsg1 and Dsg3. There were 9 cases of mucosal dominant type and 12 cases of mucocutaneous type. Eight of 9 cases of mucosal dominant type were positive for anti-Dsg3 IgG, but 3 of them were also positive for anti-Dsg1 IgG. All 12 cases of mucocutaneous type were positive for anti-Dsg3 IgG, whereas only 6 of them were positive for anti-Dsg1 IgG. There was no clear association between the clinical phenotype and anti-Dsg antibody profile in PNP as seen in PV. This finding suggests that besides anti-Dsg IgG other pathologic mechanisms such as lichenoid reaction or interface dermatitis may be involved in the blister formation in PNP.

Bullous Pemphigoid Treated With Leflunomide

Archives of Dermatology, Oct 1, 2000

CASE 1 A 70-year-old white woman presented with an 8-month history of worsening pruritus of the t... more CASE 1 A 70-year-old white woman presented with an 8-month history of worsening pruritus of the trunk and extremities, urticarial plaques on the trunk, and a few erythematousbased vesicobullous lesions on the lower extremities. She had a history of severe osteoporosis that was complicated by several vertebral fractures and incapacitating scoliosis. Her medications included pamidronate, calcitonin, calcium, and vitamin D. Histologic examination of the urticarial and bullous lesions showed a subepidermal blister with an intense eosinophilic infiltrate. Immunopathologic studies of the skin and serum samples confirmed the diagnosis of bullous pemphigoid. Prednisone therapy (30 mg/d [0.75 mg/kg per day]) was initiated. Complete resolution of the lesions and pruritus was achieved within 4 weeks, and the dosage of prednisone was tapered to 20 mg/d. A further tapering of the dosage of prednisone, to 15 mg/d, was associated with a significant flare of the disease. The dosage of prednisone was subsequently again increased to 20 mg/d, which was associated with a reinduction of complete remission. Several attempts at slowly tapering the prednisone dosage to less than 20 mg/d were unsuccessful in keeping the disease in remission. The patient refused to take steroid-sparing agents, eg, azathioprine, mycophenolate mofetil, and dapsone. Leflunomide therapy (20 mg/d) was initiated, and within 5 weeks, the dosage of prednisone was again slowly tapered to 15 mg/d. The prednisone therapy was continuously tapered and then discontinued 6 weeks later, and the dosage of leflunomide was decreased to 10 mg/d. Eight months after the patient began taking leflunomide, she remained in clinical remission on a regimen of 10 mg every other day. This regimen has been well tolerated, and the monthly complete blood cell counts and liver enzyme levels have remained normal. CASE 2 A 60-year-old white man presented with a pruritic bullous eruption of the extremities. His medical history was remarkable for coronary artery disease, hypertension, and chronic obstructive pulmonary disease. His medications included aspirin, enalapril, and diltiazem. Histologic examination of the urticarial and bullous lesions revealed a subepidermal blister with an intense eosinophilic infiltrate. Immunopathologic studies of the skin and serum samples confirmed the diagnosis of bullous pemphigoid. Prednisone therapy (40 mg/d [0.5 mg/kg per day]) was initiated, and complete resolution of the lesions was observed within 5 weeks. The dosage of prednisone was slowly tapered to 15 mg over a period of 8 weeks. However, the cutaneous eruption subsequently recurred. Rapid clinical remission was achieved when the dosage of prednisone was again increased to 20 mg/d. Treatment with antiinflammatory drugs, such as tetracycline, niacinamide, dapsone, and methrotrexate, was unsuccessful. The patient refused to take azathioprine and mycophenolate mofetil. Leflunomide (20 mg/d) was added to the regimen. The addition of leflunomide allowed the discontinuation of prednisone therapy 12 weeks later. Six months after discontinuing prednisone therapy, the patient remained in clinical remission on a 10-mg/d regimen of leflunomide. This regimen has been well tolerated, and the monthly complete blood cell counts and liver enzyme levels have remained within normal limits. THERAPEUTIC CHALLENGE Herein, we report the use of leflunomide as an adjuvant immunomodulatory agent in 2 patients with bullous pemphigoid in whom other treatment failed and who refused standard corticosteroid-sparing therapy. The age and medical history of these 2 patients precluded the use of prolonged corticosteroid therapy; therefore, they required new therapeutic alternatives. The immunosuppressive 1 and anti-inflammatory effects 2 of leflunomide, as well as its favorable safety profile, make this drug a very attractive agent in the management of bullous pemphigoid, an autoimmune skin blistering disease in which autoantibodies, complement, and polymorphonuclear blood cells play a pivotal pathogenetic role. 3

Clinical, Demographic, and Immunohistologic Features of Vancomycin-Induced Linear IgA Bullous Disease of the Skin Report of 2 Cases and Review of the Literature

Medicine, 1999

Administration of intravenous vancomycin has been associated with the development of linear IgA b... more Administration of intravenous vancomycin has been associated with the development of linear IgA bullous disease (LABD). In contrast to the idiopathic variant, vancomycin-induced LABD (VILABD) appears to be more transient and to be associated with lower morbidity. The characteristics of this entity remain undefined. Our analysis of clinical, demographic, and immunopathologic features of 2 new and 14 previously reported patients with VILABD reveals that VILABD is clinically and immunopathologically indistinguishable from its idiopathic variant. A variety of premorbid conditions and concomitant medications were observed, none of which was consistently associated with the development of VILABD. VILABD occurs independently of vancomycin trough levels, resolves promptly upon discontinuation of vancomycin, and recurs more severely and with shorter onset latency with vancomycin rechallenge. This entity should be recognized as 1 of the adverse cutaneous effects of intravenous vancomycin, and warrants prompt diagnosis through direct immunofluorescence skin examination.

Mycophenolate mofetil in autoimmune and inflammatory skin disorders

Journal of The American Academy of Dermatology, Feb 1, 1999

Mycophenolate mofetil (MMF) has been widely used as an immunosuppressant in organ transplantation... more Mycophenolate mofetil (MMF) has been widely used as an immunosuppressant in organ transplantation. MMF has recently been added to therapeutic regimens for skin disorders. Expanding the use of MMF in dermatology, we describe additional patients with autoimmune and inflammatory skin diseases, including 4 cases of pemphigus vulgaris, 1 case of pemphigus foliaceus, 1 case of perineal and metastatic cutaneous Crohn&#39;s disease, 1 case of bullous pemphigoid and psoriasis, and 1 case of psoriasis. Most of these patients had refractory disease or had developed significant side effects to conventional therapy, including azathioprine, methotrexate, prednisone, cyclosporine, acitretin, PUVA, UVB, and tacrolimus. MMF was effective and well tolerated in all these patients. The dosages of MMF ranged from 500 mg twice daily (for psoriasis and Crohn&#39;s disease) to 1250mg twice daily (for 3 of 4 patients with pemphigus vulgaris). MMF is an effective and relatively safe immunosuppressant in autoimmune and inflammatory skin diseases.

Severe nonendemic pemphigus foliaceus presenting in the postpartum period

Journal of The American Academy of Dermatology, May 1, 1999

The new onset of pemphigus in the postpartum period is exceedingly rare with only 1 case previous... more The new onset of pemphigus in the postpartum period is exceedingly rare with only 1 case previously reported in the literature. We describe a 31-year-old woman who developed extensive denudation of her skin shortly after delivering her second child. Histologic examination, immunofluorescence testing, and immunoprecipitation with desmoglein 1 confirmed the diagnosis of pemphigus foliaceus. The patient responded to treatment with prednisone, cyclophosphamide, and plasmapheresis. The effect of the postpartum period on the onset and exacerbation of immune-mediated bullous diseases is discussed.

Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain

Journal of Immunology, Nov 15, 1993

Molecular mapping of a pathogenically relevant BP180 epitope associated with experimentally induc... more

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$Research paper thumbnail of A Patient with a Refractory Cutaneous Bullous Eruption$

A Patient with a Refractory Cutaneous Bullous Eruption

Journal of Cutaneous Medicine and Surgery, 1999

A7o-year-old Caucasian woman was admitted to the Johns Hopkins Hospital for management of cutaneo... more A7o-year-old Caucasian woman was admitted to the Johns Hopkins Hospital for management of cutaneous blisters, septicemia, and uncontrolled diabetes. Five months prior to admission, she developed a pruritic vesicular skin eruption involving the neck, trunk, and proximal extremities.Skin biopsy at an outside institution had shown an intraepidermal blister with moderate intraepidermal neutrophilic infiltration, and direct immunofluorescence had revealed deposition of IgA in the epidermal intercellular space (Fig. 1). Given the findings of neutrophils and IgA in her skin biopsy samples, she was treated with dapsone at doses up to 150 mg per day. Because her condition continued to progress, dapsone was discontinued, and she was placed on prednisone, 80 mg per day, and azathioprine 300 mg per day, during the 3 months prior to admission. Despite this regimen, the disease remained poorly-controlled. Moreover, the high-dose corticosteroids resulted in exacerbation of her diabetes. Her past medical history was significant for oxygendependent chronic obstructive pulmonary disease, insulinrequiring diabetes mellitus, and peptic ulcer disease. Medications included prednisone, 80 mg per day, azathioprine, 300 mg per day, hydroxyzine, omeprazole, insulin, zafirkalust, bronchodilators, and beclomethasone inhaler. On admission, the patient had a temperature of 38°C. Cutaneous examination revealed numerous Nikolskypositivevesicles and bullae on the head, neck, trunk (Fig. 2), and proximal extremities. Palmoplantar and mucosal surfaces were spared. Laboratory studies were significant for a blood glucose concentration of 300 mg/dL, leukocytosis of 12,100/mm3 with no left shift. Urine and blood cultures yielded Escherichia coli. Serum protein immunoelectrophoresis failed to reveal paraproteinemia. Indirect

Mycophenolate mofetil in autoimmune and inflammatory skin disorders

Journal of the American Academy of Dermatology, 1999

Mycophenolate mofetil (MMF) has been widely used as an immunosuppressant in organ transplantation... more Mycophenolate mofetil (MMF) has been widely used as an immunosuppressant in organ transplantation. MMF has recently been added to therapeutic regimens for skin disorders. Expanding the use of MMF in dermatology, we describe additional patients with autoimmune and inflammatory skin diseases, including 4 cases of pemphigus vulgaris, 1 case of pemphigus foliaceus, 1 case of perineal and metastatic cutaneous Crohn&#39;s disease, 1 case of bullous pemphigoid and psoriasis, and 1 case of psoriasis. Most of these patients had refractory disease or had developed significant side effects to conventional therapy, including azathioprine, methotrexate, prednisone, cyclosporine, acitretin, PUVA, UVB, and tacrolimus. MMF was effective and well tolerated in all these patients. The dosages of MMF ranged from 500 mg twice daily (for psoriasis and Crohn&#39;s disease) to 1250mg twice daily (for 3 of 4 patients with pemphigus vulgaris). MMF is an effective and relatively safe immunosuppressant in autoimmune and inflammatory skin diseases.

Differences and similarities among expert opinions on the diagnosis and treatment of pemphigus vulgaris

Journal of the American Academy of Dermatology, 2003

As a result of a lack of large-scale controlled studies, the diagnosis and management of pemphigu... more As a result of a lack of large-scale controlled studies, the diagnosis and management of pemphigus vulgaris (PV) has been solely on the basis of expert opinion, rather than on empirical evidence. We have completed a survey of worldwide experts on the diagnostic and therapeutic approaches to PV. We conducted a telephone-based survey of 24 physicians from academic, tertiary care centers worldwide with an average of 20 years experience treating pemphigus. Survey questions included referral patterns, diagnostic techniques, and therapeutic regimens. Of those surveyed, 50% receive referrals within 6 months after onset of symptoms, 17% within 1 year, and 8% within 3 years. Diagnosis is secured by 96% using skin biopsy specimen with direct immunofluorescence, and by indirect immunofluorescence alone for 4%. None of the participating physicians make the diagnosis of PV solely on clinical and histologic evidence. Of the physicians, 75% initially treat with prednisone and 25% use other agents or attempt to eliminate potential triggers. The physicians who initially used noncorticosteroid drugs did so with no relation to the nature or extent of the disease. Of those surveyed, 50% use prednisone doses of 1 mg/kg/d, 31% use 1 to 1.5 mg/kg/d, and 19% use 1.5 to 3 mg/kg/d. Azathioprine is used as an adjuvant by 44%, mycophenolate mofetil by 20%, cyclophosphamide by 16%, and methotrexate by 8%. Complete discontinuation of prednisone was the goal for 37% whereas others were satisfied with doses from 2.5 to 10 mg/d. Wide variation exists in diagnostic techniques and treatment of PV, even among the world&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s experts. The lag time from symptom onset to referral emphasizes the need for heightened awareness. There is clearly a need for consensus standards with regard to patient stratification and randomized controlled trials.

Severe nonendemic pemphigus foliaceus presenting in the postpartum period

Journal of the American Academy of Dermatology, 1999

The new onset of pemphigus in the postpartum period is exceedingly rare with only 1 case previous... more The new onset of pemphigus in the postpartum period is exceedingly rare with only 1 case previously reported in the literature. We describe a 31-year-old woman who developed extensive denudation of her skin shortly after delivering her second child. Histologic examination, immunofluorescence testing, and immunoprecipitation with desmoglein 1 confirmed the diagnosis of pemphigus foliaceus. The patient responded to treatment with prednisone, cyclophosphamide, and plasmapheresis. The effect of the postpartum period on the onset and exacerbation of immune-mediated bullous diseases is discussed.

Chronic idiopathic acrocyanosis

Journal of the American Academy of Dermatology, 2001

Acrocyanosis is an uncommon condition characterized by symmetric coolness and violaceous discolor... more Acrocyanosis is an uncommon condition characterized by symmetric coolness and violaceous discoloration of the hands and feet. The nose, ears, lips, and nipples are also often affected. The disease is temperature dependent and generally worsens with cold exposure. Acrocyanosis is often secondary to a variety of underlying causes. We present a very interesting case of a 44-year-old woman with almost lifelong idiopathic acrocyanosis. Differential diagnoses are discussed in this article.

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