Rituximab as a dual therapeutic option for pemphigus and primary cutaneous B‐cell lymphomas: Two case reports

It is known that individuals with immune dysregulation have an increased risk of non‐Hodgkin lymphoma. This association has been proven for pemphigus as well as for other autoimmune disease. We describe the development of cutaneous B‐cell lymphoma in two patients affected by long‐standing pemphigus vulgaris and pemphigus foliaceus (i.e., characterized by histological and immunopathological features different from those of paraneoplastic pemphigus). In both cases, a therapy with rituximab allowed to achieve the complete remission for the lymphoproliferative disease (never recurred at follow up) and a substantial long‐term improvement of the clinical manifestations of pemphigus, although persistent to serological disease and occasional recurrences. We suggest that clinicians should consider that patients with long‐standing pemphigus, both vulgaris and foliaceus, may develop primary cutaneous B‐cell lymphomas, as shown in our report, and in these cases the treatment with rituximab is elective, providing a therapeutic option for both low‐grade or follicular, CD20‐positive, B‐cell non‐Hodgkin lymphomas and pemphigus. Nevertheless, as shown in our cases, a constant surveillance for pemphigus is necessary.     

Fatal outcome due to bacterial superinfection of eczema herpeticum in a patient with mycosis fungoides

Kaposi varicelliform eruption or eczema herpeticum is well known to be associated with several chronic dermatoses, including atopic dermatitis, foliaceus pemphigus, seborrheic dermatitis, Darier disease, and congenital ichthyosiform erythroderma. Although less frequently, it has also been described in cases of mycosis fungoides and Sèzary syndrome. We would like to report an extremely rare case of a woman with a T-cell cutaneous lymphoma who developed disseminated cutaneous herpes simplex with S. aureus sepsis and a fatal outcome.     

Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins

BACKGROUND: Pemphigus is a life-threatening autoimmune blistering disease usually treated with high-dose corticosteroids and other immunosuppressants. However, this regimen may prove inadequate in severe cases and cause dangerous side-effects. While protein A immunoadsorption (PAIA) induces a rapid remission in severe pemphigus, the disease usually recurs once the treatment is stopped. In contrast, anti-CD20 antibody rituximab has a delayed onset of action but may lead to a long-term remission of pemphigus. OBJECTIVE: To develop a treatment protocol combining the rapid remission induced by PAIA with the positive long-term effects of rituximab. PATIENTS AND METHODS: Five patients with pemphigus vulgaris and two patients with pemphigus foliaceus were treated with a combination of PAIA, rituximab and conventional immunosuppressants. Patients who failed to respond to this therapy subsequently received intravenous immunoglobulins (IVIg). RESULTS: All seven patients showed a sharp decline of circulating autoantibody levels and rapid improvement of cutaneous and mucosal lesions within 4 weeks of therapy. Long-term remission was induced in three patients and one further patient showed a partial improvement of his disease. The three remaining patients who could not be weaned off PAIA and remained resistant to rituximab treatment showed a good response to IVIg therapy. CONCLUSION: The combination of PAIA and rituximab induces a rapid and durable remission in a subset of patients with severe pemphigus. IVIg therapy appears to be a good treatment option for rituximab nonresponders.     

A subset of pemphigus foliaceus patients exhibits pathogenic autoantibodies against both desmoglein-1 and desmoglein-3

In pemphigus vulgaris the major pathogenic antibody binds desmoglein-3, and mediates mucosal disease. Development of cutaneous disease is associated with acquisition of antibodies to desmoglein-1. In pemphigus foliaceus, and its endemic form, fogo selvagem by contrast, the major pathogenic antibody recognizes desmoglein-1 and mediates cutaneous disease only. In this study, we sought to determine the prevalence of antibodies to desmoglein-3 in patients with pemphigus foliaceus and fogo selvagem. We produced recombinant desmoglein-1 and desmoglein-3, and used them in highly sensitive and specific enzyme-linked immunosorbent assays, as well as immunoprecipitation assays. We detected antibodies to desmoglein-3 in 19 of 276 patients with pemphigus foliaceus and fogo selvagem, who had cutaneous disease only. We showed that these antibodies to desmoglein-3 could be absorbed in a concentration-dependent manner by desmoglein-3 but not by desmoglein-1. Also antibodies to desmoglein-1 could be absorbed in a concentration-dependent manner by desmoglein-1 but not desmoglein-3. This suggests that two separate species of antibody are present rather than one antibody capable of cross-reacting with both desmoglein-1 and desmoglein-3. Finally, it was shown that affinity-purified antibodies to desmoglein-3 from patients with pemphigus foliaceus and fogo selvagem induced a pemphigus vulgaris-like skin disease in mice by passive transfer. These results suggest that a subset of patients with pemphigus foliaceus and fogo selvagem have antibodies to desmoglein-3 that may be involved in the pathogenesis of their cutaneous disease.     

Therapy of paraneoplastic pemphigus with Rituximab: a case report and review of literature

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease with poor prognosis when associated with malignant neoplasm. We report the case of a patient with PNP associated with a CD20+ non-Hodgkin follicular lymphoma who was treated with Rituximab plus corticosteroids and short courses of cyclosporin. One and a half years after Rituximab therapy, oral ulcerations had cleared and oral methylprednisolone was slowly tapered down without further recurrences. In the course of the disease, the patient developed sepsis due to Listeria monocytogenes and viral infections by human herpes virus 1 and 3. At the end-stage of the disease she developed a cutaneous infection from Mycobacterium chelonae. The patient died 2 years and 7 months after the onset of PNP. Rituximab may be useful for PNP therapy, but further studies are necessary to confirm this hypothesis.     

Generalized erythrodermic pemphigus foliaceus in a child and its successful response to rituximab treatment

Pemphigus foliaceus is an autoimmune disease that clinically manifests with cutaneous blisters of the superficial skin. The nonendemic or sporadic form of this entity is rare in children and typically presents with a milder, more localized rash that usually follows a benign course of short duration. We describe an affected patient atypical in both her young age and the severity of skin findings. Our patient presented with a full body exfoliative erythroderma at 21 months of age. After an extensive work-up to determine the etiology of her exfoliative erythroderma, direct and indirect immunofluorescence studies confirmed the diagnosis of pemphigus foliaceus. Rituximab therapy was initiated based on the patient's refractory disease course to multiple immunosuppressive agents. Rituximab is a therapeutic monoclonal antibody targeting CD20, an integral membrane protein highly expressed on the surface of pre-B lymphocytes and activated mature B lymphocytes. The patient's skin exhibited marked clinical improvement after the start of rituximab infusions over 12 weeks. Her initial desmoglein 1 antibody level was greater than 1:1280, which decreased to 1:16 after seven rituximab treatments. She has had no skin flares since initiating treatment with rituximab therapy. Based on this clinical and serologic response, the use of rituximab may be helpful in the treatment of pediatric pemphigus foliaceus refractory to mainstays of therapy.     

Pemphigus foliaceus developing after metastasis of cutaneous squamous cell carcinoma to regional lymph nodes

We describe a patient in whom pemphigus foliaceus developed after cutaneous squamous cell carcinoma (SCC) metastasized to regional lymph nodes. Immunologic analysis revealed that production of anti-desmoglein 1 autoantibodies started when SCC metastasized, and the SCC expressed desmoglein 1, suggesting a pathogenic role of metastasized SCC in developing pemphigus foliaceus.     

Disseminated superficial porokeratosis and immunosuppression

We present a patient who developed skin lesions typical of disseminated superficial porokeratosis (DSP) while on immunosuppressive therapy for pemphigus foliaceus. Phototesting with artificial light sources did not have any effect on the DSP lesions. The literature describing occurrence of DSP on immunosuppression is reviewed and possible pathogenetic mechanisms are discussed.     

Pemphigus foliaceus induced by radiotherapy and responsive to dapsone

Pemphigus foliaceus induced by ionizing radiation therapy is a rare condition. We describe the case of a 70-year-old female who developed pemphigus foliaceus after X-ray treatment for an adenocarcinoma of the left breast. The eruption started at the portal of irradiation and only subsequently spread to other cutaneous areas. Mucosal membranes were not affected. Skin lesions were completely responsive to dapsone therapy.     

天疱疮或大疱性类天疱疮合并单纯疱疹病毒感染8例临床特征及治疗分析

目的回顾分析天疱疮/大疱性类天疱疮(BP)合并单纯疱疹病毒(HSV)感染的临床特征及治疗方法。方法回顾分析2016—2021年在武汉市第一医院住院治疗的天疱疮/BP合并HSV感染病例的临床特征及治疗和随访情况。结果 8例天疱疮/BP合并HSV感染患者中, 男2例, 女6例, 年龄(50.6 ± 8.3)岁, 包括5例寻常型天疱疮, 1例落叶型天疱疮, 2例BP。7例合并HSV-1感染, 1例合并HSV-2感染。8例均因天疱疮或BP接受系统糖皮质激素及免疫抑制剂治疗, 并对治疗抵抗入院, 其中7例表现为原发病灶加重或复发, 1例表现为全身皮损增加。HSV感染位于躯干4例, 口腔4例, 头皮3例, 面部2例。皮疹表现为不规则的糜烂面, 伴血痂, 部分为中央有脐凹的脓疱, 7例伴有皮疹处明显疼痛。发生HSV感染时, 6例天疱疮患者抗Dsg1抗体均下降, 5例寻常型天疱疮中4例抗Dsg3抗体下降;2例BP患者中1例抗BP180抗体降低, 1例升高。予足量足疗程抗病毒治疗(伐昔洛韦或更昔洛韦治疗7 ～ 14 d), 所有患者HSV感染均被控制, 自身免疫性大疱性皮肤病严重程度评分较抗病毒治疗前均...     

Fogo selvagem: endemic pemphigus foliaceus

Fogo selvagem or endemic pemphigus foliaceus is an autoimmune acantholytic anti-cadherin bullous disease that primarily affects seborrheic areas, which might disseminate. Brazil has the world’s largest number of patients, mainly in the Central-West region, but the disease has also been reported in other South American countries. It affects young people and adults who have been exposed to rural areas, with occurrence of familial cases. Anti-desmoglein-1 autoantibodies are directed against desmosomal structures, with loss of adhesion of the upper layers of the epidermis, causing superficial blisters. The etiology is multifactorial and includes genetic, immune, and environmental factors, highlighting hematophagous insect bites; drug-related factors are occasionally involved. Flaccid blisters readily rupture to yield erosive-crusty lesions that sometimes resemble seborrheic dermatitis, actinic keratosis, and chronic cutaneous lupus erythematosus. The clinical presentation varies from localized to disseminated lesions. Clinical suspicion should be confirmed with histopathological and immunofluorescence tests, among others. The progression is usually chronic, and therapy varies according to clinical presentation, but generally requires systemic corticosteroid therapy associated with adjuvant immunosuppressive treatment to decrease the adverse effects of corticosteroids. Once the disease is under control, many patients remain stable on low-dose medication, and a significant proportion achieve remission.     

Pemphigus foliaceus—successful treatment with adjuvant gold therapy

We report a patient with pemphigus foliaceus who responded to adjuvant treatment with sodium aurothiomalate (myocrisin) within 3 months of commencement of therapy. This case serves as a reminder that gold is useful as a steroid-sparing agent in the treatment of pemphigus.     

Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus

Pemphigus is an autoimmune blistering disease characterized by circulating autoantibodies directed against the keratinocyte cell surface. The two variants, pemphigus foliaceus and pemphigus vulgaris, can be distinguished at the molecular level by immunochemical studies. The large majority of patients with pemphigus develop the disease spontaneously; however, there is a small group of patients who develop pemphigus after treatment with certain medications, of which penicillamine and captopril are the best documented. Most patients with drug-induced pemphigus have circulating and/or tissue bound epidermal cell surface autoantibodies; however, the molecular specificity of these autoantibodies has not been studied. We performed immunoprecipitation studies utilizing extracts of 125I-labeled suction blister epidermis and the sera of three patients with drug-induced pemphigus foliaceus (two due to penicillamine and one due to captopril) and one patient with captopril-induced pemphigus vulgaris. We found that the three patients with drug-induced pemphigus foliaceus had circulating autoantibodies that are directed against the pemphigus foliaceus antigen complex and that the one patient with drug-induced pemphigus vulgaris had circulating autoantibodies that are directed against the pemphigus vulgaris antigen complex. This study demonstrates that autoantibodies from drug-induced pemphigus patients have the same antigenic specificity, on a molecular level, as do autoantibodies from other pemphigus patients.     

Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil

BACKGROUND: Mycophenolate mofetil is increasingly being used as a corticosteroid-sparing agent in immunosuppressive regimens. OBJECTIVE: To elucidate the effectiveness of mycophenolate as adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. DESIGN: Historical prospective study. SETTING: University hospital. PATIENTS: The study included 42 consecutive patients with pemphigus (31 with pemphigus vulgaris and 11 with pemphigus foliaceus) who had relapses during prednisone taper or had clinically significant adverse effects from previous drug therapy. RESULTS: Remission was achieved in 22 (71%) and 5 (45%) of patients with pemphigus vulgaris and pemphigus foliaceus, respectively. Partial remission was achieved in 1 (3%) and 4 (36%), respectively. The median time to achieve complete remission was 9 months (range, 1-13 months). The treatment was administered for a median of 22 months, and the median follow-up period was 22 months. Seventy-seven percent of patients had no adverse effect. Two patients had side effects severe enough to necessitate discontinuation of treatment, one because of symptomatic but reversible neutropenia and the other because of nausea. CONCLUSION: Mycophenolate is an effective and safe adjuvant in the treatment of both pemphigus vulgaris and pemphigus foliaceus.     

Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma

Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality. We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.     

Prognostic factors for life expectancy in nonagenarians with nonmelanoma skin cancer: implications for selecting surgical candidates

BACKGROUND: Pemphigus foliaceus is a cutaneous, autoimmune, blistering disease comprising two major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of pemphigus foliaceus is generally a disease of the middle-aged and elderly. Objective and methods: Because the sporadic form of pemphigus foliaceus rarely affects children, information specific to this unique group is lacking. We describe a 3-year-old boy with the disease and retrospectively review data from 28 past cases. RESULTS: In comparison to pediatric cases of pemphigus vulgaris, sporadic pemphigus foliaceus in children tends to follow a generally benign course of relatively short duration. However, long-term outcome studies are lacking. A pattern of skin lesions described as "arcuate," "circinate," or "polycyclic" appears to be a unique and specific presentation of this disease in children. Occasionally, as in our case, the diagnosis may prove difficult to establish by using routine histology or immunopathology. CONCLUSION: The commercial availability of antigen-specific techniques such as enzyme-linked immunosorbent assay for serum desmoglein 1 autoantibody should eliminate delay in diagnosis. Hydroxychloroquine may be another treatment option for those children with photodistributed lesions. Further experience and long-term outcome studies in children are needed to determine whether some medication side effects may outweigh the risks from the disease itself.     

Five Japanese cases of antidesmoglein 1 antibody-positive and antidesmoglein 3 antibody-negative pemphigus with oral lesions

Background Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the ‘desmoglein (Dsg) compensation theory’. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti‐Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti‐Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus. Objectives We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme‐linked immunosorbent assay. Methods To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation‐immunoblotting analysis using five Dsg1/Dsg2 domain‐swapped molecules. Results The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus. Conclusions These results indicate that antigenic diversity of anti‐Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms.     

Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer

Brazilian pemphigus foliaceus (fogo selvagem) is a cutaneous blistering disease endemic to certain areas of South America that has distinctive epidemiologic features suggestive of an infectious disease transmitted by an insect vector. Patients with the disease have antiepithelial autoantibodies, both circulating in the serum and bound to lesional epidermis. In order to examine the possible pathogenic role of these autoantibodies, IgG from the sera of these patients was purified and injected into the peritoneum of neonatal BALB/c mice. Thirty-four of 46 mice (74%) receiving parenteral IgG fractions from these patients developed cutaneous lesions that were identical to the human disease by clinical, histologic, immunologic, and ultrastructural criteria. High-titer Brazilian pemphigus foliaceus sera produced lesions more consistently and rapidly than low-titer sera. When injections were discontinued, new lesions ceased to appear and old lesions resolved. The extent of disease correlated with the titer of human antiepithelial antibodies detected in the mouse serum (z less than 0.01). Similar concentrations of IgG fractions obtained from sera of unaffected Brazilians living in endemic areas and from American donors did not induce disease when injected into littermates. These results establish that the antiepithelial autoantibodies play an important role in the pathogenesis of the cutaneous lesions in Brazilian pemphigus foliaceus.     

Coexistence of pemphigus foliaceus and mycosis fungoides

Mycosis fungoides was documented in a patient two years after pemphigus foliaceus had been diagnosed and treated with corticosteroids. Eight years later, the patient was found to have stage IV lymphomatous disease with generalized erythroderma and palpable, histologically positive lymph nodes. Hematoxylin-eosin staining of a specimen of erythroderma revealed mycosis fungoides, while direct immunofluorescence of this tissue revealed intercellular IgG deposits diagnostic of pemphigus foliaceus.     

High-titer interferon-α antibodies in a patient with pemphigus foliaceus

Abstract Among 13 patients with pemphigus or bullous pemphigoid, high titers of anti-interferon-α (IFN-α) antibodies were present in all serum samples of one patient suffering from pemphigus foliaceus. This patient was characterized by a relatively benign course of the disease. The IFN antibodies were of oligoclonal or polyclonal origin, predominantly of the IgG subtype, and displayed a broad spectrum of specificity including various natural and recombinant IFN-α subtypes as well as recombinant IFN-ωl. In vitro, these antibodies neutralized both the antiviral and antiproliferative activities of the respective IFN types. Recognition of the patient's endogenous IFN-α demonstrated their autoantibody nature. The IFN antibodies were present at diagnosis and resistant to continued immunosuppressive treatment. Despite clinical remission, the IFN antibodies persisted, suggesting that they were not pathogenically related to the skin manifestations of the pemphigus. There were no signs of immune complex-mediated organ damage. IFN antibodies constitute a new class of autoantibodies that may occur in conjunction with pemphigus and likely interfere with the endogenous IFN system.