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Paraneoplastic pemphigus

Paraneoplastic pemphigus
Author:
Grant J Anhalt, MD
Section Editor:
John J Zone, MD
Deputy Editor:
Abena O Ofori, MD
Literature review current through: Jan 2024.
This topic last updated: Mar 16, 2023.

INTRODUCTION — Paraneoplastic pemphigus (PNP) is an often fatal paraneoplastic mucocutaneous blistering disease that is most commonly induced by lymphoproliferative disorders [1]. Paraneoplastic autoimmune multiorgan syndrome (PAMS) is an alternative term used to refer to PNP. This latter term reflects the inclusion of the nonbullous cutaneous eruptions and pulmonary involvement that may develop in the setting of PNP [2].

The pathogenesis, clinical features, and treatment of PNP will be discussed here. Pemphigus vulgaris and pemphigus foliaceus are reviewed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Fogo selvagem (Brazilian endemic pemphigus foliaceus)".)

EPIDEMIOLOGY — Although it is well-accepted that PNP is a rare disorder, the incidence and prevalence of PNP are unknown. The rarity of the disorder is supported by a review of 100,000 adverse events reports to the US Food and Drug Administration from patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia [3]. The review identified only 12 patients who likely had the disease.

Adults between the ages of 45 and 70 years constitute the most common demographic affected by PNP [4]. However, the disorder may also occur in children [5-7]. Both males and females may be affected.

The frequency of PNP may be decreasing. In one academic medical center in the United States, the number of patients diagnosed with PNP fell from 22 between 2003 and 2010 to only 4 between 2011 and 2017 [8]. Increased use of anti-CD20 monoclonal antibody therapy (eg, rituximab) for non-Hodgkin lymphoma and chronic lymphocytic leukemia may be a contributor. Theories include reduced recognition of PNP due to treatment-related alterations in the clinical presentation of PNP (suppression of B cell-mediated blistering) and a true reduction in incidence of PNP related to the early institution of effective treatment for malignancies responsive to this treatment [8].

ETIOLOGY — PNP occurs in association with a variety of neoplastic disorders [9,10]. In a review of 163 cases of PNP reported between 1990 and 2003, the frequency of associated conditions was as follows [9]:

Non-Hodgkin lymphoma (39 percent)

Chronic lymphocytic leukemia (18 percent)

Castleman's disease (18 percent)

Carcinoma (9 percent)

Thymoma (6 percent)

Sarcoma (6 percent)

Waldenström's macroglobulinemia (1 percent)

Hodgkin lymphoma, monoclonal gammopathy, and melanoma (each <1 percent)

As illustrated in this study, lymphoproliferative diseases account for the vast majority of disorders associated with PNP. The sarcomas detected in patients with PNP include liposarcoma, leiomyosarcoma, reticulum cell sarcoma, and malignant nerve sheath tumors [9]. Rare patients have tumors that are too poorly differentiated to define; these tumors are usually retroperitoneal and often have the characteristics of follicular dendritic cell sarcomas [11].

The distribution of PNP-associated neoplastic disorders may differ between children and the general population of patients with PNP. Castleman's disease is likely the most common associated disease in children. In a series of 14 children and adolescents with PNP, Castleman's disease was present in 12 patients (86 percent) [5].

The time course for the development of PNP in relation to the underlying neoplastic disorder varies. In two-thirds of patients, the discovery of the neoplastic disorder precedes PNP [12]. In our experience, the peak time for the development of PNP in patients with non-Hodgkin lymphoma is two to three years after diagnosis of the lymphoma. Although as many as 40 years have elapsed between Castleman's disease and the subsequent development of PNP, an interval of this length is highly unusual [9]. Occasionally, the underlying neoplastic disorder is not identified prior to the death of the patient. In a series of 104 patients with clinical and immunologic findings consistent with PNP, 12 patients had no detectable tumor [10].

Immune checkpoint inhibitor therapy has been proposed as a contributory factor based upon case reports describing the development or exacerbation of PNP during pembrolizumab therapy for malignancy [13,14]. However, an association has not been confirmed. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

PATHOGENESIS — Several theories on the connection between neoplasms and PNP have been proposed. In general, it appears that the neoplastic process induces an autoimmune disorder in which both humoral and cell-mediated immune responses play significant roles [2,15]. In an individual patient, the degree to which each type of immune response contributes to PNP may influence the clinical presentation of the disease.

Humoral immunity — Antibodies against multiple epithelial antigens have been detected in PNP. The primary antigenic targets are desmoplakins, intracellular proteins that play an integral role in the anchoring of intermediate filaments to desmosomal plaques and in epidermal cell adhesion [16]. The detection of antibodies against two desmoplakins (periplakin and envoplakin) are the most specific laboratory findings in PNP [17,18]. (See 'Other studies' below.)

Serum from affected patients can also contain antibodies against desmoplakin I, desmoplakin II, epiplakin, bullous pemphigoid antigen 1, plectin, and the protease inhibitor alpha-2-macroglobulin-like-1 (A2ML1) [19,20]. Antibodies against desmoglein 3, a desmosomal protein targeted in pemphigus vulgaris, have also been identified in patients with PNP [21]. In addition, rare cases of PNP in which antibodies against laminin 332 were detected in patients with follicular dendritic cell sarcoma have been reported [22,23]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pathogenesis'.)

Antibody production — The pathways that lead to the production and deposition of antibodies in the skin and mucous membranes in PNP are not well understood. Proposed mechanisms include the stimulation of antibody production by tumor-induced immune dysregulation as well as the occurrence of cross-reactivity between antibodies directed against tumor cells and epithelial antigens [15]. Epitope spreading, a phenomenon in which tissue injury leads to the exposure of antigens normally hidden from the immune system, may also play a role [15]. In such cases, a cutaneous cytotoxic or inflammatory reaction induced by the tumor could result in the immune detection of intracellular antigens in desmosomes and hemidesmosomes [15,24].

Although some authors have proposed that in certain lymphoproliferative disorders, antibody production by B lymphocytes may contribute to the development of PNP [25,26], the relatively long period required for PNP resolution after the resection of Castleman's tumors (5 to 10 months) and the association of PNP with other malignancies, such as retroperitoneal sarcomas, reduce support for this concept as a major pathogenic mechanism. Moreover, in PNP related to Waldenström's macroglobulinemia, an IgM myeloma, the autoantibodies detected are polyclonal antibodies of the IgG class. This finding suggests an alternative source for antibody production [27].

Pathogenicity — Several studies have sought to clarify which antibodies, if any, are truly pathogenic in PNP. Although antibody deposition could stimulate the local recruitment of inflammatory cells and antibody-dependent cellular cytotoxicity, antibodies against epidermal components could also form as a secondary event following epidermal injury. A pathogenic role for antienvoplakin, antiperiplakin, and antidesmoglein 3 antibodies is suggested by the following observations:

Antienvoplakin and antiperiplakin antibodies can induce dissociation of cultured human epidermal keratinocytes in vitro [28].

Levels of antienvoplakin and antiperiplakin antibodies decreased as clinical improvement occurred following surgical removal of Castleman's tumors or thymoma in one small study [28].

Removal of antidesmoglein 3 antibodies from serum taken from PNP patients prior to the injection of the serum into neonatal mice prevented the development of blisters in mice [21].

However, the contribution of these and other antibodies to the development of PNP remains uncertain. In particular, antidesmoglein 3 antibodies have not been essential for the induction of PNP in other animal models [2], and normally, desmoglein 3 is not expressed by pulmonary epithelium, which can be affected in PNP [29]. However, in one mouse model of PNP, lung inflammation produced ectopic expression of desmoglein 3 in the pulmonary epithelium [30].

Cell-mediated immunity — The presence of cellular infiltrates and features consistent with interface or lichenoid dermatitis in tissue specimens taken from patients with PNP suggests that cellular immunity contributes to this disorder. In support of this concept, CD8+ cytotoxic T lymphocytes, CD56+ natural killer cells, and CD68+ monocytes and macrophages have been detected at the epidermal-dermal junction in affected patients [2]. In addition, high levels of interleukin-6 (IL-6), a cytokine that promotes lymphocyte maturation, cytotoxic T cell activation, and antibody production, have been detected in patients with PNP [31]. Increased local production of the proinflammatory cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha has also been reported in these patients [32].

Additional support for a role for cell-mediated immunity stems from the observation that cell-mediated cytotoxic reactions are seen in other skin diseases that clinically and histopathologically resemble PNP. Cutaneous graft-versus-host disease, lichen planus, and erythema multiforme can be difficult to distinguish clinically from PNP [15]. (See 'Clinical manifestations' below.)

A cell-mediated immune reaction in the skin and mucous membranes may contribute to the stimulation of the humoral immune system. Inflammation-induced damage to the basal layer of the epithelium could result in the immune recognition of normally hidden epithelial antigens through epitope spreading. (See 'Antibody production' above.)

CLINICAL MANIFESTATIONS — Clinically, PNP is characterized by the following mucocutaneous and systemic features:

Severe erosive stomatitis

Polymorphous skin lesions

Lymphoreticular or other malignancies

Pulmonary involvement with features of bronchiolitis obliterans (may or may not be present)

Mucosal lesions — Chronic, erosive, progressive, and painful mucositis is uniformly present in patients with PNP, and in its absence, the diagnosis should not be considered. Oral involvement is most common [10,18], and patients develop a painful, erosive stomatitis that characteristically includes involvement of the tongue (picture 1A-C) [18]. Oral erosions are the initial disease manifestation in almost one-half of patients [15].

Other potential sites of mucosal involvement include the nasopharynx, conjunctiva, and anogenital area. Occasionally, lesions develop on the mucosal surfaces of the esophagus, stomach, duodenum, or colon [33,34].

Mucosal involvement may lead to significant side effects. The pain associated with oral mucosal disease often inhibits oral intake, contributing to malnutrition. Conjunctival involvement may lead to cicatrizing conjunctivitis, damage to the cornea, and visual impairment [35-37].

Cutaneous lesions — Cutaneous lesions typically develop after the onset of mucosal lesions. The morphology of the cutaneous eruption is highly variable. Patients may present with bullae resembling the flaccid bullae of pemphigus vulgaris or the tense bullae of bullous pemphigoid, inflammatory violaceous papules or plaques resembling lichen planus or graft-versus-host disease, targetoid lesions similar to those of erythema multiforme or Stevens-Johnson syndrome, or extensive cutaneous desquamation resembling toxic epidermal necrolysis (picture 2A-C) [10,12,18,38]. The cutaneous lesions of patients who develop PNP following treatment with rituximab may lack blistering and have more of a lichenoid or erythema multiforme-like appearance [39].

More than one lesion type may occur simultaneously in individual patients. Less common cutaneous manifestations include psoriasiform, pustular, and vegetative lesions, as well as the development of alopecia or palmoplantar or periungual involvement [6,15,40].

Pulmonary disease — Patients with PNP may develop a life-threatening restrictive bronchiolitis consistent with bronchiolitis obliterans. The frequency with which pulmonary involvement occurs is not well-defined. In one retrospective study of 17 patients with PNP, restrictive bronchiolitis was detected in three patients (18 percent) [41]. In contrast, in a series of 28 patients with PNP related to Castleman's disease, pulmonary involvement was detected in 26 of 28 patients (93 percent) [42].

Bronchiolitis obliterans usually occurs late in the course of the disease and is heralded by the development of shortness of breath that is out of proportion to changes visualized on chest imaging. An obstructive pattern is evident on pulmonary function tests, and CT scans may demonstrate patchy or diffuse air trapping [41]. (See "Overview of bronchiolar disorders in adults" and "Overview of pulmonary function testing in adults" and "Overview of pulmonary function testing in children".)

The mechanism through which pulmonary damage occurs is not definitively known. Acantholysis, mixed inflammatory infiltrates, and antibody deposition have been detected in pulmonary epithelium in PNP [29]. It has been suggested that pulmonary involvement results from the immune targeting of plakin proteins in the bronchial epithelium, resulting in detachment of cells and the occlusion of the distal alveolar sacs by cellular debris [2]. CD8+ T lymphocytes may play an important role in pulmonary injury; a panmural infiltrate composed of CD8+ T lymphocytes was detected in a post-mortem examination of pulmonary tissue from a patient with PNP [43].

Antibodies against epiplakin may be markers for pulmonary involvement in PNP. In a series of 48 patients with PNP in Japan, antibodies against epiplakin were more prevalent in patients with associated bronchiolitis obliterans than patients without this condition [20]. The finding that passive transfer of antiepiplakin antibodies into mice produces inflammatory changes in small airway epithelia suggests a possible pathogenic role for antiepiplakin antibodies [20].

Other organs — Antibody deposition was detected in muscle, bladder, and renal glomeruli in a study of three patients with PNP [2]. However, evidence for organ dysfunction related to these findings was not identified in these patients.

DIAGNOSIS

Diagnostic approach — Due to the variability in the clinical findings of PNP and the similarities between PNP and other disorders, the combined assessment of clinical and laboratory findings is necessary to establish the diagnosis. The key clinical findings that suggest PNP are the development of a painful erosive mucositis and polymorphous skin eruption in the setting of neoplastic disease. The laboratory studies used to support the diagnosis include light microscopy, direct immunofluorescence microscopy (DIF), and serologic studies that detect antibodies against epidermal proteins. (See "Approach to the patient with cutaneous blisters", section on 'Diagnostic tests'.)

Our standard laboratory work-up for patients with suggestive clinical findings is as follows:

A lesional skin or mucosal biopsy for light microscopy (typically a 4 mm punch biopsy)

A perilesional punch biopsy specimen from skin or mucosa for DIF (specimen must not be placed in formalin)

Serum for indirect immunofluorescence (IIF) studies on monkey esophagus and rat bladder epithelium

Serum for enzyme-linked immunosorbent assay (ELISA) for antienvoplakin and antiperiplakin antibodies

Immunoprecipitation and immunoblotting are additional serologic tests that have been utilized for the diagnosis of PNP. However, the availability of these tests is limited, and these studies are not typically utilized in the clinical setting.

Careful correlation of the clinical and laboratory findings is necessary for an accurate diagnosis of PNP because the histologic findings of PNP are not pathognomonic, and immunofluorescence studies and ELISA testing are sometimes negative. In particular, in patients who develop PNP after treatment with rituximab, an anti-CD20 monoclonal antibody, autoantibodies may not be detectable in the epidermis or serum [39].

The laboratory studies used for the diagnosis of PNP are reviewed below.

Histopathology — The most common histopathologic findings in PNP are suprabasal acantholysis (picture 3), keratinocyte necrosis, and a lichenoid interface dermatitis [15,44]. However, the histopathologic findings vary, often resembling other disorders that have similar clinical features (see 'Cutaneous lesions' above) [45]. For example, while acantholysis is typically a prominent feature in lesions that resemble pemphigus vulgaris, specimens taken from patients with tense bullae that resemble bullous pemphigoid may exhibit subepidermal clefting. Epidermal dyskeratosis, vacuolization of basal keratinocytes, and a lichenoid lymphocytic infiltrate are often found in cutaneous lesions that resemble lichen planus, erythema multiforme, or graft-versus-host disease [15].

Since the histologic findings overlap with multiple other disorders, correlation with the clinical scenario and other laboratory tests is important for diagnosis. The technique used to perform skin biopsies in blistering disorders is reviewed separately. (See "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)

Direct immunofluorescence — IgG or C3 can be detected intercellularly and/or at the basement membrane zone on DIF microscopy in many cases of PNP (picture 4). However, negative DIF studies are not uncommon [18,46]. In a study of 115 patients with PNP, pemphigus vulgaris, or pemphigus foliaceus, the sensitivity of DIF for PNP was only 41 percent [18]. The specificity of the test was higher; when compared with patients with pemphigus vulgaris or pemphigus foliaceus who had (n = 12) or did not have (n = 81) a concurrent malignancy, the specificity of DIF was 83 and 93 percent, respectively. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)

The DIF findings of PNP can be similar to the findings of pemphigus vulgaris and pemphigus erythematosus. Pemphigus vulgaris is characterized by the presence of epithelial cell surface IgG and C3, and pemphigus erythematosus sometimes presents with both epithelial cell surface and basement membrane zone deposition of IgG and C3.

Indirect immunofluorescence — IIF performed on rat bladder epithelium is particularly useful for differentiating PNP from pemphigus vulgaris. While both PNP and pemphigus vulgaris demonstrate epithelial cell surface deposits of IgG on monkey esophagus epithelium (picture 5), only PNP demonstrates this finding on rat bladder epithelium. This feature results from the absence of desmogleins (the target of antibodies in pemphigus vulgaris) in rat bladder epithelium.

The transitional epithelium of murine (eg, rat) bladder is the preferred substrate for IIF studies in patients with PNP (picture 6) [15]. When performed on rat bladder epithelium, estimates for the sensitivity and specificity of this test have ranged from 74 to 86 percent and 83 to 100 percent, respectively [18,46,47]. (See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)

Enzyme-linked immunosorbent assay — Enzyme-linked immunosorbent assays (ELISA) for antibodies against envoplakin and periplakin have been utilized in studies of patients with PNP [17,48]. In one series of 16 patients with PNP, ELISA utilizing recombinant proteins derived from human kidney cells detected antibodies against envoplakin and periplakin in all patients [17]. ELISA for desmoglein 3 was positive in 11 patients. In a separate study that evaluated serum from 31 patients with PNP and 80 controls, an ELISA based on the N-terminal fragment of envoplakin had a sensitivity and specificity for PNP of 81 and 99 percent, respectively; the ELISA for periplakin had a sensitivity and specificity of 74 and 96 percent [48].

Other studies — Immunoprecipitation and immunoblotting are additional serologic tests that have been utilized for the diagnosis of PNP. However, the availability of these labor-intensive tests is limited to research laboratories and specialized centers. Thus, in clinical practice, immunoprecipitation and immunoblotting are not typically utilized for diagnosis:

Immunoprecipitation – The immunoprecipitation assay is considered to be more sensitive and specific than indirect immunofluorescence for diagnosis [49]. The use of immunoprecipitation assays for the diagnosis of PNP involves the incubation of patient serum with radiolabeled keratinocyte proteins extracted from keratinocyte cultures [42]. The antibody-antigen complexes that result are precipitated and analyzed via gel electrophoresis.

A variety of immunoprecipitation bands have been detected in PNP, including plectin (>400 kDa), desmoplakin I (250 kDa), bullous pemphigoid antigen 1 (230 kDa), envoplakin and desmoplakin II (a 210 kDa double band), periplakin (190 kDa), and alpha-2-macroglobulin-like-1 (A2ML1, 170 kDa) [2,50]. The detection of periplakin and envoplakin or A2ML1 by immunoprecipitation is considered a highly specific laboratory finding of PNP [47]. (See 'Diagnostic approach' above.)

The high sensitivity of immunoprecipitation for the diagnosis of PNP was demonstrated in a study of 19 patients with PNP (defined by consistent mucocutaneous findings, plakin autoantibodies, and an underlying neoplasm) and 40 controls that found sensitivities of antienvoplakin ELISA, rat bladder IIF, immunoblotting, radioactive immunoprecipitation, and a novel nonradioactive immunoprecipitation procedure of 63, 74, 89, 95, and 100 percent respectively [47]. Specificities for these tests were 98, 100, 100, 100, and 86 percent, respectively.

Immunoblotting – In addition to immunoprecipitation, immunoblotting is another highly sensitive and specific method that has been used to detect autoantibodies in PNP [18,47]. In a study of 115 patients with PNP, pemphigus vulgaris, and pemphigus foliaceus, the sensitivity of immunoblotting for envoplakin and/or periplakin for the diagnosis of PNP was 82 percent [18]. The specificity of the immunoblot technique was 100 percent. Similar to immunoprecipitation, the availability of immunoblotting is limited.

Associated laboratory findings — Autoimmune cytopenias including thrombocytopenia, neutropenia, and autoimmune hemolytic anemia may be present as associated features. PNP patients may also develop clinical and serologic evidence of myasthenia gravis [51].

Evaluation for the underlying disorder — The selection of studies for the evaluation for an underlying cause in patients with PNP is based upon the spectrum of associated neoplasms. As examples, laboratory evaluation may identify hematologic disorders such as chronic lymphocytic leukemia or Waldenström's macroglobulinemia, while radiologic imaging can aid in the diagnosis of Castleman's disease and lymphomas.

We typically perform the following evaluation [15]:

Thorough patient history and physical examination for signs suggestive of malignancy or lymphoproliferative disease

Complete blood count

Serum protein electrophoresis

CT scan of the chest, abdomen, and pelvis

As noted above, the vast majority of cases in children and adolescents are associated with Castleman's disease [5]. (See 'Etiology' above.)

Evaluation for pulmonary involvement — Because pulmonary involvement in PNP is typically accompanied by dyspnea, an evaluation for pulmonary involvement can be reserved for symptomatic patients. At the initial signs of shortness of breath or dyspnea on exertion, we refer patients to a pulmonologist for further evaluation. (See 'Pulmonary disease' above.)

DIFFERENTIAL DIAGNOSIS — Due to the wide variety of clinical findings that occur in PNP, the differential diagnosis is broad. Oral mucosal lesions must be differentiated from chemotherapy-associated mucositis and the multiple other blistering disorders that may affect mucosal surfaces (see "Approach to the patient with cutaneous blisters", section on 'Mucous membrane involvement'). In patients with widespread blisters and erosions, the possibility of pemphigus vulgaris and subepidermal autoimmune blistering disorders (eg, bullous pemphigoid, epidermolysis bullosa acquisita) should be considered (see "Approach to the patient with cutaneous blisters", section on 'Generalized distribution'). Papular lesions of PNP can resemble lichenoid drug eruptions and lichen planus. (See "Lichenoid drug eruption (drug-induced lichen planus)" and "Lichen planus".)

In addition to correlation of the mucocutaneous lesions with pathologic and serologic studies, knowledge of the chronic, progressive course of PNP is useful for diagnosis. Although similar mucocutaneous lesions may occur in erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, the acute nature of these disorders (improvement usually attained within three to five weeks) distinguishes them from PNP. (See 'Prognosis' below and "Erythema multiforme: Pathogenesis, clinical features, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

TREATMENT — The treatment of patients with PNP consists of the suppression of the disease manifestations and the management of patient symptoms. Treatment of the underlying malignancy is beneficial in some cases.

Treatment of the underlying neoplasm — In PNP associated with Castleman's disease or thymoma, resection of the tumor often results in disease remission. In one series of five adults with Castleman's disease and PNP, significant improvement in mucosal lesions and resolution of skin lesions occurred in all four patients who returned for a follow-up visit six months after surgery [52]. However, remission may take up to one to two years to occur, and the disease persists after resection in some cases [42,53].

In PNP associated with other neoplastic disorders, the response of PNP to treatment of the underlying neoplasm appears to be less favorable. Once initiated, PNP often progresses independent of the status of the underlying neoplastic disease [49].

Suppression of disease — Due to the rarity of PNP, no randomized therapeutic trials have been performed and efficacy data are primarily limited to case reports. The response to treatment is highly variable. Refractory PNP, particularly refractory stomatitis, is common [53].

Conventional immunosuppressants — Systemic glucocorticoids are often the initial treatments attempted in patients with PNP [12,46,53]. High-dose regimens, usually beginning with 1 mg/kg per day of prednisone followed by a slow taper as tolerated are used [12]. We typically taper patients to a maintenance dose of 10 to 15 mg of prednisone per day over the course of six months. The cutaneous manifestations are more likely to respond to systemic glucocorticoids than the oral mucosal lesions; the latter are often refractory to therapy [53].

Other immunosuppressive agents are often combined with systemic glucocorticoids in attempts to attain further clinical improvement or to take advantage of their glucocorticoid-sparing effects. Cyclophosphamide [54,55], mycophenolate mofetil [56], azathioprine [57,58], and cyclosporine [59] have been reported to be beneficial in individual patients [53].

Rituximab — Multiple case reports have described the use of rituximab, a chimeric antibody that targets CD20 on B lymphocytes, in patients with PNP associated with various neoplastic disorders [60]. Patients have been treated with various regimens, including 375 mg/m2 of rituximab administered on a weekly basis for four weeks with or without subsequent less frequent doses [60-62].

The response to rituximab therapy is highly variable. A review of 13 reported cases of PNP that were treated with rituximab found complete responses in three patients, all of whom had non-Hodgkin lymphoma [60]. The limited efficacy of rituximab may reflect the fact that the drug reduces autoantibody levels but has a lesser effect on regulation of cell-mediated immunity. In one patient, rituximab improved the blistering mucocutaneous lesions but failed to prevent the progression of fatal bronchiolitis obliterans [63]. Further study is necessary to definitively determine the role rituximab should play in PNP.

Other therapies — In individual patients, plasmapheresis [64], myeloablation with cyclophosphamide [65], intravenous immunoglobulin (IVIG) [25,66], alemtuzumab [67,68], and daclizumab [39] have been reported to be effective in combination with other therapeutic interventions. Topical tacrolimus in a 0.03% suspension used to rinse the mouth three times daily for six weeks was associated with improvement in a relapse of oral involvement in a patient with PNP due to non-Hodgkin lymphoma [69].

Our approach — Definitive guidelines for the management of PNP have not been established. We have found the following approach most useful:

Define and treat the underlying neoplasm (particularly useful in Castleman's disease).

First-line therapy – Administer prednisone (1 mg/kg) in an attempt to provide acute improvement in mucocutaneous manifestations; initiate rituximab as soon as feasible (375 mg/m2 weekly for four weeks and repeat this course every three to six months); taper prednisone slowly as tolerated.

For patients who improve only partially with the regimen above or who develop disease flares during prednisone tapering, we typically add an immunosuppressive agent, either mycophenolate mofetil (1000 mg twice daily) or azathioprine (up to 3 mg/kg per day; dose adjustments may be made according to thiopurine methyltransferase [TPMT] activity). We generally avoid cyclophosphamide or cyclosporine due to concerns regarding the consequences of profound immunosuppression.

IVIG (2 g/kg given as 0.67 g/kg per day for three days and repeated monthly as needed) can be added to the therapeutic regimen to provide an additional immunomodulatory effect without increasing the level of overall immunosuppression.

We have observed positive responses to the nondepleting anti-CD25 monoclonal antibody daclizumab in patients who have failed to improve with the above measures, particularly in patients with progressive pulmonary involvement. However, daclizumab is no longer commercially available. We do not have experience with basiliximab, an agent with a similar mechanism of action.

Of note, the decision to initiate immunomodulatory therapy in the setting of PNP should be made in conjunction with the patient's oncologist.

Adjunctive measures — Due to the fact that PNP may be difficult to treat, management of patient symptoms is also an important component of patient management. Anesthetic mouthwashes can be attempted for oral pain, but often do not help significantly, and narcotic pain medications may be necessary. Vaseline gauze can be applied to cutaneous erosions. For patients with extensive cutaneous erosions, such as patients with a toxic epidermal necrolysis-like presentation, admission to a burn unit facilitates patient management and wound care.

Given the extent of immunosuppressive therapy often required for the management of PNP, the need for prophylaxis against Pneumocystis pneumonia should be evaluated. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

PROGNOSIS — PNP has traditionally been thought to have a very poor prognosis, with most patients dying within two years [29,46]. Affected patients usually succumb to sepsis, respiratory failure due to pulmonary involvement, or the underlying malignancy [10,11,46]. However, a French multicenter retrospective study of 53 patients with PNP who received a variety of therapies suggested that the prognosis of PNP may be better [46]. The respective one, three, and five-year overall survival rates were 49, 41, and 38 percent. Patients with erythema multiforme-like skin lesions, particularly in the context of severe skin or mucosal involvement appeared to have the worst prognosis. A separate review of 144 adults with hematologic malignancy-associated PNP found a one-year survival rate of 62 percent; toxic epidermal necrolysis-like PNP and PNP associated with bronchiolitis obliterans were associated with a particularly poor prognosis [70].

Pulmonary disease often fails to improve despite successful treatment of the malignancy and the resolution of mucocutaneous lesions [4,41]. Lung transplantation was used for the management of an adolescent with pulmonary involvement related to Castleman's disease [71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pemphigus".)

SUMMARY AND RECOMMENDATIONS

Epidemiology – Paraneoplastic pemphigus (PNP) is a rare autoimmune blistering disorder that may occur in the setting of lymphoproliferative disorders and malignancies. Although adults are most commonly affected, PNP may also occur in children. (See 'Epidemiology' above.)

Etiology – Multiple malignant and lymphoproliferative disorders are associated with PNP. The disorders most frequently linked to PNP are non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman's disease. (See 'Etiology' above.)

Pathogenesis – The pathophysiology of PNP is not well understood. It is likely that both the humoral and cellular immune system contribute significantly to this disease. (See 'Pathogenesis' above.)

Antibodies against periplakin and envoplakin are strongly associated with PNP. A pathogenic role for these and the multiple other antibodies detected in patients with PNP remains uncertain. (See 'Pathogenesis' above.)

Clinical manifestations – The clinical manifestations of PNP vary widely. Mucosal involvement occurs in all patients, with oral involvement being the most common site for involvement (picture 1A-C). The most common cutaneous manifestations are flaccid or tense bullae, lichenoid papules or plaques, targetoid lesions, and erosions (picture 2A-B). (See 'Clinical manifestations' above.)

Pulmonary involvement – A restrictive bronchiolitis consistent with bronchiolitis obliterans occurs in a minority of patients with PNP. Pulmonary involvement can be life-threatening. (See 'Pulmonary disease' above.)

Diagnosis – PNP shares clinical and pathologic features with multiple other disorders. Confirmation of a diagnosis of PNP requires the correlation of clinical, pathologic, and immunologic studies. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Treatment – Data are limited on therapies for PNP. Surgical removal of the underlying tumor can be beneficial in patients with Castleman's disease or thymoma but is much less likely to be of value for other malignancies. (See 'Treatment' above.)

For patients with PNP, we suggest the use of prednisone and rituximab as first-line therapy (Grade 2C). If this is not effective, additional therapies such as mycophenolate mofetil, azathioprine, and intravenous immunoglobulin can be added as adjunctive therapy. (See 'Our approach' above.)

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Topic 15305 Version 13.0

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