Bronchiolitis Obliterans With Anti-Epiplakin Antibodies in a Boy With Paraneoplastic Pemphigus

A 16-year-old boy with a history of recurrent painful oral ulcers, cutaneous blisters, and significant weight loss was referred to our dermatology department with a clinicopathological diagnosis of pemphigus vulgaris under treatment with prednisone (1 mg/kg) for the past 7 months. Despite previous treatment, physical examination revealed severe oral mucositis, disseminated erosions, and flaccid blisters on the face, trunk, and extremities, some covered by honey-colored hematic crusts (Fig 1 A and B). He also presented nail abnormalities, such as ungual dystrophy and onychomadesis (Fig 1 C and D). No other pathologic findings were found on physical examination. Routine hematology and biochemistry tests were within normal limits. On reappraisal PNP was suspected due to recalcitrant painful mucosal erosions, polymorphous cutaneous lesions, and suprabasal acantholysis.

The chest x-rays showed mediastinal widening, and on a thoracoabdominal CT scan, 3 enhancing mediastinal nodal masses were observed; no other lymph node enlargement was noted. The diagnosis of hyaline-vascular CD was established after a tumor biopsy. Indirect immunofluorescence (IIF) was positive in the intercellular spaces, titer 1:10240 and 1:2560 in cow nose and 1:320 in rat bladder (Fig 2 A and D). In addition, the patient’s samples were positive in 1:439 and 1:532 in a sandwich ELISA (enzyme-linked immunosorbent assay) containing EPPK1 protein. The immunoblot assay with EPPK1 protein yielded circulating IgG autoantibodies against a ∼500 kDa band that corresponded to EPPK (Fig 3A). A Western blot assay using rat bladder extract demonstrated autoantibodies against envoplakin and desmoplakin II (210 kDa), periplakin (190 kDa), α-2-macroglobulin-like protein 1 (A2ML1, 170 kDa), Dsg1 (160 kDa), and other PAMS antigens (56 kDa) (Fig 3B).

The patient met both Anhalt et al⁴  (clinical, histopathology, IIF, immunoprecipitation) and Svoboda et al⁵  (3 major and 1 minor criteria) diagnostic criteria for PNP (Tables 1 and 2). Because of the difficult surgical approach for CD, a trial with rituximab was attempted to reduce tumor size, achieving a 20% tumoral decrease. Further surgical removal of the residual tumor resulted in complete resolution of the skin and mucosal lesions (Fig 1 E and F).

However, during the course of the disease the patient developed respiratory symptoms (dyspnea, cough, and desaturation), hyperinflation in chest radiographs, a pattern of mosaic attenuation in high-resolution CT scanning, and a severe obstructive ventilatory pattern in spirometry, all compatible with the diagnosis of BO. He received treatment with inhaled fluticasone (250 μg/day), prednisone (0.1–0.5 mg/kg perday) and mycophenolate mofetil (1–2 g/day) for 2 years, with steady progression of symptoms and worsening of pulmonary function tests (reduction of the forced expiratory volume in the first second [FEV1] from 20% to 12% and forced vital capacity [FVC] from 50% to 35% without significant response to bronchodilator). At the age of 18 he was transferred to an adult health care facility with the plan of a lung transplantation in the near future.

The term PNP was originally proposed 30 years ago by Anhalt et al.⁴  It is a rare autoimmune blistering disease of the skin and mucous membranes where a neoplasm, benign or malignant, elicits the production of autoantibodies against various epidermal proteins involved in cell adhesion, which leads to the blistering. The pathogenesis is not yet completely defined.^6,7 

The incidence of PNP is unknown.⁶  There are ∼500 cases described in the literature.⁷  It mostly affects adults between 45 and 70 years of age but may also be found in younger patients.^7,8  Adolescents are the most affected group among pediatric patients.¹ 

Unlike adults, PNP in pediatric patients is most commonly caused by CD rather than by non-Hodgkin’s lymphoma. CD consists of a heterogeneous group of benign lymphoproliferative disorders.⁶  It may be localized to a single lymph node region (unicentric [UCD]), or occur systemically (multicentric [MCD]).⁹  PNP is more frequent in the context of UCD, as in our patient.¹⁰ 

The pathogenic IgG autoantibodies in PNP are polyclonal, directed against multiple antigens: Dsg3 and/or Dsg1; Desmocollin (Dsc)1, Dsc2, Dsc3; proteins of the plakin family (envoplakin, periplakin, desmoplakin I, demosplakin II, EPPK, plectin, and BP230), in addition to a protease inhibitor, A2ML1.⁶ 

Patients with PNP usually present with a consumptive syndrome (malaise, weakness, weight loss) due to underlying disease or decreased food intake associated to an extensive and recalcitrant stomatitis, which is the most frequent mucocutaneous problem and the least-responsive symptom to treatment.^3,6  In fact, both the stomatitis and the consumptive syndrome raised the suspicion of PNP in our patient. Oral lesions consist of chronic painful erosions and crusting, and they may occur throughout the entire buccal mucosa.⁶  The genital (62%) and ocular (59%) mucosae may also be involved.⁶  A wide range of skin manifestations may present, including blisters, erosions, macules, papules, and plaques. The distinct clinical presentations may coexist or evolve during the course of the disease.⁸ 

One of the most frustrating aspects of PNP is that even with a successful removal of the neoplasm with remission of the mucocutaneous lesions, it can lead to respiratory compromise such as BO, resulting in high morbidity and mortality rates.³  Pulmonary disease, when present, is irreversible despite aggressive therapy.⁸  BO is a form of obstructive lung disease that follows inflammatory and fibrotic changes primarily affecting the small airways and may occur in 30% of CD-associated PNP patients. Progressive dyspnea and hypoxemia are the most frequent and warning signs of BO and should prompt an immediate examination by a pulmonologist.¹¹ 

The pathogenesis of PNP-related BO is currently unknown. Nousari et al detected autoantibodies that reacted to plakins in respiratory epithelium and the concomitant presence of acantholysis of the bronchial epithelium in 2 patients, suggesting that autoantibodies may have a role in the mechanism of pulmonary injury, but causation has yet to be proved.¹²  It also appears that cellular responses mediated by CD8⁺ lymphocytes may play a key role in the progression of bronchiolitis.¹³ 

More recent evidence in adult populations highlights potential autoantibody-clinical phenotype correlations, with EPPK autoantibodies associated with the development of BO. Tsuchisaka et al found that the presence of anti-EPPK antibodies significantly correlated with the development of BO and increased mortality in adult Japanese patients with PNP, but this correlation was not observed in the European population, possibly caused by a different genetic background, including human leukocyte antigens.³  Anti-EPPK antibodies injected into mice induce a disruption of bronchial epithelium integrity and mononuclear cell inflammation, providing evidence of its pathogenic role in BO. Antibodies in PNP sera may react with EPPK in lung tissues and cause BO. Our patient is the first pediatric patient in whom the association of anti-EPPK antibodies and BO has been reported to date.^1,3 

The mainstay of therapy for paraneoplastic manifestations of CD is definitive surgical treatment of the neoplasm.¹⁴  However, several nonsurgical treatments have proven to be effective in achieving less morbid surgical resections or reducing symptoms in patients with inoperable neoplasms. In this case, rituximab was used to reduce the tumor size and surgical risks, but also because of its proven efficacy for refractory autoimmune bullous diseases including PNP.¹⁵  Additionally, Kaibuchi-Ando et al very recently reported the successful use of combined rituximab, intravenous immunoglobulin, and betamethasone to decelerate and stabilize respiratory function in patients with BO and PNP; however, this has not been achieved in all cases.^13,16 

The overall prognosis of PNP is poor, with a mortality of 75% to 90%, and respiratory failure the main cause of death.⁸  The detection of anti-EPPK antibodies may lead to more aggressive surveillance and treatment to detect and try to avoid the development of fatal PNP-related BO. As far as we know, this is the first pediatric PNP case where the relationship between anti-EPPK antibodies and BO has been searched for. More studies are needed to evaluate this phenomenon in children.

BO

Bronchiolitis obliterans

CD

Castleman Disease

Dsc

Desmocollin

Dsg

Desmoglein

EPPK

Epiplakin

MCD

Multicentric Castleman Disease

PAMS

Paraneoplastic autoimmune multiorgan syndrome

PNP

Paraneoplastic pemphigus

UCD

Unicentric Castleman Disease