Pemphigus

Paraneoplastic pemphigus (PNP) is an autoantibody-mediated mucocutaneous blistering disease associated with underlying neoplasms. Autoantibodies of PNP bind to the plakin family of cytoplasmic proteins and desmogleins of cell-surface target antigens. We describe a 36-year-old female patient with PNP who had non-Hodgkin's lymphoma, and who developed bronchiolitis obliterans and died of respiratory failure. Autopsy findings confirmed luminal narrowing of bronchioles by scarring, which is a histopathologic features of bronchiolitis obliterans. After the onset of respiratory failure, the reaction of autoantibodies against the plakins detected by immunoprecipitation at the onset of PNP disappeared with negative immunofluorescence within the bronchial epithelium. It is thought that autoantibodies against some of these antigens play a role in causing acute inflammation of the respiratory epithelium. In treating PNP, the possibility of the patient developing the lethal complicatlon bronchiolitis obliterans should be kept in mind. Furthermore, prevention of the initial autoantibody-mediated injury to the respiratory epithelium should be an important treatment goal.

(CHEST 2000; 117:603-607)

Key words: autoantibody; bronchiolitis obliterans; paraneoplastic pemphigus; plakins; respiratory failure

Abbreviations: DP = desmoplakin; ENV = envoplakin; PER = periplakin; PNP = paraneoplastic pemphigus;

Paraneoplastic pemphigus (PNP), a rare autoimmune bullous disease related to underlying neoplasia, is characterized by distinctive clinical symptoms such as severe, painful mucosal erosions and polymorphous skin lesions.[1] Histopathologic hallmarks include acantholysis and interface dermatitis or keratinocyte necrosis.[2] PNP patients develop characteristic autoantibodies directed against multiple antigens, mostly identified as members of the plakin family of intermediate filament-associated proteins and the desmogleins of the cadherin family in desmosomes.[3-6] Since the first report of PNP by Anhalt et al,[1] several cases of PNP with respiratory failure caused by airway obliteration have been reported,[7-9] but these reports did not describe the histopathologic features of the lung lesions in detail.

We have recently encountered an additional Japanese female patient with PNP associated with non-Hodgkin's lymphoma who developed severe airflow obstruction and died of respiratory failure. An autopsy examination revealed scarring, which narrowed the lumens of terminal bronchioles, which is the typical histopathologic feature of bronchiolitis obliterans.[10] Another unique finding is that after the onset of respiratory failure, the reaction of autoantibodies against the plakins detected by immuno-precipitation at the onset of PNP disappeared with negative immunofluorescence within the bronchial epithelium. In this report, we describe precisely the histopathologic features of this lung disease and consider the prevention of autoantibody-mediated inflammation of the respiratory epithelium that results in scarring.

CASE REPORT

In September 1996, a 36-year-old woman developed infiltrating erythema on her hands and feet, which was accompanied by pseudomembranous conjunctivitis (Fig 1, top left, A) and painful erosions and blisters on the lips and oral mucosa (Fig 1, top right, B) after radiotherapy following intensive chemotherapy for non-Hodgkin's lymphoma (stage Csb, follicular, medium-sized, B-cell), which had ended in March 1996. The chemotherapy agents used were combinations of methotrexate, mitoxantrone hydrochloride, cyclophosphamide, vincristine, etoposide and prednisolone, ranimustine and enocitabine, and carboplatin. In addition, vulvar and cervical erosions were seen. Productive cough and shortness of breath also were present. Based on an initial diagnosis of herpes simplex infection, an IV infusion of acyclovir was administered, but the patient's condition worsened. Histopathologic examination of a skin biopsy specimen showed mild suprabasilar acantholysis, individual keratinocyte necrosis, and vacuolar interface dermatitis, features that are suggestive of PNP. The diagnosis of PNP was confirmed by three findings. First, direct immunofluorescence showed pronounced IgG and [C.sub.3] deposits in the cell surfaces of the epidermis and along the dermoepidermal junction (Fig 1, bottom left, C). Second, indirect immunofluorescence demonstrated the presence of antibodies that reacted against the epithelial cell surface in the rat urinary bladder (Fig 1, bottom right, D). Third, an immunoprecipitation showed a strong reactivity against the 250-, 230-, 210-, 190-, and 170-kd PNP antigens, as well as the 130-kd protein (Fig 2, lane 1). The patient was treated orally with 50 mg of prednisolone daily for a month and 40 mg daily for another month, and her skin and lip lesions improved quickly. While she became {free from severe mucosal pain, oral and conjunctival mucosal lesions persisted with minimal improvement. All the respiratory symptoms also seemed to improve. The dose of prednisolone was slowly tapered during the next 2 months to 10 mg.

[Figure 1 ILLUSTRATION OMITTED]

Six months after the onset of PNP, the patient developed severe dyspnea with wheezing. On pulmonary function testing, her [FEV.sub.1] decreased to 1,120 mL (41% of the predicted value), maximal flow at 50% of FVC decreased to 730 mL (16.3% of the predicted value), maximal flow at 25% of FVC decreased to 310 mL (12.9% of the predicted value), and Pa[O.sub.2] decreased to 66 mm Hg. A chest radiograph and CT scan of the lungs showed no specific findings. No clinical or laboratory evidence of infection was present. A diagnosis of bronchiolitis obliterans was considered. Immunoprecipitation detected antibodies only against 170- and 130-kd proteins in the serum at this time (Fig 2, lane 2). Standard treatments for asthmatic bronchiolitis were not effective, but 30 mg prednisolone combined with 175 mg eyelosporine with the inhalant beclomethasone dipropionate showed some effect for a limited period. Bronchoscopy performed 3 months after the onset of dyspnea showed only moderate bronchial mucosal edema. Bronchial biopsy spedmens showed no obvious cantholysis or blister formation by respiratory epithelial cells. Direct immunofluorescence of the biopsy specimen did not show any deposition of Igs or complement components. Despite treatment for respiratory failure with noninvasive positive-pressure ventilation combined with an inhalant steroid, dyspnea gradually worsened and pulmonary function continued to deteriorate. Within the last month of the patient's life, respiratory tract infections occurred repeatedly, and the patient died of respiratory failure 10 months after the onset of dyspnea.

[Figure 2 ILLUSTRATION OMITTED]

A postmortem examination of the lung revealed extensive cavitation caused by fungal infection and hemorrhagic necrosis. The bronchial epithelium showed squamous metaplasia and chronic inflammatory infiltrates with associated fibrin deposition. Alveolar duets were dilated significantly with abundant mucin inside. No nuclear inclusion bodies were found in alveolar epithelial cells. In addition, where healthy lung structures were relatively preserved, luminal narrowing was prominent in terminal bronchioles (Fig 3). In these areas, suprabasilar acantholysis was not observed; ciliated bronchiolar epithelial cells were partially exfoliated with the formation of granulation tissue and were infiltrated by a small number of lymphocytes and foamy macrophages (Fig 3, top right, B). Elastica van Gieson staining showed a remarkable mural thickening of bronchioles as a result of submucosal collagenosis (Fig 3). Direct immunofluorescence of autopsy specimens did not show any deposition of Igs or complement components within the bronchial epithelium.

[Figure 3 ILLUSTRATION OMITTED]

DISCUSSION

Our patient died of progressive airflow obstruction resulting in respiratory failure. Autopsy dearly demonstrated luminal narrowing that resulted from submucosal collagenosis, which is consistent with the effects of bronchiolitis obliterans.[10] Because no other known causes of this condition, such as smoking, infections, collagen diseases, mineral dust or toxic/fume exposure, or transplantation,[10] were found, its occurrence was ascribed to PNP. In this report, we described the case of a patient with PNP with clear histopathologic confirmation of bronchiolitis obliterans.

In previous reports, airflow obstruction was not evident at the onset of PNP and developed at least a few months later.[7-9] Bronchiolitis obliterans is caused by severe inflammation and destruction involving the bronchiolar epithelium that induces fibrosis and remodeling of bronchiolar walls. Our patient showed some respiratory symptoms at the onset of PNP, suggesting the presence of acute bronchiolitis. Because of the patient's good response to prednisolone, this symptom was not thought to be infection but, rather, an autoimmune reaction. Neither biopsy nor autopsy specimens near the areas showing bronchiolitis obliterans-like changes disclosed findings of an acute-phase inflammation. This absence is probably because the specimens were obtained during the late stage of the disease. A biopsy was deferred until [is greater than] 9 months after the onset of PNP, since respiratory symptoms present at the onset of PNP largely abated with initial therapy. Later severe respiratory failure further delayed performance of a bronchoscopic biopsy. Although high-dose prednisolone therapy appeared to suppress acute bronchiolar inflammation that was present at the onset of PNP, mucosal lesions persisted until the patient's death. Our therapy proved insufficient to quickly and completely suppress the inflammation, and postinflammatory fibrosis of the bronchioles supervened.

In PNP patients with respiratory complications, the deposition of IgG has been demonstrated on bronchial epithelial cell surfaces and/or basement membranes.[7-9] Nousari et al[9] also proved that acantholysis-like lesions developed in the bronchial pseudostratified columnar epithelium. PNP patients develop characteristic auto-antibodies against multiple antigens, including a diagnostic antigen complex of proteins with relative molecular weights of 250, 230, 210, 190, and 170 kd. The 250-and 210-kd proteins were identified as desmoplakin (DP) I and DP II, which are the major cytoplasmic plaque proteins of desmosomes. The 230-kd protein was bullous pemphigoid antigen 230, the major plaque protein of the epidermal hemidesmosomes.[1,4,5] The 210-kd protein was subsequently recognized to be a doublet of DP II and envoplakin (ENV).[3-5] The 190-kd protein corresponds to periplakin (PER), and the 170-kd is a transmembrane cell-surface protein that has not been identified.[4,5] DP I, bullous pemphigoid antigen 230, DP II, ENV, and PER belong to the plakin family of proteins, which are involved in the organization of intermediate filaments and cytoskeletal architecture that plays an important role in the anchorage of the cytoskeleton to filament attachment sites on plasma membranes.[4,5] The 130-kd protein corresponds to desmoglein 3 (pemphigus vulgaris antigen), a member of the cadherin family of cell-to-cell adhesion molecules in desmosomes.[5,6] The healthy human bronchial epithelium expresses DP I, bullous pemphigoid antigen 230, DP II, ENV, PER, and plectin but neither the 170-kd PNP antigen nor desmoglein 3.[9] Therefore, tissue-bound autoantibodies have been considered important to epithelial cell detachment and inflammation in the bronchial epithelium. In the present case, however, no deposition of IgG or [C.sub.3] was demonstrable in respiratory mucosa, another negative finding that is explained by the late timing of the histologic examination. After the onset of respiratory failure, reaction against the plakins, DP I, bullous pemphigoid antigen 230, DP II/ENV, and PER, which were detected by immunoprecipitation and were present at the onset of PNP, disappeared. This reactivity might already have been decreased by therapy, which may explain the negative immunofluorescence finding for tissue-bound IgG and complement in the respiratory mucosa. These findings suggest that some of the autoantibodies against these proteins were deposited in the respiratory mucosa at the early stage and played a role in causing the acute inflammation, although another initiative factor may be needed for these autoantibodies directed against intracellular antigens to bind to their target antigens within respiratory epithelium.

The association of bronchiolitis obliterans must be kept in mind when we treat patients with PNP. In particular, symptoms of respiratory epithelial inflammation at the onset of PNP should demand intervention. Once severe inflammation occurs in bronchioles, an irreversible fibrotic reaction leading to bronchiolitis obliterans appears to follow. Therefore, quick and complete suppression of acute-phase inflammation is essential. Although typical immunosuppressive therapy may have suppressed the acute phase of inflammation and abolished tissue-bound IgG, this treatment did not prevent bronchiolar fibrosis. Therefore, additional therapy must be needed. Recently, Schoen et al[11] have reported that immunoapheresis was effective against the oral mucosal lesions of PNP, which are well known to be refractory to standard immunosuppressive therapy. Therefore, immunoapheresis may be able to prevent the development of bronchiolitis obliterans, especially when used in combination with intensive immunosuppressive drug treatment in the early stage of PNP.

ACKNOWLEDGMENT: The authors thank Grant J. Anhalt, MD, for performing the immunoprecipitation study of our patient.

REFERENCES

[1] Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. N Engl J Med 1990; 323:1729-1735

[2] Horn TD, Anhalt GJ. Histologic features of paraneolastic pemphigus. Arch Dermatol 1992; 128:1091-1095

[3] Hashimoto T, Amagai M, Watanabe K, et al. Characterization of paraneoplastic pemphigus autoantigens by immunoblot analysis. J Invest Dermatol 1995; 104:829-834

[4] Borradori L, Trueb RM, Jaunin F, et al. Autoantibodies from a patient with paraneoplastic pemphigus bind periplakin, a novel member of the plakin family. J Invest Dermatol 1998; 111:338-340

[5] Proby C, Fujii Y, Owaribe K, et al. Human autoantibodies against HD1/plectin in paraneoplatic pemphigus. J Invest Dermatol 1999; 112:153-156

[6] Amagai M, Nishikawa T, Nousari HC, et al. Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest 1998; 102:775-782

[7] Fullerton SH, Woodley DT, Smoller BR, et al. Paraneolastic pemphigus with autoantibody deposition in bronchial epithelium after autologous bone marrow transplantation. JAMA 1992; 267:1500-1502

[8] Osmanski JP, Fraire AE, Schaefer OP. Necrotizing tracheobronchitis with progressive airflow obstruction associated with paraneolastic pemphigus. Chest 1997; 112:1704-1707

[9] Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 1999; 340:1406-1410

[10] Wright JL, Cagle P, Churg A, et al. Diseases of small airways. Ann Rev Respir Dis 1992; 146:240-262

[11] Schoen H, Foedinger D, Defiler K, et al. Immunoapheresis in paraneoplastic pemphigus. Arch Dermatol 1998; 134:706-710

(*) From the Department of Dermatology (Drs. Takahashi and Kazama), Niigata University School of Medicine, Niigata, Japan; the Department of Dermatology (Dr. Takahashi), the Department of Internal Medicine (Drs. Shimatsu and Otsuka), and the Department of Pathology (Dr. Kimura), Shibata Prefectural Hospital, Shibata, Niigata, Japan; and the Department of Dermatology (Dr. Hashimoto), Kurume University School of Medicine, Kurume, Fukuoka, Japan.

Manuscript received May 6, 1999; revision accepted August 10, 1999.

Correspondence to: Michiyo Takahashi, MD, PhD, Department of Dermatology, Shibata Prefectural Hospital, 4-5-48 Ootemachi, Shibata, Niigata 957-00.52, Japan; e-mail: michiyo@sbt.lamen. or.jp

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