Interstitial Pneumonia Associated with Linear Immunoglobulin A/Immunoglobulin G Bullous Dermatosis

• The presence of immunoglobulin A (IgA) and IgG antibodies bound to the basement membrane zone of skin lesions is accepted as a characteristic feature of linear IgA/IgG bullous dermatosis.

• Lung disorders associated with linear IgA/IgG bullous dermatosis are extremely rare, and interstitial pneumonia associated with this dermatosis has not been previously reported.

• We describe the first case of linear IgA/IgG bullous dermatosis-associated interstitial pneumonia in which direct immunofluorescence was used to demonstrate the deposition of IgA, IgG and C3 along the epithelial cell membrane and basement membrane of the bronchioles and alveoli.

• Similarly to in the skin, certain components in the epithelial cell membrane and basement membrane of the bronchioles and alveoli may be targeted by autoantibodies; this might contribute to the progression of interstitial pneumonia.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune subepidermal bullous disease characterized by linear IgA deposits in the epidermal basement membrane zone [1]. Some cases demonstrate linear deposits of IgG and IgA, i.e. linear IgA/IgG bullous dermatosis (LAGBD) [2]. Lung disorders associated with LABD or LAGBD are extremely rare. Here we describe the first case, to our knowledge, of interstitial pneumonia associated with LAGBD.

A 76-year-old man with interstitial lung disease was referred to our institution after developing persistent dyspnea upon effort of grade 2 based on the modified Medical Research Council Dyspnea Scale [3]. He denied having any cough. He was an exsmoker (20 cigarettes/day for 51 years), having quit 6 years previously. He had been diagnosed with vesicular pemphigoid 21 years previously, and had been stable on a maintenance dose of oral prednisolone of 8 mg/day. However, his skin lesions had relapsed at the time of his referral.He had been taking the following medications other than prednisolone:zolpidem tartrate, alendronate sodium hydrate, famotidine, ketotifen fumarate, telmisartan, furosemide, torasemide and allopurinol. These were all prescribed by his primary care physician and had not been changed for several years. He had never been exposed to any infectious, toxic or environmental factor that could cause interstitial lung disease. Physical examination demonstrated multiple pustules, vesicles and erosions with erythema on the trunk and proximal upper and lower extremities (fig. 1). He was afebrile. On chest auscultation, fine crackles were detected bilaterally. No extrathoracic signs were detected besides the skin lesions. Arterial blood gas analysis on room air revealed a pH of 7.48, PaO₂ of 77 mm Hg and PaCO₂ of 32 mm Hg. Laboratory examinations upon admission revealed a white blood cell count of 10,600/mm³ with 66% neutrophils. Anti-single strand deoxyribonucleic acid antibody was positive (27.8 AU/ml), but other autoantibodies to specific antigens, including anti-nuclear antigen, were all negative. Pulmonary function tests demonstrated the following diffusion impairment: % predicted vital capacity (%VC) 83.3%, % predicted forced vital capacity (%FVC) 84.0% and % predicted diffusing capacity for carbon monoxide (%DLCO) 64.5%. A biopsy specimen from a skin lesion showed subepidermal blisters with lymphocyte infiltrates in the dermis and inside the blister cavity. Direct immunofluorescence of the specimen showed the linear deposition of IgG, IgA and C3 along the basement membrane. These findings indicated a definitive diagnosis of LAGBD. Chest radiography showed reticular shadowing with basilar predominance (fig. 2). Chest computed tomography (CT) showed patchy ground-glass attenuation and reticular opacities, predominantly in the peripheral lung fields (fig. 3). Although chest CT revealed traction bronchiectasis in the bilateral lower lobes, neither honeycombing nor mediastinal lymphadenopathy were evident. Bronchoscopy revealed no abnormalities from the pharynx to the subsegmental bronchi. Examination of bronchoalveolar lavage fluid from the left B5 bronchus showed a total cell count of 1.18 × 10⁵ cells/ml, comprising 65% macrophages, 30% lymphocytes, 2% neutrophils and 3% eosinophils. The CD4/CD8 ratio of lymphocyte subsets was 1.42. Siderophages were not evident. Transbronchial lung biopsy specimens of the left lateral basal segment (S9) showed alveolar septal thickening and inflammatory cell infiltration (fig. 4). Direct immunofluorescence of the specimen revealed deposition of IgA, IgG and C3 along the epithelial cell membrane and basement membrane of the bronchioles and alveoli (fig. 5). Although bronchoalveolar lavage fluid findings, imaging findings and histopathological analysis of the transbronchial lung biopsy specimens suggested a pattern of nonspecific interstitial pneumonia, it was difficult to make a definite pathological diagnosis because a surgical lung biopsy was not performed. Oral prednisolone was increased to 20 mg/day, which was then tapered off gradually to a maintenance dose of 13 mg/day. Although the skin lesions improved, the pulmonary lesions did not. The patient's dyspnea upon effort and the chest CT findings remained stable over 18 months of follow-up. However, pulmonary function tests demonstrated a gradual deterioration, and the results 18 months after presentation were as follows: %VC 74.2%, %FVC 73.2% and %DLCO 32.5%.

To our knowledge, this is the first reported case of interstitial pneumonia associated with LAGBD. Both LABD and LAGBD may present with lesions of the skin or mucous membranes, or both. Any mucosal surface may be affected, including the oral cavity, conjunctiva, nose, genitalia, pharynx, larynx, anus and esophagus [4,5]. Serious adverse consequences of cicatrizing mucosal disease include airway obstruction in the pharynx and larynx [5,6]. LABD or LAGBD rarely involves the lower respiratory tract. The few case reports of respiratory lesions associated with these skin conditions have described involvement of the bronchial mucosa with subepithelial blister formation [7], sarcoidosis [8] and tracheomalacia [5,9]. However, in this case, bronchoscopy revealed no abnormalities from the pharynx to the subsegmental bronchi. To the best of our knowledge, interstitial pneumonia associated with LAGBD has not been reported previously.

Although the presence of IgA and IgG antibodies bound to the basement membrane zone is considered a characteristic feature of LAGBD, the mechanism of lesion formation is not well understood. Tissue injury resulting from an antibody-induced local inflammatory response and the release of proteolytic enzymes by neutrophils and other inflammatory cells may contribute to the development of skin and mucosal lesions [4]. Most patients with LABD have IgA1 antibodies that target a 97-kDa antigen and a 120-kDa antigen within the basement membrane zone. Both of these antigens are fragments of the extracellular portion of BP180, a transmembrane protein with a key role in epidermal-dermal adhesion [10,11]. Other reported autoimmune targets for LABD include collagen VII, BP230 and LABD97 [2].

Abnormalities in epithelial cell function have been proposed as central to the pathogenesis of interstitial pneumonia. In this case, direct immunofluorescence of the biopsied lung specimen showed deposition of IgA, IgG and C3 along the epithelial cell membrane and basement membrane of the bronchioles and alveoli. Similarly to in the skin, certain components in the epithelial cell membrane and basement membrane of the bronchioles and alveoli may be targeted by autoantibodies. Yoshioka et al. [12 ]reported similar findings in a patient with bullous pemphigoid. This immunological reaction might have contributed to the progression of interstitial pneumonia in our patient.

In conclusion, we described the first case of LAGBD-associated interstitial pneumonia. Clinicians should be aware that interstitial pneumonia may be a pulmonary manifestation of LAGBD.

The authors do not have any competing interests and/or bias with regard to the publication.