Interstitial lung disease is a common and often life-threatening manifestation of different connective tissue disorders, often affecting its overall prognosis. Systemic lupus erythematosus, Sjögren syndrome, and mixed connective tissue disease, although all unique diseases, can have lung manifestations as an important part of these conditions. This article reviews the different pulmonary manifestations seen in these 3 systemic rheumatologic conditions.
Systemic lupus erythematosus (SLE) has varied and frequent lung manifestations.
Sjögren syndrome (SS) is an exocrinopathy that can affect the respiratory epithelium, leading to airway disease as the main pulmonary manifestation.
In SLE and mixed connective tissue disease (MCTD), the main pulmonary manifestations are pleuritis and interstitial lung disease.
The more common form of ILD in SS, SLE, and MCTD is nonspecific interstitial pneumonitis.
Beside scleroderma, SLE and MCTD are the connective tissue diseases associated more commonly with pulmonary arterial hypertension.
Pulmonary manifestations of Sjögren syndrome
Sjögren syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands. The term sicca syndrome is the result of dry eyes (xerophthalmia) and dry mouth (xerostomia) secondary to this involvement. It may present as a primary disease, called primary SS (pSS), or be associated with other autoimmune rheumatic diseases, when is called secondary SS (sSS).
The new American–European criteria have been used internationally during the last decade, but they present some limitations because they do not include the systemic manifestations, which predict prognosis. A new approach to classification has been recently proposed.
SS is an exocrinopathy and epitheliitis characterized by lymphoproliferation and lymphocyte infiltration of glandular and nonglandular tissue. It is also a lymphocyte aggressive disease with infiltration of T and B cells into affected tissues. This lymphocyte proliferation initially contains T helper cells (CD4), B cells, and plasma cells, but in a small percentage of patients, it may continue in a dysregulated fashion to develop into lymphoma. Extraglandular involvement has been associated with an higher incidence of autoantibodies, immune complexes, and lower complement levels, which suggests that immune complex deposition plays a role in the pathogenesis of lung disease.
The population-based annual incidence of SS is 5.1 per 100,000 population, and diagnosis of pSS increases with age (18–44 years, 2.1 per 100,000 vs >75 years, 12.3 per 100,000). Survival of these patients is comparable with that of the general population. There is female predominance (9:1). On the other hand, it is estimated that up to 50% of pSS patients are currently underdiagnosed, and up to 30% of patients with other autoimmune diseases can be diagnosed with sSS.
Assessment of the prevalence of pulmonary involvement in SS varies considerably because of the nonstandardized diagnostic criteria and the inclusion of patients with pSS and sSS in different trials. In addition, there is no clear consensus regarding the definition of lung involvement. Most published studies indicate a prevalence of around 9 to 12%; however, if general clinical examination, pulmonary function tests (PFT), and radiologic tests are used, the prevalence increases to up to 60%. Cough and dyspnea are the most common respiratory abnormalities seen in SS, and incidence of these findings increases over the duration of the illness. The consensus is that patients who have secondary disease (sSS) are more likely to have more severe lung involvement because the underlying primary diseases also contribute to pulmonary pathology. Risk factors for lung disease include hypergammaglobulinemia, lymphopenia, positive rheumatoid factor, presence of anti-Ro and anti-La antibodies, decreased forced vital capacity and forced expiratory volume in 1 second, smoking history, male gender, and advanced age at diagnosis.
Chest x-rays described in early studies showed nonspecific findings. High-resolution CT (HRCT) of the chest improved sensitivity. The main findings are signs of small airway disease, parenchymal nodules, patchy areas of ground glass attenuation, subpleural small nodules, nonseptal linear opacities, and parenchymal cysts. When the main finding is ground glass opacities, there is a predominant lower lung distribution. In contrast, pulmonary nodules are found mostly over the upper lobes.
Multiple, thin-walled air cysts are rare in other disorders and may be a crucial finding in pSS. On HRCT, they appear as well-defined, round, thin-walled airspaces that have a tendency to spread to peribronchovascular regions. Overall, the HRCT features correlate well with the histopathologic findings, when biopsy is available for evaluation.
Pulmonary function tests
The frequency and type of physiologic impairment described in SS have varied widely, with trials showing reduced diffusion capacity for carbon monoxide (DLCO), restriction, and obstruction, but, in general, small airway dysfunction is likely the more prevalent.
In addition, almost all studies agree that the degree of physiologic damage is typically mild, as demonstrated in a 10-year follow-up study of 30 patients with pSS, in which there was evidence of improvement in DLCO in some patients, suggesting that most patients do not develop progressive disease.
Bronchoalveolar lavage and lung pathology
A few specimens of bronchoalveolar lavage have been analyzed in different series, with lymphocytosis commonly found, and there have been some additional reports of increased numbers of neutrophils. Transbronchial biopsies have been obtained rarely, with reported findings including amyloidosis and organizing pneumonia, but it was through open lung biopsy that different patterns were defined, the most common of which were nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), and lymphocytic interstitial pneumonia (LIP).
Airway lesions owing to glandular dysfunction and destruction may involve the trachea, bronchi, and bronchioles (distal airways), and these are the more frequent tissues affected in this disease.
Exocrine glandular lesions are more frequently associated with tracheobronchial symptoms. Sixty percent of patients in different series report having dry cough day and night. Recurrent respiratory infections (bronchitis, pneumonia) are associated with airway dysfunction in 20% of the patients with SS. Proximal airway destruction may be responsible for bronchiectasis, as demonstrated by a cohort of 41 patients with pSS, who had cylindrical bronchiectasis on CT. These patients tended to be older at the time of diagnosis of SS and had a higher frequency of hiatal hernias.
Distal airway disease
Airway inflammation has been detected, and increased numbers of lymphocytes in the bronchial mucosa have been documented. In addition, bronchiolitis secondary to extraglandular lesions may be isolated or associated with interstitial disease, such as LIP or NSIP. Follicular bronchiolitis is an uncommon bronchiolar disorder characterized by the presence of hyperplastic lymphoid follicles with reactive germinal centers distributed along bronchovascular bundles, and has been noted in SS. The main symptoms associated with bronchiolitis are dry cough, recurrent infections, and dyspnea. Chest CT findings in bronchiolitis are characterized by signs of small airway disease with centrolobular nodules, nonseptal linear opacities, cysts, and in some cases, mild bronchiectatic changes. In addition, mosaic attenuation, which indicates obstructive bronchiolitis, may be observed and demonstrate enhancement on expiratory HRCT. In cases of follicular bronchiolitis, areas of nodular centrilobular or ground glass attenuation, mild thickening of interlobular septa and bronchovascular bundles, and occasionally air cysts can be present. Based on scattered data, it seems that the bronchial and bronchiolar disease in SS is benign with a stable course and good response to treatment.
Interstitial lung disease
Interstitial lung disease (ILD) is well-described in SS. Historically, the predominant form of ILD in pSS was deemed to be LIP, but more recently the more common pathologic pattern identified has been NSIP, UIP, and organizing pneumonia.
NSIP is characterized histologically by varying proportions of interstitial inflammation and fibrosis that are temporally uniform. The findings in CT chest images include ground glass opacities with subpleural and basilar predominance. Most patients present with dyspnea with exertion as the main symptom and restrictive pattern with decreased DLCO on PFT.
UIP was documented in 17% of cases in 1 cohort. It is characterized histologically by areas of fibrosis alternating with normal lung. As in NSIP, patients present with progressive dyspnea, and the PFT show restriction and decreased DLCO. The radiologic pattern shows as well predominant findings in the lower lobes, but includes reticulation and honeycombing. Among all subtypes of ILD associated with connective tissue disease (CTD), UIP has the worst prognosis, and in fact, in this cohort of patients, when this pattern was documented in SS in this cohort of patients, they had progressive disease.
SS is among the most common diseases associated with LIP. It is characterized by diffuse interstitial infiltration of lymphocytes and plasma cells that diffusely expand the alveolar septa and small airways. The patients develop dyspnea, cough, and sometimes chest pain. PFT can present with a mixed pattern of obstruction and restriction. The chest CT reveals diffuse ground glass opacity and consolidation, with occasional thin-walled cysts, presumably owing to follicular bronchiolitis. In this last case, cystic lung disease can be documented.
Organizing pneumonia is an entity characterized by intraluminal inflammatory debris composed of masses of fibroblasts and myofibroblasts in the alveolar ducts and airspaces with coexistent chronic inflammation of the surrounding alveoli. Clinical findings of dyspnea, associated with fever, constitutional symptoms, and lung infiltrates, could be present. Chest CT chest shows areas of consolidation.
Patients with SS are at increased risk of developing non-Hodgkin lymphoma. The largest cohort of patients analyzed showed that the risk was increased either in primary pSS and sSS, but the group of patients with pSS has the greatest incidence. Subsequent trials, including only patients with pSS, have shown a 16-fold increased risk for development of non-Hodgkin lymphoma compared with the general population. Typically, these lymphomas are mostly composed of mucosa-associated lymphoid tissue (50%) and marginal zone B-cell lymphoma (40%) with low-grade malignancy. The prognosis is usually good, with an average survival rate of 65% to 90%. Risk factors include major gland enlargement, mainly bilateral parotid, and non-exocrine manifestations, such as skin vasculitis, lymphadenopathy, and peripheral nerve involvement. Radiologic findings in pulmonary pSS lymphoma are nonspecific; chronic alveolar opacities, reticular or reticular nodular opacities, diffuse nodular lesions, or pleural effusion have been reported. Bilateral disease is present in 25% to 50% of cases. Mediastinal involvement is not described commonly. In general, LIP with unexpectedly aggressive behavior raises the question of a possible malignancy.
Psuedolymphoma, also called pulmonary nodular lymphoid hyperplasia, is a benign lesion characterized by infiltration of mature polyclonal lymphocytes and plasma cells, with the presence of solitary nodule or consolidation on CT chest. It usually responds to corticosteroid therapy and progresses rarely to frank lymphoma.
This is a rare complication of SS, and most of the data are based on case reports. Most cases (91%) occur in pSS, with women being most frequently affected. CT of the chest shows diffuse septal, nodular infiltrates, cystic lesions, and areas of calcification.
Pleural involvement is rare in pSS, and its presence should prompt evaluation for the underlying etiology. Some cases of unilateral or bilateral pleuritis attributed to SS have been reported. Pleural thickening has been seen as well.
Mediastinal manifestations include lymphadenopathy, thymic lymphoid hyperplasia, and multilocular thymic cysts. The coexistence of these mediastinal lesions and pulmonary abnormalities may indicate pSS. On CT, these lesions are indicated by the presence of multiple nodules and increased attenuation of anterior mediastinal fat tissue.
In the setting of SS, pulmonary hypertension (PH) can be the result of vasculopathy or can also be associated with lung disease, given that in the few known case series, the prevalence of lung disease has been significant. In a trial that analyzed proven cases of PH by RHC, patients presented with advanced disease (New York Heart Association class III–IV) at the time of the diagnosis. On the other hand, in a recent trial, 11 patients (all women) with pSS were found to have evidence of PH on transthoracic echocardiography and, although the diagnosis was not confirmed by RHC, these patients were significantly younger at the time of the diagnosis compared with patients without PH, which suggests that perhaps more aggressive and early investigation of this complication should be considered in this population. In both studies, the patients with PH were more likely to have Raynaud phenomenon and cutaneous vasculitis, and antinuclear, anti-Ro/SSA, anti-RNP autoantibodies, positive rheumatoid factor, and hypergammaglobulinemia.
The treatment for pulmonary disease in SS has not been well established, given the low number of cases evaluated. In 1996, a cohort of 11 patients was treated with azathioprine, and significant improvement in forced vital capacity after 6 months was reported compared with nontreated patients. In a subsequent trial that included 18 patients, 15 received only corticosteroids and 4 received azathioprine or cyclophosphamide in addition to corticosteroids (2 were on azathioprine and 2 on cyclophosphamide), with a good response in most of cases. More recently, the efficacy of rituximab in systemic manifestations of pSS was analyzed in the autoimmune and rituximab registry, and in 9 cases with pulmonary compromise (1 with bronchial involvement and 8 with ILD), its efficacy was 78%. Finally, in a trial which evaluated the effect of mycophenolate mofetil on lung function in CTD–associated ILD, which included 4 patients with pSS, this medication was associated with functional improvement.