Current Respiratory Medicine Reviews - Volume 11, Issue 2, 2015

The increased sensitivity and specificity of high-resolution computed tomography (HRCT) has allowed medical imaging to become an essential part of the diagnosis and management of interstitial lung disease (ILD). ILD is a common finding of many different collagen vascular diseases (CVDs) especially rheumatoid arthritis and scleroderma. As our understanding of CVD-associated ILD (CVD-ILD) improves, HRCT becomes an increasingly important tool for diagnosis and management.

Interstitial lung disease (ILD) has been described as a potential clinical finding in essentially all of the connective tissue diseases (CTD). Patients with Rheumatoid Arthritis most commonly develop a fibrotic pattern consistent with Usual Interstitial Pneumonia while Non-Specific Interstitial Pneumonia is more commonly seen in the remainder of the collagen vascular diseases, in particular in patients with Scleroderma-spectrum disease. The etiology of ILD in the CTDs is poorly understood and the progression of lung disease may not correlate with the more typical autoimmune manifestations. Therapy of CTD-associated ILD remains unsatisfactory and the clinical picture may be clouded by the probability that some patients with apparently idiopathic ILD will, eventually, evolve into a more clearly-defined CTD and by the possibility that in some patients with lung-dominant disease subtle evidence of underlying CTD may be missed. In this review we will examine the etiologic, histologic, radiographic, and epidemiologic features of the Idiopathic Intersitial Pneumonias in comparison with their CTD-associated counterparts as well as address some of the difficulties in assessing whether ILD is truly idiopathic or instead part of an underlying autoimmune process.

Pulmonary complications associated with autoimmune connective tissue disease (CTD) are common causes of clinical interstitial lung disease (ILD). Pleural manifestations are dominated by inflammation and varying amounts of diffuse fibrosis. In the lung, a wide spectrum of histologic injury patterns are encountered in every anatomic location including small airway disease most commonly in the form of chronic bronchiolitis, vascular changes, and interstitial lung disease ranging from diffuse alveolar damage to advanced pulmonary fibrosis. The most common interstitial pattern, seen in nearly all of the different CTDs, is a cellular and variably fibrotic ILD referred to as nonspecific interstitial pneumonia (NSIP). Each of the major CTDs has particular manifestations more commonly manifested, but the histopathologic changes found in these CTDs are often not specific and a definitive diagnosis usually requires detailed clinical, serologic, and pathologic correlation as well as close patient follow-up.

Interstitial lung diseases comprise a large group of pulmonary disorders characterized by lung inflammation and fibrosis. Often, these disorders are progressive leading to irreversible tissue scaring. The absence of effective and safe anti-fibrotic drugs has prompted the search for targets for intervention that could lead to new strategies for treatment. Animal models of lung fibrosis, although not resembling exactly the human condition, represent invaluable tools for the exploration of the factors and mechanisms involved in the development of lung fibrosis. In this review, we briefly discuss current concepts related to the pathogenesis of lung fibrosis followed by a more thorough discussion of currently available animal models of lung fibrosis. Experimental models induced by chemical agents, haptens, infection, genetic manipulation, and irradiation are discussed as are cell-mediated models and spontaneous models of lung fibrosis in domestic animals.

Systemic sclerosis is a disease of typically middle aged women, with significant morbidity and mortality predominantly caused by lung involvement. Screening for and diagnosis of interstitial lung disease is critical given the decreased survival associated with progressive fibrotic lung disease. Monitoring of disease is necessary once the diagnosis has been made, and surgical lung biopsy is usually unnecessary. Treatment centers on immunosuppressants without additional steroids with attention to identification and management of co-existing complications, such as pulmonary hypertension and gastro-esophageal reflux, as well as supportive therapy with supplemental oxygen and exercise. Referral for lung transplant evaluation should be considered when there is persistent progression.

Lung disease is a major morbidity of rheumatoid arthritis (RA). Lung involvement is heterogeneous, and may occur in some form in over 50% of patients with RA. Clinically apparent interstitial lung disease (ILD) affects about 8 % of patients, most commonly usual interstitial pneumonitis. Pulmonary disease is a major cause of death in patients with RA; patients with ILD have a median survival of 2.6 years following diagnosis of the lung disease, lowest in patients with diffuse alveolar damage. Risk factors for RA related lung disease include male sex, older age, smoking, and more severe RA with erosive joint and other extraarticular involvement. Drugs used in management of RA may be associated with pulmonary toxicity, including methotrexate, leflunomide and some biologics. In ILD, lung function studies show a restrictive pattern, with low DLC0 a sensitive parameter of early ILD. High resolution chest computed tomography is sensitive for demonstrating ILD. Treatment of RA associated lung disease is guided by the type of pulmonary disease, recognizing that control of the underlying RA is critical to reducing the impact of disease related comorbidities. Much remains to be done to better understand the pathogenesis and management of this disease manifestation.

The clinical, radiographic, and histopathologic features of ILD in myositis are similar to idiopathic ILD. Patients with a known diagnosis of inflammatory myopathy require a prompt clinical evaluation and the assessment of myositis-associated autoantibodies. Patients possessing autoantibodies associated with ILD or those with any pulmonary symptoms should have pulmonary functions test and high resolution CT (HRCT) scanning of their lungs. Despite the lack of placebocontrolled trials, systemic glucocorticoids are considered the mainstay of initial treatment of myositisassociated ILD. Glucocorticoid-sparing agents are often started concomitantly with glucocorticoids, particularly in patients with severe disease. The first-line conventional immunosuppressive drugs include either mycophenolate mofetil or azathioprine. If these agents fail or if the features are more severe or rapidly progressive, then more aggressive immunosuppressive or immunomodulatory therapy including cyclophosphamide, tacrolimus or cyclosporine, or rituximab should be considered. Further investigations are required to assess the role of novel therapies in the treatment of myositis-associated ILD.

Interstitial lung disease is a serious complication of connective tissue disorders causing significant morbidity and mortality. While interstitial lung disease is a less commonly noted respiratory manifestation in systemic lupus erythematosus where other pulmonary processes predominate, it is increasingly recognized in patients with Sjogren’s syndrome and can be severe and progressive in patients with mixed connective tissue disease as well. Interstitial lung disease may be the initial or predominant presentation of these connective tissue diseases, thus a systematic evaluation for autoimmune symptoms and serologies is required for accurate diagnosis. The objective of this review is to present our current knowledge of interstitial lung disease in systemic lupus erythematosus, Sjogren’s syndrome and mixed connective tissue disease. We discuss the clinical presentation and highresolution CT and histopathologic patterns typical of interstitial lung disease in each of these three connective tissue diseases. We review management recommendations, and when available, present the evidence regarding specific medications used for treatment. We begin with general comments about the diagnostic evaluation of patients with connective tissue disease associated interstitial lung disease and conclude with a brief discussion of our clinical practice for follow-up of these patients. While our knowledge of the manifestations of interstitial lung disease in systemic lupus erythematosus, Sjogren’s syndrome and mixed connective tissue disease has increased, data regarding management and evidence for benefit of therapy remains limited.

The connective tissue diseases (CTD) are frequently associated with Interestitial lung diseases (ILD). The presence of an ILD in a patient with CTD is associated with a higher morbidity and mortality. Management of a patient with connective tissue interstitial lung disease (CTD-ILD) depends on disease severity with a focus on improving quality of life. Therapeutic interventions include medications, which aim to prevent progression to fibrosis and decrease inflammation or alveolitis, supplemental oxygen; and pulmonary rehabilitation. Comorbidities including gastroesophageal reflux disease (GERD) and obstructive sleep apnea should be addressed in all CTD-ILD patients. Appropriate referral to support groups, lung transplantation centers, and palliative care are considerations for all patients with CTDILD. The management of a patient with CTD-ILD is a multidisciplinary personalized process that is driven by the specific disease, clinical pattern, and associated comorbidities.

There is a paucity of research and a lack of necessary guidance for proper characterization of pulmonary hypertension presenting in patients with connective tissue disease and interstitial lung disease, specifically related to differentiating between WHO group 1 pulmonary arterial hypertension and WHO group 3 pulmonary hypertension due to lung disease and/or hypoxia. Without a mechanism for proper differentiation of the type of pulmonary hypertension that exists, appropriate management of this subset of individuals is particularly challenging. This review presents the pertinent research that exist regarding the intricacies of this disease state with the goal of providing improved guidance as to who may benefit from screening, diagnosis, treatment in a facility with expertise in the field, and referral for lung transplant.

The chronic fibrosing idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous pulmonary parenchymal disorders described by radiologic and histological patterns termed usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). These include idiopathic pulmonary fibrosis (IPF) and those related to connective tissue disease (CTD) and are associated with substantial morbidity and mortality. Beyond the importance of establishing an appropriate diagnosis, designing optimal clinical trials for IIPs has been fraught with difficulties in consistency of clinical endpoints making power analyses, and the establishment of efficacy and interpretation of results across trials challenging. Preliminary recommendations, developed by rigorous consensus methods, proposed a minimum set of outcome measures, a ‘core set’, to be incorporated into future clinical trials (Saketkoo et al, THORAX. 2014.). This paper sets out to examine the candidate instruments for each domain (Dyspnea, Cough, Health Related Quality of Life, Imaging, Lung Physiology and Function, Mortality). Candidate measures that were not selected as well as measures that were not available for examination at the time of the consensus process will also be discussed.

Objective: The impact and natural history of connective tissue disease related interstitial lung disease (CTD-ILD) are poorly understood; and have not been previously described from the patient’s perspective. This investigation sought insight into CTD-ILD from the patients’ perspective to add to our knowledge of CTD-ILD, identify disease-specific areas of unmet need and gather potentially meaningful information towards development of disease-specific patient-reported outcome measures (PROMs). Methods: A mixed methods design incorporating patient focus groups (FGs) querying disease progression and life impact followed by questionnaires with items of importance generated by >250 ILD specialists were implemented among CTDILD patients with rheumatoid arthritis, idiopathic inflammatory myopathies, systemic sclerosis, and other CTD subtypes. FG data were analyzed through inductive analysis with five independent analysts, including a patient research partner. Questionnaires were analyzed through Fisher’s Exact tests and hierarchal cluster analysis. Results: Six multicenter FGs included 45 patients. Biophysiologic themes were cough and dyspnea, both pervasively impacting health related quality of life (HRQoL). Language indicating dyspnea was unexpected, unique and contextual. Psycho-social themes were Living with Uncertainty, Struggle over Self-Identity, and Self-Efficacy - with education and clinician communication strongly emphasised. All questionnaire items were rated ‘moderately’ to ‘extremely’ important with 10 items of highest importance identified by cluster analysis. Conclusion: Patients with CTD-ILD informed our understanding of symptoms and impact on HRQoL. Cough and dyspnea are central to the CTD-ILD experience. Initial FGs have provided disease-specific content, context and language essential for reliable PROM development with questionnaires adding value in recognition of patients’ concerns.