Current Rheumatology Reviews - Volume 6, Issue 2, 2010

The issue of interstitial lung disease (ILD) often comes up in the clinical practice of rheumatology. The etiology, risk factors, exacerbating factors, and treatment of ILD in the context of autoimmune diseases is the topic of this month's Current Rheumatology Reports. As laid out by Dr. Matteson in his editorial, research in this field is complicated by the lack of standardized criteria for the diagnosis and the lack of widely accepted outcome measurements. The international CTD-ILD interest group is trying to address this problem by developing standardized clinical trial assessments. In a thought provoking piece in this issue of the journal, this group has laid out their vision of how to achieve such a standardization. Additionally, superb reviews on ILD in scleroderma, SLE, RA, Sjogren's and myositis are presented here. The reader will also find useful insights in the review of The idiopathic interstitial pneumonias and CTD associated ILD by Swigris and colleagues. It has been our goal at the journal to provide a forum for thought leaders to share their insights on the state of their field of expertise. Indeed, we have achieved this goal spectacularly in this issue of the journal.

The interstitial lung diseases (ILD) are a heterogeneous group of pulmonary disorders which diffusely affect the lung parenchyma including the small airways and alveolar structures. While many are of unknown cause, others have known clinical associations including infection, a diversity of inhaled, oral or parenteral exposures (including drugs, tobacco smoke, occupational and environmental exposures), and a variety of systemic diseases. In particular, ILD frequently complicates connective tissue disease (CTD), having a major negative impact on quality of life and disease course; pulmonary involvement is the leading cause of death in systemic sclerosis and an important cause of morbidity and mortality in other connective tissue diseases including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus and inflammatory myopathies. In many ways, connective tissue disease-associated ILD (CTD-ILD) remains an enigma. Our understanding of underlying pathogenesis and ability to detect these conditions early remain quite limited. For the clinician and clinical researcher, there exists no consensus on appropriate measurement of disease activity or what constitutes a significant response to therapeutic intervention. The lack of this information inhibits effective drug development and hampers the regulatory evaluation of candidate therapies. For example, in recent years, using pathologic insights gleaned from the biologic investigation of autoimmunity, a diverse range of data-driven “rational” therapies has emerged, from broad immunosuppressants (cyclophosphamide, mycophenolate mofetil) and antifibrotics (tyrosine kinase inhibitors, pirfenidone) to more specifically targeted interventions (rituximab, TGF-β trapping strategies). While substantial progress might have been expected from trials evaluating their efficacy, lack of validated and accepted criteria for assessment of disease activity or response to treatment has hampered our ability to interpret their results. Without cohesive domains and measures, there is no way to safeguard the investments made by research and development. This issue of Current Rheumatology Reviews addresses this important area. There are emerging data relevant to ILD in the setting of each specific CTD yet there are also strong commonalities between them. Many questions remain regarding shared pathogenic mechanisms but also importantly about approaches which should be taken by the bedside clinician and the clinical researcher. Is there a core group of measures that can define activity, response and outcome? Is quantification of the extent of lung disease by high resolution CT a generalizable measure or only a tool for focused research? Pulmonary physiologic testing, e.g. forced vital capacity, is accessible, reproducible, cost effective and sensitive to change but is it confounded by concurrent chest wall weakness or pleural disease? What about exercise capacity, e.g. six minute walk testing - a robust outcome measure in trials of pulmonary hypertension? How does this apply to the individual with active lower extremity joint disease? Importantly, also, each of the CTDs has its own unique set of clinical features which may affect not only the type and expression of associated lung disease but also the exact nature of pulmonary involvement in individual patients. This relationship is particularly relevant to the study of specific CTD-ILD in randomized controlled trials (RCTs). For example, what is the utility of exercise testing in a patient with rheumatoid arthritis who has a high disease activity score and/or lower extremity joint involvement? How do these disease features affect the performance and interpretation of pulmonary function tests? To what extent does muscle involvement in patents with dermatomyositis, or sicca syndrome in patients with Sjogren's syndrome, adversely affect the performance of pulmonary function testing. To date, there is no agreement on the best approach to evaluation of lung involvement in the clinic or in the context of clinical trials for any single CTD-associated ILDs. How best to approach the problem of lung disease assessment in CTD-ILD for study in an RCT? To address this, a review of the available relevant literature can serve as a useful starting point, as presented in this volume of CRR. Information from the literature, interpreted by clinician scientist's expert in these diseases, forms a useful basis for evaluating the best evidence for developing outcome criteria for RCTs in CTD-ILD. A formal process to develop consensus can then provide an initial approach for assessment of lung disease in these CTDs, which necessarily will be followed by formal testing in RCTs and longitudinal observational studies (LOS)....

The idiopathic interstitial pneumonias (IIP) are seven fibro-inflammatory interstitial lung diseases of unknown cause, grouped together because of potentially similar clinical features. Each of the seven has a distinct histologic pattern; however, these patterns are not specific to the IIP, and they provide a framework for defining interstitial lung disease (ILD) of known-cause, including ILD associated with underlying connective tissue disease (CTD). With the exception of respiratory bronchiolitis, the histologic patterns corresponding with the other six IIP can be found in association with CTD. Considering all CTD together, the pattern of non-specific interstitial pneumonia is most common. High-resolution computed tomography (HRCT) can hint at the histologic pattern, track changes over time, and assess response to therapy. The goal of this article is to review histologic patterns and HRCT findings of the IIP as they relate to CTD-associated ILD.

Systemic lupus erythematosus (SLE) is a systemic, inflammatory disorder with a predilection for young women. A wide array of pulmonary manifestations can occur in patients with SLE, including interstitial lung disease. In this review, we will discuss the scope, pathogenesis, management, and prognosis, along with the clinical and pathologic features of SLE-associated ILD (SLE-ILD).

The lung is one of the most common extra-muscular targets in idiopathic inflammatory myopathies (IIM) and interstitial lung disease (ILD) is a prevalent and often devastating manifestation of IIM. IIM-associated ILD (IIM-ILD) contributes to nearly 80% of the mortality in IIM with a reported prevalence of 65% of newly diagnosed IIM cases. Although ILD frequently accompanies clinical and laboratory findings of myositis, overt signs of muscle disease may be absent in the setting of significant lung disease. Understanding the varied scope of presentation of these diseases is essential to providing optimal patient care. This review will provide an in depth examination of ILD in IIM both from a rheumatologic and pulmonary perspective and will discuss the scope of disease, presenting features, genetic associations, pathogenesis, diagnosis, radiographic and histopathologic findings, along with biomarker assessment and a rationale for therapeutic intervention.

Rheumatoid arthritis (RA) affects 1-2% of the general population. Although often thought of as primarily a localized inflammatory disorder with associated joint destruction, it is a diffuse systemic disease. Extra-articular manifestations of rheumatoid arthritis can be demonstrated in almost 50% of patients with RA, and include pulmonary, cardiac, ocular, renal, hematologic, and neurologic involvement. In this article, we review recent studies of interstitial lung disease (ILD) in RA with a focus on clinical and pathological features of rheumatoid arthritis associated interstitial lung disease (RA-ILD). We discuss an approach to the diagnosis and treatment of RA-ILD including potential biomarkers, and conclude by outlining areas for future research.

Sjogren's syndrome (SS), whether primary, or secondary to other autoimmune rheumatic diseases, is classically associated with the sicca complex of keratoconjunctivits and xerostomia. However, extraglandular manifestations are also relatively common, affecting up to 25% of patients. In this article, we discuss respiratory system involvement in SS, with a focus on interstitial lung disease (ILD). We review the histopathologic variants, clinical features, diagnosis and treatment of SS-ILD. Novel and emerging diagnostic and prognostic biomarkers for SS-ILD are also discussed. We offer an approach to the management of SS-ILD including possible goals of therapy. We conclude by highlighting areas for future research.

Pulmonary involvement including interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (scleroderma; SSc). This article reviews the current evidence based medicine regarding available therapies for SSc-ILD; discusses the lessons learned from recent SSc-ILD randomized controlled trials (RCTs); and proposes outcome measures and recommendations for design of future RCTs for SSc-ILD.

This review article discusses the proposed methodology that will be utilized to develop core set items for connective tissue disease-associated interstitial lung disease (CTD-ILD). CTD-ILD remains an important enigma in clinical medicine. No consensus exists on measurement of disease activity or what constitutes a significant response to therapeutic interventions. Lack of appropriate measures inhibit effective drug development and hamper regulatory evaluation of candidate therapies. An interdisciplinary and international Steering Committee (SC) will oversee the execution of a 3-tier Delphi exercise involving experts in CTD and ILD. In parallel to the Delphi, qualitative information will be gathered from patients with ILD using focus groups. These data will subsequently be used to construct surveys to collect quantitative response from patients with ILD. The final Delphi and Patient Perspective results are to be scrutinized by SC and specialty sub-groups (including patient advocates) for truth, discrimination and feasibility - the OMERACT filters. Through application of Nominal Group technique, a core set of outcome measures will be proposed. Subsequent exercises will evaluate the applicability of a proposed core set to the unique issues posed by individual CTDs in addition to guidelines on screening, prognostication and damage scoring.

Accuracy of implant positioning and precise reconstruction of leg alignment offers the best way to achieve good long-term results in total knee arthroplasty. Computer instrumentation was developed to overcome the inherent limitations of mechanical instrumentation, improving the final position of the component and restoring the normal mechanical axis of the lower limb. Current navigation systems use either optical or electromagnetic tracking both having advantage and disadvantage. Knee navigation systems are not yet universally accepted in the orthopedic community, and their cost/benefit ratio remains a matter for further discussion. Despite and high number of clinical trials demonstrating that Computer-assisted navigation is a tool which makes possible the accurate and reproducible performance of a total knee procedure, we have to observe at the moment an absence of high quality endpoint studies demonstrating a longer implant survival in contraposition of standard technique. The current methodology of tracker systems and the anatomical referencing of the patient's landmark are probably the main sources of the limitation of the eventual systems. Finally the cost/benefit ratio of the computer assisted technology remains a matter of debate.