Novel aspects in the epidemiology, pathophysiology and treatment of connective tissue diseases
Department of Rheumatology, University Hospital Zurich, Switzerland and 1Department of Rheumatology and Clinical Immunology, University of Giessen and Marburg, Kerckhoff Clinic Bad Nauheim, Germany.
Correspondence to: O. Distler, MD, Department of Rheumatology, University Hospital Zurich, Gloriastr. 25, 8091 Zurich, Switzerland. E-mail: Oliver.Distler{at}usz.ch
The past decade has been marked by rapid advances in molecular biology techniques, which are now routinely and commercially available for research groups around the world. Examples include the microarray technique and methods for gene silencing such as small interference RNA (siRNA) and cell transfection with anti-sense constructs. For research groups interested in the pathogenesis of certain diseases, these novel techniques allow a rapid high throughput screening for genes which are differentially expressed in health and disease, and might thus be of functional importance for disease development or disease progression [1].
In this context, there has been major progress in our understanding of the pathophysiology of connective tissue diseases. Connective tissue diseases form a wide spectrum of disorders including, among others, systemic lupus erythematosus, systemic sclerosis, dermato-polymyositis, mixed connective tissue disease and Sjogren's syndrome. The pathophysiology and clinical presentation of these diseases are diverse. However, the discovery of key molecules as well as key mechanisms in the specific pathogenesis have significantly increased the options to treat their organ-based complications. While the conventional non-selective therapies are still of importance in daily clinical life, most of the new agents target specific molecules or mechanisms that have been shown to play a functional role in the pathogenesis of the overall disease or certain organ manifestations [2, 3].
To provide a comprehensive background for these new therapeutic options and to summarize novel developments, this supplement of Rheumatology has gathered experts in the fields of rheumatology, dermatology and nephrology to cover different aspects in the epidemiology, pathophysiology, clinical features and their pathophysiology, and treatment of patients with connective tissue diseases.
Regarding epidemiology, it is shown in this supplement that the incidence and prevalence of connective tissue diseases are low compared with other inflammatory rheumatic diseases such as rheumatoid arthritis or spondarthropathies; however, they are potentially life-threatening. As connective tissue diseases often occur in younger women during the childbearing period, treatment and clinical care during pregnancy is a major challenge for clinicians. Classification criteria used in clinical studies to obtain well-defined study populations frequently underestimate the prevalence of the disease by excluding patients with early disease or incomplete disease manifestations. Since novel therapeutic agents need to be validated in clinical trials, there is an urgent need for the validation of outcome criteria covering both the activity and damage of connective tissue diseases.
Besides systemic lupus erythematosus, the strongest efforts in understanding disease mechanisms have been made in systemic sclerosis. This supplement reviews novel findings in the pathogenesis of different disease aspects including vascular dysfunction, impaired angiogenesis as well as immunological alterations. According to current concepts, both immune alteration and vascular dysfunction occur early in the disease, finally leading to an ongoing activation of dermal fibroblasts with an unbalanced accumulation of extracellular matrix proteins [4]. Juvenile systemic sclerosis is a rare and often overlooked disease entity. As far as it can be concluded from the limited data that are available, its clinical presentation significantly differs from adult systemic sclerosis. In addition to juvenile systemic sclerosis and the pathogenesis of adult systemic sclerosis, evidence-based recommendations for vasoactive therapies, the role of disease modifying drugs and phototherapy are summarized in this supplement.
The best known examples for target-specific therapies that have made their way from bench to bedside are the tumour necrosis factor (TNF) blocking agents for rheumatoid arthritis and other inflammatory arthritides [5]. In the connective tissue diseases, TNF blocking therapies are of uncertain value (systemic lupus erythematosus [6]), have not been formally tested (systemic sclerosis) or have failed to show substantial benefits (Sjogren's syndrome [7]). In contrary, endothelin-1 plays a major role in the pathogenesis of pulmonary arterial hypertension, and targeting therapies with endothelin-1 receptor antagonists such as bosentan showed clinical benefits in both haemodynamic and functional outcome parameters in patients with pulmonary arterial hypertension associated with connective tissue diseases [8]. While we are still about to learn more about the physiological and pathophysiological role of endothelin-1 including interactions with nitric oxide, and while the role of endothelin-1 in the progression of fibrosis remains unclear, recent data indicate that the clinical effects of bosentan are not limited to pulmonary arterial hypertension. Additional indications might be the prevention of fingertip ulcers in patients with systemic sclerosis as well as the treatment of patients with severe Raynaud's phenomenon [9]. Moreover, experimental models support a role of endothelin-1 in conditions associated with progressive glomerular and tubulointerstitial damages, which are also reviewed in this supplement.
Taken together, these examples show that the recently developed and established Functional Genomics techniques are a valuable tool to characterize key mechanisms in the pathogenesis and to identify potential molecular targets for therapeutic approaches. This also holds true for rare, but potentially life-threatening disorders such as the connective tissue diseases. In addition to the endothelin-1 antagonists, we await the evaluation of an increasing number of additional targeted therapies in clinical trials in the near future. Although we have to be aware that not all of the new molecular specific therapies will make their way into daily clinical practice, there is great hope that these approaches will lead to more potent drugs for the treatment of patients with connective tissue diseases.
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This work was supported by grants from the BMBF and the DFG.
U. M.-L. and O. D. received speaker's honoraria for participation at Actelion Winter School 2006.
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