In systemic sclerosis (SSc), vasculopathy is a central mechanism and is a major initial event in the process of sclerosis and causing different complications such as Raynaud's phenomenon, ulcer(s) or pulmonary hypertension, the latter being life threatening. Therefore, vasoactive therapies are important when taking care of patients with SSc. However, as treatment has been difficult, numerous therapeutic modalities have been suggested. Until now, the interpretation of most studies is limited due to the heterogeneity of patient groups, the low number of patients, the short duration of the treatments and, possibly, further pathogenic mechanisms such as autoimmunity. Several drugs are now available with effects on vasculopathy and, furthermore, on specific pathogenic mechanisms in SSc. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have potential effects on fibrosis, inflammation and endothelial cells, suggesting a disease-modifying capacity in systemic sclerosis. This review summarizes evidence-based therapy recommendations.

The aim of this review is to evaluate the evidence for disease-modifying anti-rheumatic drugs (DMARDs) for treatment of systemic sclerosis (SSc). In the previously published trials, DMARD therapy was usually initiated for severe skin thickening, organ involvement and alveolitis. These studies suggest beneficial effects of methotrexate, azathioprine, ciclosporine A and cyclophosphamide therapy in SSc patients. However, many of these data were derived from retrospective analyses with low numbers of patients, short-term follow-up and often without an appropriate control group. Finally, some of these studies led to inconsistent results. At the present time there is no DMARD therapy of proven efficacy in SSc. Immunosuppressive therapy should only be considered in patients with early diffuse disease, overlap syndromes or pulmonary fibrosis. Current expert recommendations suggest a therapy with methotrexate for skin thickening or cyclophosphamide for acute alveolitis. However, more clinical trials with larger numbers of patients with recent onset SSc are needed.

Endothelin (ET)-1 is a potent renal vasoconstrictor with pro-inflammatory, profibrotic and mitogenic potential. Animal studies support a pathogenetic contribution of ET-1 and its cognate receptors in several renal manifestations of autoimmune disorders. However, data in humans are limited. The present minireview thus summarizes the observations available in humans. Similar to animal models, ET-1 is overexpressed in glomerular and tubulointerstitial lesions, which is reflected by an increased urinary excretion of ET-1. Since antagonizing the ET system has beneficial effects in experimental models, this approach may be translated to the human kidney, thus counteracting vasoconstriction, inflammation and extracellular matrix deposition during the course of human autoimmune disease.

Endothelin (ET)-1 is a potent vasoconstrictor with profibrotic and proinflammatory effects. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders, including diabetes, hypertension and glomerulonephritis. Several laboratory studies have demonstrated elevated expression of ET-1, which colocalizes with glomerular and tubulointerstitial injury, in addition to enhanced urinary excretion. Moreover, ET-1 expression correlates with disease severity and renal function. With the availability of ET receptor antagonists, a pathogenetic role has been further corroborated in animal models, demonstrating both structural and functional improvement. Thus, antagonizing the ET system may be useful in major renal pathologies associated with glomerular and tubulointerstitial damage.

According to the so-called vascular hypothesis, Raynaud's phenomenon (RP) is one initial event in the pathophysiological cascade leading to sclerosis in systemic sclerosis (SSc). It is characterized by recurrent, reversible spasms of small arterioles and digital arteries, usually triggered by cold and emotional stress. Clinical signs of RP are a sudden pallor of single digits of fingers followed by reactive hyperaemia and in severe cases also by cyanosis. Besides imbalances between vasoconstrictive and vasodilatory processes, structural alterations of the involved vessels are fundamental to secondary RP in SSc. The latter is the reason why secondary RP in SSc, in contrast to primary RP, often leads to ischaemia and re-perfusion injuries. New insights into the pathophysiology of RP feature a special role for alpha2c-adrenoreceptors, Rho-kinase signalling pathways and soluble mediators. They have resulted in promising therapeutic options, including antagonism of endothelin receptors, inhibition of phosphodiesterases or selective blockade of alpha2c-adrenoreceptors. They should also have a positive impact on the course of SSc in general.

Connective tissue diseases (CTD) such as systemic lupus erythematosus diffuse or limited systemic sclerosis and numerous others affect women frequently during the childbearing period. Every pregnancy in a patient with CTD should be regarded as high-risk pregnancy, and requires intensive monitoring and immediate treatment of clinical problems. For these reasons, for women suffering from CTD, who are pregnant or who intend to become pregnant, an interdisciplinary setting addressing all aspects of rheumatology, ob-gyn and neonatalogy needs to be provided. This setting includes particular diagnostic tools and laboratory parameters prior to and during pregnancy as well as in the post-partal period. Aside overt organ dysfunction, key problems in pregnant CTD patients consist mainly of haemostaseological problems such as antiphospholipid antibodies, neonatal lupus erythematosus, congenital heart block and drug therapy of the underlying disease, which will be outlined in this review.

The reported prevalence and incidence of connective tissue disorders are quite variable, depending on differences in study methodology. Most important differences are the study duration, the classification criteria used for diagnosis and the country in which the study was undertaken. Sjögren's syndrome has the highest prevalence ranging between 0.5 and 3% of a given population. The prevalence of systemic lupus erythematosus (SLE) is estimated between 15 and 50 per 100 000 individuals, with a female:male ratio of 6-10:1 in the age group between 15 and 40 yrs. The prevalence of systemic sclerosis is lower, however, varying significantly between different studies and countries. The prevalence of overlap syndromes, especially mixed connective tissue disease, is unknown, and polymyositis and dermatomyositis are regarded as very rare rheumatic diseases. Though the classification criteria for the connective tissue disorders have not been developed for the purpose of diagnosing an individual patient, these criteria still are the most valuable tool for the identification of patients with systemic rheumatic diseases such as connective tissue disorders.

Juvenile systemic sclerosis (jSSc) is a rare disease of childhood, and the amount of published data is limited. It appears that its clinical presentation differs from adult disease and the limited form affects only very few children. The organ involvement pattern differs also from the adult form. Prognosis seems to be better with a 5-yr survival of 95% of the jSSc patients. The validation of the outcome measures for children with jSSc is currently in progress. Regarding effective treatment, there are no paediatric data and the paediatric rheumatologist needs to rely on the experiences in adult disease.

In addition to inflammatory infiltrates and an accumulation of extracellular matrix proteins, vascular changes are a hallmark in the pathogenesis of systemic sclerosis (SSc). Consistent with the ongoing endothelial cell apoptosis, several markers of EC damage are up-regulated in the serum of SSc patients. Surprizingly, vascular endothelial growth factor (VEGF), a very potent angiogenic molecule, is overexpressed in SSc patients despite the insufficient angiogenesis. VEGF can protect patients from fingertip ulcers, but a prolonged overexpression of VEGF might have paradoxical effects leading to the formation of irregular vessels similar to that observed in SSc. Besides defective angiogenesis, recent studies suggest that vasculogenesis is also impaired in SSc patients with reduced numbers and functional defects of endothelial progenitor cells.

Systemic sclerosis (SSc) is a disease of unknown aetiology characterized by excessive and often progressive fibrosis in skin and multiple internal organs, an aberrant immune activation marked by multiple humoral and cellular immunological abnormalities and pronounced alterations in the microvasculature. The pathogenesis of SSc is complex and, although progress in the understanding of the multiple processes underlying SSc has been made in recent years, no single unifying hypothesis explaining all aspects of this disease exists. Recent studies have suggested that the activation of the immune system is a key stimulus to vascular abnormalities and fibrosis. Once T-cells are activated, they infiltrate the skin lesions early, and produce the profibrotic cytokine IL-4. They are also required for autoantibody production. B-cells may contribute to fibrosis, as deficiency of CD19, a B-cell signal transduction molecule, results in decreased fibrosis in animal models. In recent years, clinical advances have occurred in parallel with a better understanding of the underlying disease mechanisms. In this article, the immunological aspects and multiple altered immunological processes found in SSc are discussed.

Cutaneous autoimmunity is characterized by the presence of autoantibodies and/or autoreactive T cells. Several mechanisms have been developed to avoid loss of immunotolerance to self such as activation-induced cell death, deletion, ignorance and active suppression of autoreactivity. Regulatory ('suppressor') T cells play a pivotal role in inhibiting the activation and function of effector T cells. CD4(+)CD25(+) T cells constitute a subset of regulatory T cells, which have been shown to suppress the development of organ-specific autoimmunity in mice. Recent understanding in the generation and function of human regulatory T cells indicates that these cells are involved in the appearance of inflammatory as well as bullous autoimmune dermatosis. These findings suggest that modulation of regulatory T cell numbers or function might be a promising therapeutic alternative for the treatment of such disorders. In the following, recent strategies aimed at inducing antigen-specific or non-specific regulatory T cells for the immunotherapy of ongoing cutaneous autoimmunity are presented and discussed. Hopefully, pursuing these strategies in the future will result in the initiation of randomized clinical studies analysing the usefulness of regulatory T cells for human skin diseases in great detail.

When studying the impact of endothelins (ETs) on physiology and pathophysiology, this needs to be done in the context of nitric oxide (NO) synthesis and action, since these two are closely intertwined in their action. Here, we will review the work demonstrating the crosstalk between endothelin-1 (ET-1) and NO, and the recent developments regarding the role of these two mediators in inflammatory processes. Moreover, we will discuss the role of NO in pro-inflammatory diseases and the potential mechanisms of the anti-inflammatory activity of ET receptor antagonism.

The pathophysiology of cutaneous lupus erythematosus (CLE) has been investigated in numerous studies demonstrating that the combination of specific cellular and molecular events is leading to inflammation and tissue damage in this disease. However, a complete understanding of the diverse pathophysiological mechanisms and interactions does not exist. Various environmental factors influence the clinical expression of CLE and a striking relationship has emerged between sunlight exposure and the various subtypes of this disease. In the past years, photoprovocation tests with different ultraviolet (UV) wavelengths have been approved to be an optimal way to evaluate photosensitivity in patients with CLE. Furthermore, research on the pathogenetic mechanisms of UV-induced skin lesions has become an increasingly dynamic field and several new aspects of this disease could be identified. In this review, the impact of UV exposure that contributes to the manifestations of CLE is discussed and recently reported mechanisms in the pathophysiology of this disease are considered including the clearance of apoptotic cells, expression of inducible nitric oxide synthase, function of CD4(+)CD25(+) regulatory T cells, and the role of chemokines for lymphocyte recruitment. Elucidation of the relevant factors might lead to future development of effective strategies to prevent abnormal reactivity in patients with CLE.

Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the small pulmonary vascular bed as a result of vascular proliferation and remodelling of the vessel wall leading to permanently increased pulmonary vascular resistance and elevated pulmonary artery pressures, which result in right heart failure and premature death. Pathologic processes behind the complex vascular changes associated with PAH include vasoconstrictor/vasodilator imbalance, thrombosis, misguided angiogenesis and inflammation. Besides idiopathic PAH, it can also occur in association with portal hypertension, HIV infection, congenital cardiac left-to-right shunts and connective tissue diseases (CTD). Unfortunately, despite recent major improvements in PAH treatment, no current therapy can yet cure this devastating condition. This review will briefly highlight epidemiology, pathogenesis, and diagnostic and treatment options known so far for PAH occurring in connection with CTD.

Cardiac involvement is one of the main complications substantially contributing to the morbidity and mortality of patients suffering from systemic autoimmune diseases. All the anatomical heart structures can be affected, and multiple pathogenic mechanisms have been reported. Non-organ-specific autoantibodies have been implicated in immune complex formation and deposition as the initial triggers for inflammatory processes responsible for Libman-Sacks verrucous endocarditis, myocarditis and pericarditis. Anti-phospholipid antibodies have been associated with thrombotic events in coronary arteries, heart valve involvement and intra-myocardial vasculopathy in the context of primary and secondary anti-phospholipid syndrome. Antibodies-SSA/Ro and anti-SSB/La antigens play a major pathogenic role in affecting the heart conduction tissue leading to the electrocardiographic abnormalities of the neonatal lupus syndrome and have been closely associated with endocardial fibroelastosis.

Raynaud's phenomenon (RP) represents the most frequent clinical aspect of cardio/microvascular involvement and is a key feature of several autoimmune rheumatic diseases. Moreover, RP is associated in a statistically significant manner with many coronary diseases. In normal conditions or in primary RP (excluding during the cold-exposure test), the normal nailfold capillaroscopic pattern shows a regular disposition of the capillary loops along with the nailbed. On the contrary, in subjects suffering from secondary RP, one or more alterations of the capillaroscopic findings should alert the physician of the possibility of a connective tissue disease not yet detected. Nailfold capillaroscopy (NV) represents the best method to analyse microvascular abnormalities in autoimmune rheumatic diseases. Architectural disorganization, giant capillaries, haemorrhages, loss of capillaries, angiogenesis and avascular areas characterize >95% of patients with overt scleroderma (SSc). The term 'SSc pattern' includes, all together, these sequential capillaroscopic changes typical to the microvascular involvement in SSc. The capillaroscopic aspects observed in dermatomyositis and in the undifferentiated connective tissue disease are generally reported as 'SSc-like pattern'. Effectively, and early in the disease, the peripheral microangiopathy may be well recognized and studied by nailfold capillaroscopy, or better with nailfold video capillaroscopy (NVC). The early differential diagnosis between primary and secondary RP is the best advantage NVC may offer. In addition, interesting capillaroscopic changes have been observed in systemic lupus erythematosus, anti-phospholipid syndrome and Sjogren's syndrome. Further epidemiological and clinical studies are needed to better standardize the NCV patterns. In future, the evaluation of nailfold capillaroscopy in autoimmune rheumatic diseases might represent a tool for the prediction of microvascular heart involvement by considering the systemic microvascular derangement at the capillary nailfold.

Cardiovascular features in rheumatoid arthritis (RA) are common. Among those are the classical extra-articular features that not only include pericarditis, cardiomyopathy/myocarditis, cardiac amyloidosis, coronary vasculitis, arrhythmia and valve diseases, but also congestive heart failure and ischaemic heart disease which are found more frequently and are associated with an increased mortality compared with the general population. This overview discusses the epidemiological aspects of these cardiovascular diseases and their relevance for diagnosis and treatment of RA.

Rhythm and conduction disturbances and sudden cardiac death (SCD) are important manifestations of cardiac involvement in autoimmune rheumatic diseases (ARDs). In patients with rheumatoid arthritis (RA), a major cause of SCD is atherosclerotic coronary artery disease, leading to acute coronary syndrome and ventricular arrhythmias. In systemic lupus erythematosus (SLE), sinus tachycardia, atrial fibrillation and atrial ectopic beats are the major cardiac arrhythmias. In some cases, sinus tachycardia may be the only manifestation of cardiac involvement. The most frequent cardiac rhythm disturbances in systemic sclerosis (SSc) are premature ventricular contractions (PVCs), often appearing as monomorphic, single PVCs, or rarely as bigeminy, trigeminy or pairs. Transient atrial fibrillation, flutter or paroxysmal supraventricular tachycardia are also described in 20-30% of SSc patients. Non-sustained ventricular tachycardia was described in 7-13%, while SCD is reported in 5-21% of unselected patients with SSc. The conduction disorders are more frequent in ARD than the cardiac arrhythmias. In RA, infiltration of the atrioventricular (AV) node can cause right bundle branch block in 35% of patients. AV block is rare in RA, and is usually complete. In SLE small vessel vasculitis, the infiltration of the sinus or AV nodes, or active myocarditis can lead to first-degree AV block in 34-70% of patients. In contrast to RA, conduction abnormalities may regress when the underlying disease is controlled. In neonatal lupus, 3% of infants whose mothers are antibody positive develop complete heart block. Conduction disturbances in SSc are due to fibrosis of sinoatrial node, presenting as abnormal ECG, bundle and fascicular blocks and occur in 25-75% of patients.

Invasive diagnostic and therapeutic techniques are indispensable for the diagnosis and interventional treatment of coronary artery disease, valvular involvement and, in particular, if the specific components of the inflammatory or degenerative processes in rheumatic disease are to be identified in the different components of the heart. Although impairment of cardiac function and ischaemia can be suspected also by non-invasive techniques, coronary involvement needs the final proof by angiography. Endomyocardial or epicardial biopsy identifies the key players of autoreactivity: the infiltrating cells and the bound and circulating antibodies. Before corticoid treatment is started, a viral or microbial aetiology has to be excluded at the site of cardiac inflammation. This again can only be done by the analysis of cardiac tissue samples.

The majority of the imaging techniques in cardiology could be applied in rheumatic diseases (RDs), such as echocardiography, single-photon emission computed tomography (SPECT), radionuclide ventriculography, angiography, cardiovascular MRI and CT. Inflammatory pericardial involvement is the most common cardiac manifestation in various forms of RD. Echocardiography is the gold standard for diagnosis of pericardial abnormalities, demonstrating location and amount of pericardial effusion. Cardiac MRI and CT can be used to assess the features of pericardial effusions and pericardial structures. In patients with valvular heart disease in RD, transoesophageal echocardiography is a superior method and offers reliable information about valve morphology, the severity of the disease and left ventricular (LV) function. In addition, cardiac MRI is a valuable tool for the evaluation of valvular stenosis and regurgitation severity. Myocardial involvement in RD is demonstrated by abnormalities in LV size and function, indicating myocardial inflammation. In these patients Doppler echocardiography and myocardial tissue imaging can provide essential diagnostic information. Both LV angiography and cardiac MRI can provide reliable information on LV size, function and mass. In patients with coronary disease associated with RD, LV ejection fraction and ventricular wall motion can be assessed by echocardiography, radionuclide ventriculography, gated SPECT and MRI. Three-dimensional (3D) echocardiography is considered superior to 2D echocardiographic techniques. Stress echocardiography is the most used method for detection of myocardial ischaemia. The only accurate visualization of the coronary arteries is by selective coronary arteriography, which remains the gold standard. Although new non-invasive techniques have been developed, including CT and MRI angiography, some limitations apply.