Scleroderma

Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor thus reducing the number of IL-6-responsive cells. Transsignalling, the shedding of the membrane-bound form of the IL-6 receptor into the local microenvironment, greatly increases the range of cells that can respond. IL-6 has been demonstrated to have a pivotal role in the pathogenesis of rheumatoid arthritis, Castleman’s disease and Crohn’s disease exemplified by the use of an anti-IL-6 biological therapy.

Systemic sclerosis (SSc) is a clinically heterogeneous, systemic disorder affecting connective tissue of skin, internal organs, and walls of blood vessels. It is characterized by alterations of the microvasculature in the form of hypoxia, digital ulcers, and pulmonary arterial hypertension; disturbances of the immune system, including dysbalance of cytokine expression, autoantibodies (Auto-ab), and abnormalities of blood progenitor and/or effector cells; and by massive deposition of collagen in the connective tissue of the skin and various internal organs.

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options.

The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis.

Systemic sclerosis, or scleroderma, is a chronic, multisystem, connective tissue disorder characterized by abnormal fibrotic processes and excessive collagen production, which manifests itself in skin thickening and fibrosis of internal organs. Approximately 80% of SSc patients are women, with highest onset rates between ages 30–60. Common causes of disability include limitations in physical mobility, pain, fatigue, depressive symptoms, and body image distress from disfigurement.

In the general population, sexual activity and impairment rates are, among other factors, highly associated with age and marital status

Systemic sclerosis is a multisystem, connective tissue disease of unknown aetiology characterized by vascular dysfunction, autoimmunity, and enhanced fibroblast activity resulting in fibrosis of the skin, heart, and lungs, and ultimately internal organ failure, and death. One of the most important and early modulators of disease activity is thought to be oxidative stress.

Evidence suggests that the free radical nitric oxide, a key mediator of oxidative stress, can profoundly influence the early microvasculopathy, and possibly the ensuing fibrogenic response.

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) and one of the leading causes of morbidity and mortality in this disease. Although several recent studies have suggested an improvement in the prognosis of SSc-PAH, especially since the availability of specific therapies, the overall survival at 3 years remains poor (around 50%) and worse than in patients with idiopathic PAH. Many studies have addressed the survival and prognostic factors in SSc-PAH.

The past decade has witnessed extensive progress in basic and clinical research in the field of pulmonary hypertension (PH), a group of chronic conditions characterised by high pressure in the pulmonary circulation. National and international PH registries have achieved much to advance our understanding of the epidemiology, demographics, aetiology, clinical course, haemodynamics, disease management and treatment outcomes of PH. Therapies available to target the pathology of pulmonary arterial hypertension (PAH) have expanded considerably and more options are expected in the near future.

L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte-leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form.

Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc).

Marta Baleva and Krasimir Nikolov
Received 12 June 2011; Revised 28 August 2011; Accepted 28 August 2011

Scleroderma is progressive autoimmune disease associated with severe disability. The major underlying pathological process in Scleroderma is progressive development of fibrous tissue and obliteration of the microvasculature. Currently, there are no medical products for the treatment of Scleroderma that provide both sufficient immunosuppression and low-risk side safety profile with negligible side effects.

There are a large number of experimental data showing that intravenous immunoglobulin (IVIG) has multiple clinical and morphological effects. On the other hand, some authors report good effect of intravenous immune globulins in patients with Scleroderma. The less frequent side effects of IVIG in doses below or equal to 2 g/kg/month divided in 5 consecutive days make IVIG a promising treatment of choice in Scleroderma.

Systemic sclerosis- (SSc-) related vasculopathy, as manifested by Raynaud’s Phenomenon (RP) and digital ulcers (DUs), is associated with significant impairment of the quality of life and morbidity. The current vasoactive approach for SSc-RP, although employing vasodilators, is entirely off-label. PDE-5 inhibitors improve peripheral circulation, are well tolerated, and are widely used for various forms of constrictive vasculopathies.

This class of medications has become one of the first lines of treatment of SSc-RP and SSc-DUs among rheumatologists that routinely treat SSc patients.

Silicone, a synthetic polymer considered to be a biologically inert substance, is used in a multitude of medical products, the most publicly recognized of which are breast implants. Silicone breast implants have been in use since the early 1960s for cosmetic and reconstructive purposes, and reports of autoimmune disease-like syndromes began appearing in the medical literature soon thereafter. Over the previous year, silicone implants have been suggested as playing a role in a new syndrome that encompasses a wide array of immune-related manifestations, termed ASIA (‘Autoimmune Syndrome Induced by Adjuvant’).

Scleroderma, a relatively rare connective tissue disease with skin manifestations and systemic effects, has also been described in association with silicone implantation and rupture.

T. W. van Hal, L. van Bon, and T. R. D. J. Radstake
Received 20 May 2011; Revised 18 August 2011; Accepted 7 September 2011

Systemic sclerosis (SSc) is typified by vascular alterations and immunological disturbances and fibrosis of the skin and internal organs, which culminates in severe disabilities and not seldom premature death. Although the abovementioned pathways are all clearly involved, their sequel and relative contributions are still a matter of debate.

About 90% of the patients diagnosed with SSc experienced Raynaud’s phenomenon long before the appearance of other clinical symptoms that drives the patient to visit a physician. The diagnosis is often made when patients suffer from a full-blown SSc with rarefaction of the small capillaries as identified by capillaroscopy, digital ulcers, and progressive fibrosis of the skin. Both Raynaud’s phenomenon and the rarefaction of capillaries suggest the presence of hypoxia during certain stages of disease.

Theresa C. Barnes,Marina E. Anderson, and Robert J.Moots
Received 1 June 2011; Accepted 21 July 2011

Systemic sclerosis (SSc) is a connective tissue disease characterised by fibrosis, vasculopathy, and immunological abnormalities. Over recent years, it has become clear that inflammation plays a crucial role in mediating the pathophysiological process underlying SSc, especially early in the disease. Endothelial cell activation and dysfunction are central to the disease pathogenesis, may be driven by a proinflammatory environment, and may result in the generation of a profibrotic phenotype.

Interleukin-6 (IL-6) is a pleiotropic cytokine. In addition to its role in the acute phase response, IL-6 has diverse roles in driving chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis. Therefore, it is currently attracting a great deal of interest in the rheumatology community as a potential therapeutic agent in SSc, a disease which at present lacks treatments directed at the underlying pathogenesis.