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.

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.

Georgios Androutsopoulos, Georgios Adonakis, Athanasios Tsamandas, Andreas Andonopoulos, Georgios Decavalas.

Background: Systemic sclerosis is a rare, chronic, multisystem, autoimmune disease. There is an overall increased risk of malignancy in patients with systemic sclerosis. However, multiple cancers of the female genital tract in patients with SSc are a very rare event. Our aim is to present a case of SSc and multiple cancers of the female genital tract, with prolonged survival following current treatment strategies.

Case: The patient, a 43-year-old, nulliparous premenopausal Greek woman suffering of systemic sclerosis, presented with a history of abdominal pain and abnormal uterine bleeding. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, total omentectomy, appendectomy and pelvic lymph node dissection. The histopathology revealed synchronous primary cancers of the endometrium and left ovary.

Tracy Frech, Kirsten Novak, Monica P. Revelo, Maureen Murtaugh, Boaz Markewitz, Nathan Hatton, Mary Beth Scholand, Edward Frech, David Markewitz, and Allen D. Sawitzke
Received 31 May 2011; Accepted 14 July 2011

Systemic sclerosis (SSc; scleroderma) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs including the skin, lungs, and gastrointestinal tract (GIT). This chronic disease process results in pain and pruritus, two distinct, but interacting phenomena. Pruritus is most common in the early stages of disease and may subside as the disease progresses. SSc patients that complain of pruritus have more significant skin involvement, more severe finger ulcers, worse respiratory symptoms, and a greater number of GIT complaints. Of interest, pruritus is independently associated with GIT symptoms in SSc. Although pruritus is associated with significant disability, management guidelines for pruritus in SSc do not exist.

Pruritus is also a feature of primary biliary cirrhosis (PBC), which occurs more commonly in SSc than the normal population. There is a known association with PBC and oxidative stress as well as endothelial dysfunction. Pharmaceutical management suggestions for treatment of pruritus in PBC include cholestyramine, rifampin, sertraline, and naloxone. More recently, pilot trials of low-dose naltrexone hydrochloride (LDN), which is a pharmaceutical similar to naloxone, have recently gained increasing recognition for treating chronic pain associated with fibromyalgia, multiple sclerosis, and Crohn’s disease.

St´ephane Chabaud and V´eronique J. Moulin
Received 1 June 2011; Revised 6 July 2011; Accepted 6 July 2011

Systemic sclerosis (scleroderma, SSc) is a heterogeneous disease which develops into three forms: limited, intermediate, and diffuse. The limited form only affects skin of the limbs. In addition to cutaneous disorders, the diffuse one also affects internal organs such as lungs, heart, and kidneys. After a debilitating phase, the most severe form leads to death. This disease is characterized by a strong autoimmune reaction, although it is not clear whether this is a consequence of the disease or a causal factor. Nevertheless, autoantibodies, principally raised against nuclear epitopes, are used like prognostic markers.

In the United States, the disease strikes more African American people and females than Caucasians and males. Besides, the disease appears more prematurely in the African American group and hits them more severely than the Caucasians. The mortality rate for SSc in the group of women has increased by seventy percent over the last twenty years without convincing explanations. The cost of the medical care associated with this disease was estimated at more than $20,000 per patient per year in Canada. The disease is particularly devastating because it strikes people during the most productive period of their professional life.

M. E. Hettema, H. Bootsma, R. Graaff, R. de Vries, C. G. M. Kallenberg, and A. J. Smit
Received 24 May 2011; Accepted 8 August 2011

Vascular involvement is a key factor in major manifestations of systemic sclerosis (SSc), such as Raynaud’s phenomenon (RP), myocardial dysfunction, pulmonary hypertension, and renal involvement. Microvascular involvement, in which endothelial injury is present, is the main characteristic of SSc. Oxidative stress has been suggested as a major player in the process of endothelial dysfunction found in SSc. Endothelial damage may be induced by oxygen free radicals and reactive nitrogen species, generated locally by the inflammatory process and by periods of tissue ischemia followed by postischaemic reperfusion. This socalled ischaemic-reperfusion injury can be seen in RP. Increased levels of antibodies against oxidised low-density lipoproteins (LDL) and increased serum levels of 8-isoprostane, being markers of oxidative stress, have, indeed, been observed in SSc.

Oxidative or carbonyl stress, leading to formation of so-called reactive carbonyl compounds, is an important source for the generation of so-called advanced glycation endproducts (AGEs). AGE generation as a result of oxidative stress has also been found in inflammatory diseases, such as rheumatoid arthritis and SLE.

Clive M. K. Yeung; Ian A. Lai; C. H. Chu; W. Keung Leung; Mo Yin Mok
The University of Hong Kong
Received: 22 July 2010 / Accepted: 28 September 2010 / Published online: 12 October 2010

Scleroderma is a symptom of a group of diseases that involve the abnormal growth of connective tissue, which supports the skin and internal organs. It has two broad categories which are localized scleroderma (LS) and systemic sclerosis (SSc). LS is a disorder of the skin and sometimes the deeper tissues. The most visible effects of the disease are skin lesions which are often referred as morphea. Morphea may only cause cosmetic problems, but generalized morphea or linear scleroderma has widespread skin lesions in which scarring spreads down to the underlying structures. SSc indicates a more extensive skin involvement and even internal organ diseases. It is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs, and the walls of blood vessels.

Diagnosis of SSc is largely dependent on medical history and physical examination. The signs included changed skin appearance and texture, calcium deposits developing under the skin and changes in the tiny blood vessels at the base of the fingernails. Hematological screening may also be employed to confirm the diagnosis. Patients suffering from SSc usually exhibit CREST syndrome.

Begonya Alcacer-Pitarch, Maya H Buch, Janine Gray, Christopher P Denton, Ariane Herrick, Nuria Navarro-Coy, Howard Collier, Lorraine Loughrey, Sue Pavitt, Heidi J Siddle, Jonathan Wright, Philip S Helliwell, Paul Emery, Anthony C Redmond
Study protocol, Submitted 14 December 2011, Accepted 6 February 2012, Published 6 February 2012

Foot problems associated with Systemic Sclerosis (SSc)/Scleroderma have been reported to be both common and disabling. There are only limited data describing specifically, the mechanical changes occurring in the foot in SSc. A pilot project conducted in preparation for this trial confirmed the previous reports of foot related impairment and reduced foot function in people with SSc and demonstrated a link to mechanical etiologies. To-date there have been no formal studies of interventions directed at the foot problems experienced by people with Systemic Sclerosis. The primary aim of this trial is to evaluate whether foot pain and footrelated health status in people with Systemic Sclerosis can be improved through the provision of a simple pressure-relieving insole.

The proposed trial is a pragmatic, multicenter, randomised controlled clinical trial following a completed pilot study. In four participating centres, 140 consenting patients with SSc and plantar foot pain will be randomised to receive either a commercially available pressure relieving and thermally insulating insole, or a sham insole with no cushioning or thermal properties.

Julie Baraut, Dominique Farge, Elena Ivan-Grigore, Franck Verrecchia, and Laurence Michel

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive sclerosis of the skin and internal organ dysfunction. Cytokine production and release are key events in SSc pathogenesis as they are involved in T and B cell activation leading to inflammation, auto-antibodies production, microvascular damage and fibrosis (Katsumoto et al. 2011). The Th1/Th2/Th17/Treg balance is one of the hallmarks of SSc pathogenesis, as the Th2 and Th17 cytokines response leads to tissue fibrosis, whereas Th1 and Th17 cytokines promote inflammation in SSc patients. In our previous review, we analyzed the relationship between cytokine release and SSc pathogenesis, based on experimental and clinical data. We concluded that circulating or in situ cytokine levels could be assessed as diagnostic and prognostic markers in SSc patients (Baraut et al. 2010).

The precise pathogenesis of SSc is still poorly understood. The use of microarray technology showed significant differences of gene patterns in skin biopsies from diffuse scleroderma (dSSc) and limited scleroderma (lSSc) patients, which also differed from normal controls (Milano et al. 2008). An immune signaling cluster was evidenced, suggestive for a role of B and T cells in SSc pathogenesis.

Jessica Gordon and Robert Spiera
Received 1 June 2011; Revised 2 August 2011; Accepted 2 August 2011

Systemic sclerosis (SSc) is a heterogeneous, multisystem disorder characterized by vasculopathy, fibrosis, and autoimmunity in the context of both genetic and environmental factors. Although the pathogenesis of SSc is not completely understood, there is strong evidence for a central role of abnormal signaling through the transforming growth factor beta (TGFβ) pathway. The intracellular tyrosine kinase (TK) c-abl has been implicated in the downstream signaling pathways of TGFβ. There is additional evidence for abnormalities in the platelet-derived growth factor (PDGF) axis, signaling through the receptor TK the PDGF receptor (R), as contributory to the pathogenesis of SSc as well.

Because of the roles of these pathways, there has been interest in evaluating the specific tyrosine kinase inhibitors (TKIs) which are able to block c-abl and the PDGFR in the treatment of SSc. These include imatinib mesylate (Gleevec; Novartis Pharmaceuticals; Basel, Switzerland), dasatinib (Sprycel; BristolMyers Squibb; New York, NY), and nilotinib (Tasigna; Novartis Pharmaceuticals) all of which inhibit c-abl and the PDGFR with different degrees of potency. All three of these medications are FDA approved for the treatment of chronic myelogenous leukemia (CML), and imatinib is additionally FDA approved for the treatment of gastrointestinal stromal tumor (GIST) in addition to other hematologic and oncologic conditions.