Scleroderma Research Foundation

Pfizer Submits Regulatory Filings for Revatio as a Treatment for Pulmonary Arterial Hypertension (Abstracted press release) - December 03, 2004
Pfizer Inc today announced it has submitted regulatory filings in the United States and Europe for Revatio(TM) (sildenafil citrate) as a treatment for pulmonary arterial hypertension (PAH), a rare, aggressive and life-shortening vascular disease. Sildenafil is the active ingredient in Viagra(R), Pfizer's erectile dysfunction medication used by more than 23 million men worldwide.

The company filed a New Drug Application for Revatio with the U.S. Food and Drug Administration and submitted its Revatio dossier to regulatory authorities in the Netherlands and Spain, the rapporteur and co-rapporteur sponsors, and the European Medicines Agency (EMEA).

Clinical studies conducted throughout the world have shown sildenafil 20 mg taken three times daily to be effective in treating PAH. Patients treated with sildenafil had improved physical functioning as demonstrated by increased walking distance over a six-minute time interval. Patients on sildenafil also had both a reduction in blood pressure in arteries of the lungs and an increase in cardiac (heart) output which is critical in treatments of this disease.

The most commonly reported adverse events in PAH patients were headaches, flushing and dyspepsia. The overall side effect profile was similar to what has been observed with Viagra.

Revatio will be manufactured and marketed in a different dosage, color and shape than Viagra.

Viagra Found Effective Against PAH in Clinical Trial
Results of a clinical trial for a new use of Viagra (sildenafil citrate) in Pulmonary Arterial Hypertension (PAH) were reported by Pfizer on October 28 at the American College of Chest Physicians in Seattle. The results were positive: in a randomized, placebo-controlled trial of 278 patients, patients who received the drug were able to walk farther than patients who received placebo. The six minute walking test is a standard for trials in PAH. After 12 weeks of dosing, patients on drug were able to walk 45 to 50 meters farther than the control.

Pfizer will sell the drug under a different name than Viagra and in a different form. The company is discussing with the FDA and European regulators when the drug may be approved for this new use.

Phase 3 Clinical Trial Subgroup Results for Thelin Announced at ACR
Thelin is a small molecule drug that blocks the action of endothelin, a potent mediator of blood vessel constriction and growth of smooth muscle in the vascular walls. Pulmonary arterial hypertension (PAH) involves high blood pressure and structural changes in the walls of the pulmonary arteries, which are the blood vessels that connect the right side of the heart to the lungs. Thelin, whose generic name is Sitaxsentan, was investigated in a Phase 3 trial as a treatment for PAH.

Data was presented at the American College of Rheumatology meeting in October, 2004 for a subgroup of people in a broader trial (STRIDE-1) diagnosed with scleroderma, lupus and other connective tissue diseases. Patients given sitaxsentan showed significant improvements in the six minute walk distance measure, an improved cardiac index and pulmonary vascular resistance.

The study was a multicenter, randomized, double-blind, placebo-controlled trial of the once daily drug. 178 patients were enrolled and given the drug or placebo for 12 weeks. Two different dose levels were administered. A number of side effects were noted.

Thelin is being developed by Encysive Pharmaceuticals which is testing the drug in six different clinical trials.

Following are abstracts of recent scientific papers on scleroderma that have been published in peer reviewed journals. We have summarized the topic of the paper and provided a citation should you wish to locate the original article, which is written at an advanced scientific level.

Trying to understand the basics of Scleroderma
Once a disease has been defined, scientists begin to look for a source of the disease in an attempt to fine the definitive cure. These papers look into the basic science of scleroderma and attempt to understand the chemistry and biology of the disease. By sharing their results, these scientists are playing a key role in helping each other understand the disease and develop a cure.

Microchimerism: An Investigative Frontier in Autoimmunity and Transplantation
Adams KM, Nelson JL, JAMA. 2004;291:1127-1131
Microchimerisms can be broadly defined as genetically foreign material that is introduced from one person to another. In many cases, such as the transfer of cells from a mother to a fetus, this transfer can be beneficial. However, some scientists believe that this transfer may induce an autoimmune response (an immune response to your own tissue). This paper presents the recent findings that support this hypothesis and how this knowledge can be used to develop therapies for various autoimmune diseases, including scleroderma.

Insights Into the Molecular Mechanism of Chronic Fibrosis: The Role of Connective Tissue Growth Factor in Scleroderma.
Leask A, Denton CP, Abraham DJ, J Invest Dermatol. 2004;122:1-6
Two chemicals, connective growth factor (CCN2) and transforming growth factor beta (TGF-beta) are abundant in the skin lesions of scleroderma patients. This study finds that either one of these chemicals can induce a transient generation of fibrosis, but the presence of both of these tissues results in persistent fibrosis. These two chemicals are important in the development of skin fibrosis and this paper elucidates how these chemicals interact with particular emphasis on the role of CCN2 and scleroderma. A thorough understanding of the biochemical changes in the skin lesions of scleroderma patients may help develop new therapies.

Scleroderma fibroblasts constitutively express the long pentraxin PTX3.
Luchetti MM, Sambo P, Majlingova P, Svegliati Baroni S, Peri G, Paroncini P, Introna M, Stoppacciaro A, Mantovani A, Gabrielli A., Clin Exp Rheumatol. 2004 Jan-Feb;22(3 Suppl 33):S66-72.
PTX3 is a protein that is overproduced in fibroblast cells of scleroderma patients. This paper analyzes the overproduction of PTX3 in cultured fibroblast cells and investigates methods to regulate the biochemical signaling involved in the overproduction of PTX3. The authors find that IL-1beta and TNF-alpha induce production of PTX3. The data suggests that PTX3 plays a critical role in activating fibroblast proliferation in systemic scleroderma. Further studies may lead to novel methods to control fibrosis in scleroderma patients.

What did we learn by studying scleroderma fibroblasts?
Trojanowska M., Clin Exp Rheumatol. 2004 Jan-Feb;22(3 Suppl 33):S59-63.
Many of the complications that scleroderma patients experience are the result of extensive fibrosis in various organs. This paper attempted to understand the development of this fibrosis by studying collagen and other proteins in the extra-cellular matrix. Using a cell culture model, the cellular and molecular changes in the fibrotic tissue is discussed and the pathogenesis of the fibrosis is considered. A further understanding of the collagen production in these cells may lead to methods to regulate tissue fibrosis.

Thrombin-mediated cellular events in pulmonary fibrosis associated with systemic sclerosis (scleroderma).
Ludwicka-Bradley A, Bogatkevich G, Silver RM., Clin Exp Rheumatol. 2004 Jan-Feb;22(3 Suppl 33):S38-46.
Vascular injury is usually followed by the rapid release thrombin from the injured tissue. This paper reviews the current link between thrombin production and the onset of fibrosis, particularly in lung disease associated with scleroderma. Since the production of thrombin is tied to the development of other chemicals that are involved in lung fibrosis, methods of regulating thrombin production are discussed. For example, the inhibition of binding between thrombin and the major thrombin receptor, PAR-1, may be a suitable goal for future drug development. If thrombin is successfully regulated and the signaling among these chemicals is better understood, novel therapies can be developed.

Distinct PKC Isoforms Mediate Cell Survival and DNA Synthesis in Thrombin-induced Myofibroblasts.
Bogatkevich GS, Gustilo E, Oates JC, Feghali-Bostwick C, Harley RA, Silver RM, Ludwicka-Bradley A., Am J Physiol Lung Cell Mol Physiol. 2004 Sep 24.
Thrombin is an important chemical in the generation of fibrosis in the lungs of scleroderma patients. Under normal conditions, cells in this environment have a self-destruct mechanism (apoptosis) that would limit the damage caused by the fibrotic tissue. In scleroderma patients, thrombin plays a role in turning off the self-destruct mechanism and the fibrotic growth proliferates. This paper studies the chemicals involved in this tissue that lead to a malfunction in the self-destruct mechanism. By thoroughly understanding the biochemical changes, novel methods to re-activate the self-destruct pathway can be tested.

Increased dermal elastic fibers in the tight skin mouse.
Chatterjee S, Mark ME, Wooley PH, Lawrence WD, Mayes MD., Clin Exp Rheumatol. 2004 Sep-Oct;22(5):617-20.
The development of an accurate and predictive animal model is a key step in studying any disease. This publication analyzes the Tsk-1 mouse and compares the biochemical and structural abnormalities in the mouse tissue to the abnormalities observed in tissue from scleroderma patients. These studies find that the increased levels of elastic fibers and dermal collagen in the Tsk-1 mouse mimic the increased levels of these chemicals in human scleroderma patients. Therefore, this model may be similar to scleroderma and may be useful in the discovery of novel compounds to treat the disease.

Emerging Therapies and Treatments
These papers present some of the most recent studies that focused on drugs that may have potential use in the controlling the progression and/or symptoms of scleroderma. Frequently, these papers build upon the basic science and translate these discoveries into drugs.

Scleroderma Renal Crisis: New Insights and Developments
Rhew EY, Barr WG, Curr Rheumatol Rep. 2004;6:129-136
A significant number of scleroderma patients experience scleroderma renal crisis (SRC). Angiotensin converting enzymes (ACE) inhibitors have helped improve the quality of life for many scleroderma patients. While these inhibitors are helpful as a treatment, further development is needed to find a more suitable therapy. This paper reviews the pathogenesis, risk factors and clinical aspects of SRC.

Topical Tacrolimus in the Treatment of Localized Scleroderma
Mancuso G, Berdondini RM, Eur J Dermatol. 2003;13:590-592
Tacrolimus is an immunosuppressive antibiotic that may be useful in the treatment of autoimmune diseases. This study presents the preliminary results of a study in which the skin lesions of localized scleroderma patients were treated with a 0.1% topical ointment of tacrolimus. The positive results suggest that this therapy may be useful in the future treatment of localized scleroderma.

Long-term Evaluation of Lung Function in Patients Affected by Scleroderma Treated With Cyclic Iloprost Infusions
Caramaschi P, Biasi D, Ferrari M, et al, Rheumatol Int. 2004 Feb 13
Pulmonary malfunction in a common problem for patients with scleroderma. This study presents the results of treating this malfunction by infusing cyclic iloprost over three years. The absence of severe pulmonary arterial hypertension in treated patients suggests that this therapy is helped to stabilize lung function and limited those cases of pulmonary arterial hypertension. Further studies are required before this therapy is introduced as a common clinical treatment.

Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model.
Kelly DJ, Zhang Y, Gow R, Gilbert RE., J Am Soc Nephrol. 2004 Oct;15(10):2619-29.
Tranilast is a chemical that has been used to control fibrosis in hypertrophy scars and scleroderma. To further understand the effects of tranilast on regulating fibrosis in the kidneys, a detailed study was conducted in a small animal study. This study evaluates the effects of tranilast on the various biochemical markers of fibrosis and kidney structure of rats. The results of this study support the current clinical data, suggesting that tranilast may be useful in the treatment of progressive kidney disease caused by scleroderma.

Keratinocyte-derived cytokines after photodynamic therapy and their paracrine induction of matrix metalloproteinases in fibroblasts.
Karrer S, Bosserhoff AK, Weiderer P, Landthaler M, Szeimies RM., Br J Dermatol. 2004 Oct;151(4):776-83.
Two proteins, both matrix metalloproteinase enzymes (MMP1 and MMP-3), are produced in fibroblasts in response to a combination of photodynamic light therapy (PLT) and a small chemical, 5-aminolaevulinic acid (ALA). These enzymes can break down the chemicals causing fibrosis. Since the combination of PLT and ALA has been used to treat localized scleroderma, this paper further investigates PLT and ALA therapy in cultured cells, focusing on the effects of this therapy on the generation of the MMP-1 and MMP-3 enzymes.

Physiological Effects of Scleroderma
These papers focus on how scleroderma can affect the proper function of different organs and systems in humans. These studies help patients and clinicians understand the symptoms of the disease and search for possible treatments.

The Pathogenesis of Fibrosis and Renal Disease in Scleroderma: Recent Insights From Glomerulosclerosis
Lee S, Lee S, Sharma K, Curr Rheumatol Rep. 2004;6:141-148
Renal malfunction is a common complication of systemic scleroderma. This paper presents a technical overview of the effects of scleroderma on kidney function, including a detailed discussion of the biochemical changes that occur. These changes affect the rennin-angiotensin system, the probiotic growth factors, transforming growth factor beta, connective tissue growth factor, and oxygen radicals. Studying these biochemical processes will result in a better understanding of the disease and can lead to novel therapies.

The Heart in Systemic Sclerosis
Steen V, Curr Rheumatol Rep. 2004;6:137-140
Systemic scleroderma frequently leads to cardiac abnormalities, such as arrhythmias and various diseases of the cardiac tissue. This paper outlines these abnormalities and links them systemic scleroderma. Special emphasis is given to diastolic dysfunction, a symptom that is controversially linked to scleroderma. A further understanding of the link between these cardiac abnormalities and systemic scleroderma will help physicians treat the life-threatening aspects of this disease.

Diagnosing Scleroderma
The proper treatment of any disease requires understanding the symptoms and properly diagnosing the disease in humans. This section outlines the recent studies that have focused on the criteria for diagnosis, with a recent emphasis on the different forms of scleroderma and differentiating scleroderma from similar autoimmune diseases.

The TNF-863A Allele Strongly Associates With Anticentromere Antibody Positivity in Scleroderma.
Sato H, Lagan AL, Alexopoulou C, et al, Arthritis Rheum. 2004;50:558-564
Scleroderma is typically characterized by measuring three antibodies: anticentromere antibody (ACA), antitopoisomerase antibody, and anti-RNA polymerase antibodies. This study evaluates two methods that are used to measure the levels of these antibodies: the traditional method, which measures class II MHC molecules, and the experiments method, which measures TNF promoter polymorphisms. The results of these methods are compared and the implications on the diagnosis and pathogenesis of scleroderma are discussed.

A working classification of scleroderma spectrum disorders: a proposal and the results of testing on a sample of patients.
Maricq HR, Valter I., Clin Exp Rheumatol. 2004 Jan-Feb;22(3 Suppl 33):S5-13.
The broad category of scleroderma spectrum disorders (SDS) often complicates the diagnosis of these diseases. This paper reviews the clinical data from over 150 patients who presented with SDS symptoms. After reviewing discussing the various SDS subgroups and presenting the clinical criteria, adjustments to the methods used to diagnose these disorders are suggested. Earlier and accurate diagnosis of scleroderma is key to successful treatment.

Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy).
Levine JM, Taylor RA, Elman LB, Bird SJ, Lavi E, Stolzenberg ED, McGarvey ML, Asbury AK, Jimenez SA., Muscle Nerve. 2004 Sep 7;30(5):569-577.
Nephrogenic fibrosing dermopathy (NFD) is a disease that appears to have many symptoms that are similar to systemic scleroderma. Typically brought on by long-term kidney dialysis, this rare disease first appears as fibrosis in the kidney, but then extends to other tissues. This paper presents five cases of NFD and outlines the pathogenesis and disease progression. Currently NFD is considered to be a purely cutaneous disease, but the presented cases provide evidence that NFD may be the early stage of a disease that is more systemic.

Clinical optimization and multicenter validation of antigen-specific cut-off values on the INNO-LIA ANA update for the detection of autoantibodies in connective tissue disorders.
Pottel H, Wiik A, Locht H, Gordon T, Roberts-Thomson P, Abraham D, Goossens K, Dobbels C, De Bosschere K, Hulstaert F, Meheus L., Clin Exp Rheumatol. 2004 Sep-Oct;22(5):579-88.
A similar multi-parameter test is currently used to diagnose scleroderma and many other autoimmune diseases. While this test is reliable, this paper presents a more detailed analysis of this test and suggests methods to improve the diagnostic criteria. The results suggest that setting detailed diagnostic criteria of specific autoantibodies can be used to differentiate scleroderma from these other autoimmune diseases with up to 98% specificity.

Case Studies
This section presents papers that are studies of specific cases of scleroderma or diseases that present with symptoms that are very similar. By sharing their experiences in the clinic, doctors can help keep patients and other clinicians informed.

Vitamin B12-associated localized scleroderma and its treatment.
Ho J, Rothchild YH, Sengelmann R., Dermatol Surg. 2004 Sep;30(9):1252-5.
Patients may experience drug-induced localized scleroderma after receiving injections of certain drugs. This paper presents a case of localized scleroderma following injection of vitamin B12. The diagnosis and treatment of this patient is reviewed.

Scleroderma and Paul Klee: Metamorphosis of life and art work?
Ostendorf B, Maiburg B, Schneider M., Z Rheumatol. 2004 Aug;63(4):318-25.
[Article in German] Paul Klee was born in Germany and lived in Switzerland through his life. This paper presents an overview of his life, his writings, and his artwork and how he lived with scleroderma.

Eosinophilic Gastroenteritis Associated With Systemic Lupus Erythematosus.
Barbie DA, Mangi AA, Lauwers GY., J Clin Gastroenterol. 2004 Nov;38(10):883-886.
Eosinophilic gastroenteritis is a connective tissue disease that affects that gastrointestinal tract. In many cases, the symptoms of this disease appear in patients with scleroderma. This paper presents a case study of a patient who presents with eoisinophilic gastroenteritis, but who suffering from systemic lupus erythematosus.