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Laura Hummers, M.D.

 Treatment

Abstract 1851: Anti-TGFb1 Therapy for Diffuse Cutaneous Systemic Sclerosis: a Multicenter, Randomized, Placebo-controlled Phase I/II Trial of CAT-192
Christopher P. Denton1, Peter A. Merkel, Daniel E. Furst, Dinesh Khanna, Paul Emery, Vivien M. Hsu, Nancy Silliman, James Streisand, John Powell, Joseph H. Korn, Carol M. Black1, James R. Seibold, with CAT-192 Study Group, and SCTC.

Summary: This study evaluated the safety of an inhibitor or TGF-b(human recombinant IgG4 antibody) in patients with diffuse cutaneous scleroderma. Forty-five patients with early diffuse skin involvement were enrolled and randomized into 4 groups, placebo, 0.5 mg/kg, 5 mg/kg and 10 mg/kg. The medication was infused on weeks 0, 6, 12 and 18 and patients were followed for adverse events and secondary outcomes included skin score, health assessment questionnaires, organ disease severity and possible biomarkers of fibrosis.

Pharmacokinetic data was also obtained. Four deaths were noted during the trial, none of which were attributable to the medication, but were thought to be scleroderma associated. Serious adverse events occurred equally among the groups and were not thought to be treatment related. There were no significant changes noted in any of the secondary measurements between groups, but this study was not powered to assess efficacy for skin disease. There was an improvement in the modified Rodnan skin score during the trial and this correlated with disease duration. No changes were noted with treatment in biomarkers of skin fibrosis in skin biopsy specimens.

Editiorial Comment: TBF-bhas been strongly implicated as a major mediator of fibrosis in scleroderma. This is the first trial investigating a neutralizing antibody to TGF-b1. The medication appeared to be well tolerated. Skin scores in this study were stable or improved in all groups, and improvements in skin score correlated with increased disease duration, likely reflecting the natural history of the skin disease, which does improve with time in most patients. Although active serum levels were observed, none of the biologic markers of treatment effect could be demonstrated in skin biopsy specimens. Despite these limitations, we should be encouraged that agents such as this appear safe and well tolerated and anti-TGF-btherapy should remain a target of investigation.

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Abstract 1852: Sitaxsentan Improves 6MW in Patients with Pulmonary Arterial Hypertension (PAH) Related to Connective-Tissue Diseases (CTD)
Vallerie V. McLaughlin, Nicholas Hill, Victor F. Tapson, Adaani E. Frost, David Langleben, Ronald Oudiz, Shelley Shapiro, Ivan M. Robbins, Robyn J. Barst, on behalf of the STRIDE-1 Study Group.

Summary: This study reports the first data from the STRIDE-1 trial in connective tissue disease-associated pulmonary hypertension. This trial is a multicenter, randomized, placebo-controlled, double-blind study evaluating 2 doses of sitaxsentan (100 mg and 300 mg orally once daily) and placebo for 12 weeks in patients with pulmonary arterial hypertension. This study examined the subgroup of patients with CTD-associated PAH in this trial (42 of 178 patients). For this analysis the two active treatment arms were pooled as there were no significant differences between these two groups in the total study population. The 42 CTD patients were WHO functional class II-III at baseline and their six minute walk test was 356 meters. The treatment group (100mg and 300mg pooled) had in improvement in six minute walk of 20 meters while the placebo group declined by 38 meters (p=0.0274). Of the 33 patients in the treatment arms, eight had improvement in their WHO functional class compared to one of nine in the placebo group. No LFT abnormalities were noted in this group.

Editiorial Comment:This trial evaluated the efficacy of a selective endothelin-A inhibitor, sitaxsentan in patients with pulmonary arterial hypertension. This study reports the subgroup analysis of patients with CTD-associated PAH (included scleroderma, lupus and other connective tissue diseases). There was a significant improvement in the six minute walk time in treated patients compared to controls representing both a decline in the placebo arm and a significant improvement in the treated groups. Long term data, including mortality data will be needed to look for sustained response, but this data is encouraging that a second, oral medication for the treatment of this deadly complication of CTD will be safe and effective.

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Abstract 1702: Intravenous Epoprostenol for Severe Digital Ischemia in Scleroderma
Robert W. Simms, Harrison Farber, Eugene Kissin, Peter A. Merkel, Joseph H. Korn

Abstract 1704: Alprostadil IV Treatment Of Severe Raynauds Phenomenon In Collagen Diseases
Beltran Emma, Perez Garcia Carolina, Blanch Josep, Padro Isabel, Garcia Javier, Pros Ana

Summary:
Abstract 1702:
Five patients with severe digital ischemia and digital gangrene were treated with IV epoprostenol in an open label experience. Each of the five patients has a diagnosis of scleroderma (4) or lupus (1) and had persistent temperature loss and cyanosis with pain for greater than 24 hours with threatened digital infarct. Seven infusions were administered to the five patients at a mean dose of 8 ng/kg/min for a mean of 5 days duration given as a continuous infusion. Two patients had a history of prior amputations and patients had previously been treated with a number of vasodilator therapies, anticoagulants or surgical sympathectomies. Two patients with early gangrene at baseline progressed to require digital amputation. Two patients had complete reversal of ischemia and 3 patients stabilized.

Abstract 1704:
Nine patients with either scleroderma or scleroderma with overlap of other connective tissue diseases (5 with diffuse scleroderma, 3 with limited scleroderma, one with scleroderma/dermatomyositis overlap and 1 with dermatomyositis/polymyositis overlap) with severe Raynauds phenomenon (symptomatic digital ischemia, with our without ulcers or gangrene) who failed calcium channel blocker therapy were treated with alprostadil as a continuous IV infusion at 40 mg/day for 5 days. Two patients also had infected ischemic ulcers requiring systemic antibiotic therapy. Pain improved in all patients and all ulcerations healed (n=8). Two patients had recurrent digital ulcerations at 5 and 24 months after the initial infusion and both responded to retreatment with alprostadil. No adverse events were reported.

Editiorial Comment:These two open label experiences suggest benefit of intravenous prostaglandins for severe digital ischemia associated with scleroderma. The obvious limitation of these trials is that they are uncontrolled, but this data along with other data of IV prostaglandins support the use of these medications in severe situations. Lack of availability and lack of expertise in the use of these medications may hinder their more widespread use in the community.

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Abstract 1856: High-Dose Immunosuppressive Therapy (HDIT) for SSc: Results of 3 year follow-up demonstrate continued improvement in function and skin with stability in the lungs.
D. E. Furst, P. A. McSweeney, L. J. Crofford, K. T. McDonagh, K. M. Sullivan, M. D. Mayes, J. Lee Nelson, T. A. Gooley, L. A. Holmberg, C. S. Chen, M. H. Wener, J. Lee, G. Henstorf, M. Abidi, R. A. Nash

Abstract 1700: Autologous Hematopoietic Stem Cells Transplantation in Severe Scleroderma: Long Term Results from the French ISAMAIR Multicenter Phase I-II Study
Zora Marjanovic, Corneliu Henegar, Marjan Daneshpouy, Doina Ilie, Xavier Mariette, Robert Damade, Pascal Roblot, Joseph Emmerich, Nicolas Mounier, Serge Arfi, Jean Cabane, Jean Sibilia, Joel Constans, Francoise Sarrault Raynaud, Eliane Gluckman, Dominique Farge

Summary:
Abstract 1856
This study examined the clinical outcomes of 33 patients treated with high dose immunosuppression followed by stem cell rescue. All patients had a disease duration of less than 4 years at baseline with a mean mild reduction in FVC, normal creatinine and normal ejection fraction. All patients were treated with the same protocol of: 1. mobilization with GCSF, 2. leukophoresis with CD-34 selection, 3. High dose immunosuppression with cyclophosphamide 120 mg/kg, ATG 90 mg/kg and total body irradiation (25 patients had lung shielding). At three years, 9 patients have died (5 treatment related and 4 scleroderma progression) and 13 patients have follow-up data (other 11 patients have shorter follow-up period due to staggered enrollment). Of the 13 surviving patients with data, the mean skin score improved by 23 (80% reduction) and HAQ improved by 1.34 units. Lung function testing revealed a decrease in DLCO by 3% and increase in FVC by 3% of predicted, neither of which was a significant change. Creatinine increased slightly by 1.5 mg/dL and ejection fraction was reduced 2.3% (p = 0.05 and 0.06 respectively). Three patients had a significant decline in FVC and 5 patients had a significant rise in their creatinine. Of those 5 patients, 2 died, 1 required dialysis and 3 stabilized.

Abstract 1700
This study examined the open-label experience of stem cell transplant in 14 patients with severe scleroderma in a French centers recruited over 40 months. All patients were treated with the same protocol: 1. mobilization with GCSF + cyclophosphamide 4gm/m2 (held if EF <40%), 2. leukophoresis to yield 2.5 x 106 CD34+ cells/kg, 3. conditioning with either cytoxan 200 mg/kg or melphalan (140 mg/m2) (used if EF <40%), 4. stem cell reinfusion. One patient did not have successful mobilization but was transplanted, one patient was withdrawn after mobilization and one patient had an early treatment related death. The remaining 12 patients had a mean follow-up of 44 months (range 33-48). At 6 months 6/12 patients had major response, 3/12 patients had partial response, 4/12 patients had no response. At last follow-up, 8 patients are alive, 4 additional patients died from disease progression. Of the 8 living patients, one had no response and 5/7 patients with at least partial initial response relapsed. These patients were then treated with mycophenolate mophetyl and had either a major (1) or partial (4) response.

Editiorial Comment: These two uncontrolled studies evaluate the use of aggressive immunosuppression with stem cell rescue in the treatment of patients with severe scleroderma. These studies both demonstrate a durable response in a small number of patients. What is unclear is what the response rates would be in patients treated with less aggressive regimens or untreated as these are both uncontrolled studies. The long term data, therefore, includes some element of survival bias. The variability in the mobilization and immunosuppression and the outcome measurements make interpreting this data from the U.S. and Europe difficult to comprehend together. There is however combined a 13% treated-related mortality in the two studies. There are controlled trials underway now in the US and Europe that will give us a better understanding of the role of stem cell transplant in scleroderma.

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Abstract # 1855 Protective Effect of Pravastatin on Vascular Endothelium in Patients with Systemic Sclerosis: A Pilot Study
Shin Furukawa, Shinsuke Yasuda, Yoshie Sakai, Makoto Kondo, Yujiro Kon, Olga Amengual, Yoshiharu Amasaki, Tatsuya Atsumi, Takao Koike

Summary: This uncontrolled study examined the effect of pravastatin on vascular endothelial markers in patients with scleroderma. Eighteen patients with scleroderma were evaluated and 9 patients were treated with pravastatin 10 mg/day for 8 weeks and 9 were not along with 10 normal controls. The patients were mostly females (17:1) and 10/18 had diffuse skin involvement. Patients with hyperlipidemia were excluded. Laboratory measurements were performed at day 0, 28 and 56 and included von Willebrand factor activity (vWF), thrombomodulin (TM), thrombin-antithrombin complex (TAT), soluble ICAM-1, soluble VCAM-1 and P-selectin, which are markers of activity of the vascular endothelium. At baseline, scleroderma patients had significant increases in almost all factors compared with healthy controls. At baseline no differences were found between scleroderma patients treated with pravastatin and those that were not treated. At eight weeks, levels of vWF and TAT were significantly lowered in the treatment group. No differences were found in the other markers. No changes were appreciated in the lipid levels.

Editorial Comment: This is the first study to examine the use of statins in patients with scleroderma. Statins are reported to have multiple positive effects on the endothelium, which we know to be disturbed in scleroderma. These positive effects are likely independent of their lipid lowering capabilities. Therefore, there are theoretic reasons to consider the use of these medications in scleroderma. Although small and uncontrolled this study suggests that these medications warrant further study in scleroderma.

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 Clincal Outcomes

Abstract 1052: Changes in Causes of Death in Systemic Sclerosis Over the Past 30 Years.
Virginia Steen. Georgetown University, Washington, DC

Summary: This study examines the causes of death in a large cohort of scleroderma patients and the variation in causes of death with time over a 30 year time period (1972-2001). At time of evaluation (2001), 982/2000 patients initially seen between 1972 and 1995 have died (49%). Cause of death was determined by interviewing family members and by reviewing medical and hospital records. Cause of death could be determined in 90% of the 982 patients by these methods. The frequency of non-scleroderma related deaths remained stable over the 30 year period. The mean disease duration at time of death increased with time (10-12 years before 1990 and 15 years after 1990, p<0.01). Scleroderma-associated GI, cardiac (non-PAH related) and multiorgan failure were stable over this 30 year period. The frequency of scleroderma renal crisis-associated death significantly declined, while the frequency of pulmonary (pulmonary fibrosis and pulmonary arterial hypertension) increased with time and in the most recent periods account for 25% of all causes of death in this group of scleroderma patients.

Editiorial Comment: This study supports the feeling of the scleroderma community, that pulmonary disease is the leading cause of death among patients with scleroderma. Since the advent of ACE inhibitors, death from scleroderma renal crisis has significantly diminished with time. Unfortunately any data that retrospectively examines causes of death is fraught with inaccuracy and possible bias. As we understand scleroderma better, there may be a trend with time of more accurately diagnosing scleroderma-associated causes of death as well. This does stress the importance, however, on focusing therapeutic efforts at treating the pulmonary complications of scleroderma.

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Abstract 1057: The Point Prevalence of Undiagnosed Pulmonary Hypertension (PAH) in Patients with Connective Tissue Disease (CTD) attending Community Based Rheumatology Clinics (UNCOVER Study).
Fredrick M. Wigley, Maureen D. Mayes, Joao A.C. Limia1, David A. McLain, Lincoln Chapin, Clive Ward-Able

Summary: This study examines the point prevalence of undiagnosed pulmonary arterial hypertension at a community practice level. Fifty community rheumatology practices in the US and Canada were asked to review all of records of their patients with either scleroderma or mixed connective tissue disease to see if they carried a diagnosis of PAH. In those without known PAH, new 2D echocardiograms were performed. Of 791 evaluable patients, 122 carried the diagnosis of PAH and 669 did not. After new echocardiograms were performed on these 669 patients, 13.3% (89/669) had a RVSP >40 mmHg. 20/89 patients had a RVSP >50 mmHg and a similar number had RV or RA abnormalities. An RVSP>40 in correlated with increased dyspnea compared to those with an RVSP<40 and a decrease in their DLCO (p=0.005) without significant difference in FVC.

Editiorial Comment: The prevalence in this community based screening evaluation of echocardiograms suggests that 13% of patients with scleroderma and mixed connective tissue disease may have pulmonary arterial hypertension. While the value of the echocardiogram in the diagnosis of PAH is debated and is clearly not the gold standard, the fact that these patients have a decline in DLCO and increased dyspnea likely reflect some degree of pulmonary vascular disease. The simple screening tool can identify a population of patients who are at least at risk for developing significant pulmonary hypertension and deserve further evaluation and careful monitoring.

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Abstract 1678: Intima-Media Thickness Evaluation in 45 Systemic Sclerosis Compared to Healthy Subjects Matched for Sex and Gender
Odile Beyne-Rauzy, Philippe Leger, Aurelie Godel, Pierre Delobel, Frederic Bidegain, Sophie Arista, Clement Gaudin, Henri Boccalon, Daniel F.P. Adoue.

Abstract 1683: Macrovascular Disease Assessment in Systemic Sclerosis: Results of a Prospective Case-Control Study
Philippe Leger, Odile Beyne-Rauzy, Sophie Arista, Aurelie Godel, Frederic Bidegain, Clement Gaudin, Pierre Delobel, Franoise Fortenfant, Henri Boccalon, Daniel Adoue

Summary:
Abstract 1678 This case control study examined intima-media thickness of the carotid arteries in 45 patients with scleroderma to 45 age and sex matched healthy control patients. Data on other risk factors for vascular disease was collected in these patients as well including hypertension, body weight, diabetes, tobacco use and dyslipidemias. IMT was assessed by ultrasound of the internal carotid arteries. The scleroderma patients had a mean disease duration of 12 years and the majority were in the limited subgroup (33/45). No significant differences in traditional cardiovascular risk factors between groups were identified individually, but the scleroderma group overall had a significantly smaller number of risk factors per patient compared to controls (0.9 per SSc patient vs. 1.7 per healthy control). Mean IMT in scleroderma patients was 0.55 compared to 0.65 in the controls (p<0.0002). Also, 55% of scleroderma patients were being treated with calcium channel blockers and 25% were on ACE inhibitors.

Abstract 1683
This study examined the prevalence of macrovascular disease of the extremities in 45 scleroderma patients and 45 control patients by Doppler examination and systolic index measure. Cardiovascular risk factors were ascertained in each group and presumed not different between groups (not stated in abstract). 23 scleroderma patients compared to 3 controls showed abnormal Doppler evaluation of the extremities. Among the 23 effected scleroderma patients, 14 had upper limb involvement, 3 had lower limb involvement and 6 had evidence of both. The 3 control patients had upper limb involvement only. Systolic index (a measure of rigidity) was abnormal in 5 scleroderma patients and no controls. No data was presented on medication differences between the patients and control groups.

Editiorial Comment: These 2 studies from the same center evaluated macrovascular disease in scleroderma patients compared to control patients. There appeared to be less carotid disease and more macrovascular disease of the extremities among the scleroderma patients. There were differences in cardiovascular risk factors in one study and differences in the use of cardiovascular agents which may explain some of the differences but should not explain an increase in the extremity changes in the second study (if in fact these are the same patients, which they presumably are). This difference is likely real and supports other findings in the past of macrovascular disease of the upper extremities in scleroderma patients. The authors conclusions, however, that this is scleroderma specific and a marker of early disease are unfounded by this study. There is no longitudinal data presented and no other disease states were examined.

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