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| Laura Hummers, M.D.
Treatment Clinical Manifestations Epidemiology | ||
| Treatment | ||
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Abstract 624: The Scleroderma Lung Study (SLS) Shows the Beneficial Effects of Cyclophosphamide (CYC) over Placebo (PL) in Systemic Sclerosis (SSc) Patients with Active Alveolitis Summary: This is a multi-center, randomized, placebo-controlled trial evaluating treatment with oral daily cyclophosphamide (CYC) for active lung disease in scleroderma. Active lung disease was identified by the presence of any ground glass by high-resolution CT scan of the chest or by the finding of alveolitis by bronchoalveolar lavage. 162 patients from multiple US centers with evidence of active lung disease were randomized to placebo or oral daily cyclophosphamide (goal dose 2 mg/kg) for 12 months. The main outcome measure was % predicted FVC. Secondary outcome measures included % predicted TLC and DLCO, and several measures of dyspnea, quality of life and functional indices. At 12 months, patients who were treated with cyclophosphamide had a statistically significant change in FVC compared to placebo treated patients. Patients on active treatment had a decrease of 1.4% predicted compared to placebo (decrease of 3.2%, p=0.05). The vitality and health transition portions of the SF-36 were significantly better in CYC treated patients versus placebo, as were the transitional dyspnea index and the HAQ-DI. Interestingly, as well there was an improvement in the skin score in those diffuse patients treated with CYC and this was significantly better than placebo (-3.9 vs. -0.2, p=0.03). Editorial Comment: This is the first positive study for the treatment of scleroderma lung disease. The treatment effect was modest (about 2% predicted FVC at 12 months), but statistically significant. Whether this change is clinically significant is debatable. However, the fact that the other measures of treatment effect were also significantly improved, including the skin score, give credence to the notion of using immunosuppressive therapy in patients with active disease. Defining active disease, of course, remains a challenge. Abstract L29: Fibrosing Alveolitis in Scleroderma Trial (FAST) - a Multi-Centre Prospective Randomised Double-Blind Placebo-Controlled Trial RK Hoyles, RW Ellis, AL Herrick, NJ McHugh, NM Foley, SB Pearson, P Emery, DJ Veale, CP Denton, AU Wells, CM Black, RM du Bois Summary: This study examines the use of cyclophosphamide in treating alveolitis in scleroderma in 5 British scleroderma centers. The treatment protocol includes patients randomized to either 1) prednisone (20 mg QOD)with 6 monthly infusions of cyclophosphamide (600 mg/m2) followed by oral azathioprine (2.5 mg/kg/day) or 2)matched placebos. The primary outcomes were change in % predicted FVC and DLCO at 12 months. 22 patients received the experimental therapy and 23 placebo therapy with no significant differences at baseline in demographic or disease severity data. Nine patients withdrew due to significant decline in lung function (6 in placebo arm) and 2 (both in active treatment arm) due to side effects and only 62% of patients total completed the 12 month study period. At 12 months there was a statistically significant treatment difference in active treatment vs. placebo in the FVC. This treatment difference was 4.76% favoring cyclophosphamide compared to placebo (p=0.04). No differences were noted in the DLCO or secondary outcome measures (CT changes and dyspnea scores). No significant treatment-related effects (i.e. hemorrhagic cystitis) were noted in the active treatment group. The authors conclude that these data are consistent with the results of the SLS study and may be a safer alternative to oral daily cytoxan. Editorial Comment: This study also suggests an improvement in lung disease in those patients with alveolitis treated with cytoxan. This treatment regimen is significantly different than the SLS study with the use of monthly IV vs. oral daily cytoxan. In addition, the treatment duration was shorter and oral steroids and azathioprine were used during treatment. The number of treated patients was small and there was significant drop-out. The data was analyzed by intention to treat, which may actually underestimate the treatment effect, which was actually larger than what was seen in the SLS study. Although this seems to be a more attractive alternative in terms of toxicity, it seems troubling that there were no differences noted in dyspnea scores, a difference that was fairly striking in the SLS study. Additional data is needed before this treatment strategy is employed. Abstract 357: Bosentan Alleviates the Pro-Fibrotic Phenotype of Lung Scleroderma Fibroblasts: Implications for Treatment of Scleroderma Summary: Endothelin-1 is thought to potentially be involved in stimulating fibrosis in scleroderma lung disease. This study examines the ability of a dual endothelin receptor antagonist (bosentan) to modulate the pro-fibrotic or scleroderma phenotype of fibroblasts in culture. Lung fibroblasts from scleroderma patients with fibrosing alveolitis and normal controls were analyzed by micro-array analysis before and after an 18 hour treatment with bosentan as well as in functional assays. Significant baseline differences were noted between scleroderma/alveolitis cases and controls with over 350 genes being upregulated in scleroderma. Of these 350 genes, 25% were reduced by bosentan therapy in scleroderma cases only. Hierarchical clustering analysis suggests that bosentan therapy reduced the clustering differences seen between scleroderma and control fibroblasts at baseline. The genes that seem to be turned off by bosentan therapy represent a wide array of function including adhesion, transcription and cell proliferation. In addition, the over-expression of ECM-associated genes seems to be blocked by bosentan therapy. Some of the functional/morphologic features of the scleroderma fibroblasts (adhesion, contractility) also appear to be decreased by bosentan therapy. Editorial Comment: There is now a significant amount of in vitro data suggesting a role for endothelin-1 in the pathogenesis of scleroderma, particularly the vascular disease. Its role in promoting fibrosis in scleroderma is still unclear. This study suggests that the scleroderma phenotype of fibroblasts from the lung may be altered by therapy with bosentan, a dual endothelin receptor antagonist. This study has the limitations of any micro-array study and it is always unclear if scleroderma fibroblasts in culture maintain the same properties as in vivo. The role of endothelin inhibitors in the therapy of interstitial lung disease in scleroderma is currently being investigated in several ongoing clinical trials. | ||
| Clincal Manifestations | ||
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Abstract 938 Differences in Cytokine Composition in Bronchoalveolar Lavage Fluid among African-American and Caucasian Populations: Implications for Scleroderma Lung Disease Summary: The composition of cytokines in the bronchoalveolar lavage (BAL) fluid was examined in African-American and Caucasian patients with scleroderma. The patients studied were 20 AA scleroderma, 20 C scleroderma, 12 AA normal controls and 12 C normal controls. Seventy-nine cytokines were assessed by a Cytokine Array. 28 cytokines were elevated in scleroderma patients overall compared to controls, including IL-8, IL-6, MCP-1, HGF, MIP-1d and osteoprotegrin. Other cytokines were noted to be differentially higher in AA scleroderma vs. C scleroderma patients including fractalkine, IGRBP, MIP-1d, RANTES and thrombopoietin. Interestingly, many differences were also noted in the healthy control patients between AA and C subjects, including some that were elevated in scleroderma patients. Interestingly, HGF, which is elevated in the control AA patients compared to C controls and increased in scleroderma patients overall, was decreased in AA scleroderma patients compared to AA controls. Editorial Comment: This study examines the potential role of differing patterns of cytokine production in AA vs. C patients as a cause of increased burden of lung disease in AA scleroderma patients. There appear to be significant differences among healthy control patients in the basal level of cytokine production between AA and C, which is accentuated in several cytokines in the AA scleroderma patients. This suggests that fundamental differences in the milieu of the lung in AAs which may account for the increase frequency and severity of interstitial lung disease among AA scleroderma patients. Also, HGF which is a potent pro-angiogenic and antifibrotic cytokine is decreased in AA scleroderma patients vs. AA controls potentially implicating this cytokine in the pathogenesis. Abstract 365: Plasma N-Terminal Pro-Brain Natriuretic Peptide, Pulmonary Function Tests, and Six-Minute Walk Test in the Assessment of Systemic Sclerosis-Related Pulmonary Arterial Hypertension Abstract 373: Brain Natriuretic Peptide as an Indicator of Diastolic Dysfunction and Pulmonary Arterial Hypertension at an Early Stage in Patients with Scleroderma Abstract 364: N-Terminal Pro-Brain Natriuretic Peptide in the Diagnosis of Pulmonary Arterial Hypertension in Systemic Sclerosis Abstract 365 Summary: This study examined the utility of various studies in the diagnosis of pulmonary arterial hypertension (PAH) in 54 consecutive scleroderma patients undergoing an evaluation for dyspnea. Patients were excluded if they had significant left heart disease, renal failure or significant anemia. Pulmonary hypertension was defined by Doppler echocardiogram (RVSP > 35 mmHg). NT-Pro-BNP levels were significantly higher in those with an elevated RVSP compared to those with an RVSP <35 (980 vs. 114, p=0.001). NT-Pro-BNP levels negatively correlated with DLCO and with 6-Minute Walk Test distance. NT-Pro-BNP was not different in those with or without interstitial lung disease (FVC,<70% predicted or significant pulmonary fibrosis by HRCT). Elevated NT-Pro-BNP levels (>135) was more sensitive than DLCO (<55% predicted) in identifying those with PAH. Abstract 373 Summary: This group studied patients being screened for cardiopulmonary disease in scleroderma who had evidence of diastolic dysfunction (E/A ratio <1) by echocardiogram. This group had echocardiogram, pulmonary function testing, 6 Minute Walk Test and Pro-BNP. Echocardiogram specifically evaluated indices of diastolic dysfunction. Patients were excluded who had other cardiac disease, hypertension or diabetes. Those patients with elevated RVSP by echocardiogram were further assessed by either exercise echocardiogram or right heart catheterization. They noted that in 2 patients with an elevated Pro-BNP (>100) level and evidence of diastolic dysfunction had a borderline RVSP at rest but evidence of pulmonary hypertension by exercise echocardiogram. Abstract 364 Summary: This study evaluated 113 scleroderma patients with Pro-BNP levels and echocardiogram. Pulmonary hypertension (PAH) was defined by and RVSP of > 40 mmHg. Sixteen patients were diagnosed with PAH. There was a significant increase in Pro-BNP levels in scleroderma patients with PAH than those without and normal controls (188 vs. 41 vs. 18). There was a positive correlation seen with Pro-BNP level and RVSP. A Pro-BNP level of 144 was identified to have a sensitivity of 100% and specificity of 65% for the diagnosis of PAH by echocardiogram. Editorial Comment: Pro-BNP is a marker of ventricular dysfunction or strain. In pulmonary hypertension, Pro-BNP may be a marker of increased mortality. There combined data suggest that Pro-BNP levels may be useful to identify those scleroderma patients with pulmonary arterial hypertension. A deficiency in these studies is that most patients pulmonary hypertension was diagnosed by echocardiogram, an indirect measurement of the pulmonary artery pressure. Despite this limitation, Pro-BNP levels may serve an important adjunct in the evaluation of the scleroderma patient with dyspnea. The utility of Pro-BNP levels in diagnosing those with early PAH or pre-clinical PAH remains unknown and prospective studies will be needed to evaluate its role as a true biomarker of the development of PAH. | ||
| Epidemiology | ||
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Abstract 374: Ethnic Differences in Severe Organ Involvement in Systemic Sclerosis Abstract 375: Race and Independent Association with Disease Subtype, Organ System Involvement and Serologic Status in Scleroderma Abstract 374 Summary: This study uses the Pittsburgh Scleroderma Databank to evaluate the organ involvement in African-American (AA) versus Caucasian (C) patients with scleroderma. 123 AA and 1951 C patients with scleroderma were evaluated for the presence of severe internal organ involvement: pulmonary fibrosis (FVC <55% predicted), pulmonary hypertension (by echocardiogram), myositis, cardiac involvement, scleroderma renal crisis and severe gastrointestinal disease. In addition, these differences were examined in the entire group (AA vs. C) and in the subgroups with particular autoantibodies (topoisomerase, non-topo nucleolar) and in those specifically with diffuse scleroderma. AA patients more commonly had severe lung disease, pulmonary hypertension, muscle disease and GI disease. When analysis was limited to those with diffuse scleroderma pulmonary disease, pulmonary hypertension, GI and muscle disease were still more frequent in AA patients. As well, when analysis was limited to those with topoisomerase antibodies, these features remained more frequent in AA patients. However, when the analysis was restricted to those with nucleolar antibodies (and without topoisomerase) only GI disease remains more frequent in AA patients. Abstract 375 Summary: Differences in severe organ disease in black vs. white scleroderma patients were also examined in the Johns Hopkins Scleroderma Center Database. 288 black and 1217 white patients were assessed for the presence of severe organ disease: diffuse skin disease, interstitial lung disease (FVC <70% predicted), pulmonary hypertension (RVSP by echocardiogram > 50), renal disease (Medsger severity score >2), cardiac disease (Medsger severity score >1) and GI disease (Medsger severity score >2). Multivariate analysis then adjusted for other factors potentially related to organ severity including age, gender and autoantibody status (positive for topoisomerase and centromere). Black patients were more likely to have topoisomerase antibodies, less likely to have centromere antibodies and were younger at the time of diagnosis. In univariate logistic regression analysis, black patients were noted to have higher odds of having diffuse skin involvement and restrictive lung disease. In the multivariate model, black patients were still noted to have increased odds of diffuse disease and lung disease as well as increased odds of pulmonary hypertension and cardiac disease. Editorial Comment: These studies utilize data from 2 large scleroderma databases to examine the differences in severe organ disease in African-American vs. Caucasian patients. Although the methodologies differ somewhat between the 2 studies, both studies find more frequent severe organ involvement in AA patients vs. C patients. This effect remained even when other factors were controlled for including age, gender and autoantibody status. Interestingly, the effect of race was less pronounced among the patients with non-topoisomerase nucleolar antibodies, suggesting that race and antibody status may confer separate risk. Abstract 1556: Antinuclear Antibodies and Non-SSc Autoimmune Diseases in First-Degree Relatives of Scleroderma Patients: Data from the Scleroderma Family Registry and DNA Repository Summary: In this study, the frequency of antinuclear antibodies (ANAs) was examined in cases with scleroderma, their first degree relatives and healthy unrelated controls. Data/serum samples were obtained from the large Scleroderma Family Registry and DNA repository collected at the University of Texas. 479 cases with 740 first degree relatives and 160 unrelated spouse or friend control patients were studied for the presence of ANAs by indirect immunofluorescence using Hep2 substrate. History of autoimmune disease in family members was obtained by self report and follow-up questionnaires, chart review or interview. The mean age at sample collection was similar across all 3 groups. Among the first degree relatives, 8.95% were ANA positive, compared to 9.38% of unrelated controls (p=0.9834). Female relatives were more frequently ANA positive compared to male relatives and this difference was not noted in the control populations (ratio of M: F was not significantly different in each group). Of the 68 relatives, 20 had a known autoimmune disease (11 scleroderma, 3 polymyositis/dermatomyositis, 1 systemic lupus, 1 MCTD, 3 RA, 1 Raynauds). Additionally, self reported autoimmune diseases were reported and verified in 27 relatives (18 RA, 10 Raynauds, 4 myositis, 1 systemic lupus, 3 multiple sclerosis and 1 primary biliary cirrhosis). Editorial Comment: Using a large family repository/databank, the frequency of ANA positivity was examined in the first degree relatives of patients with confirmed scleroderma. ANA positivity, surprisingly, was not different in family members compared with healthy control subjects. Presumably, however, unrelated controls were only chosen if they were healthy therefore excluding those with known/self-reported rheumatic/autoimmune illnesses, making this finding even more surprising. Increased frequency of ANAs has been reported in the family members of other autoimmune rheumatic diseases (SLE). Diagnosed rheumatic illnesses were relatively common, however, among first degree relatives despite the equal frequencies of ANA positivity to the healthy control population. This data would need to be formally compared to population-based frequencies of autoimmune diseases to determine the increased hazard among family members of scleroderma patients. | ||
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