| Systemic sclerosis (SSc, scleroderma) is an inflammatory rheumatic disorder characterized by striking heterogeneity in clinical expression. In this dissertation, we examine previously unrecognized demographic (age at disease onset) and immunologic predictors (recognition of granzyme B-cleaved fragments) of two important clinical outcomes in SSc, pulmonary arterial hypertension (PAH) and ischemic digital loss (IDL), respectively. In addition, predictors of reduced survival among SSc lung transplant recipients are examined.; In the first study, we examined consecutive patients who underwent echocardiography at a Scleroderma Center. We demonstrated twofold greater risk of PAH (OR 2.30, 95%CI, 1.32–3.99) for late-onset (age ≥60 years) versus earlier-onset (<60 years) disease. Increasing age at disease onset, therefore, represents a previously unrecognized risk factor for PAH.; In the second study, sera from 19 cases with limited SSc and IDL, and 15 matched controls without IDL, were used to immunoblot HeLa cell lysates and chromosome preparations incubated in vitro, in the absence or presence of granzyme B. Cleaved autoantigens were immunoblotted by 16 of 19 (84.2%) IDL sera compared with 6 of 15 (40.0%) non-IDL sera. An identical 60 kd granzyme B-generated fragment, arising through cleavage of CENP-C, was recognized by 5 of 16 (31.3%) of the IDL sera. We conclude that antibodies against granzyme B-generated centromeric peptide fragments identity the unique SSc subset of IDL.; Finally, survival following lung transplantation at two large centers for patients with SSc, idiopathic pulmonary fibrosis (IPF) and primary pulmonary hypertension (PPH) was determined by Kaplan Meier method. Cumulative survival at six months was 69.0% for SSc compared with 80% for IPF (p = 0.21) and 79.0% for PPH (p = 0.38). Over the subsequent 18 months, there was convergence in mortality patterns between transplant groups. Among patients with SSc, longer disease duration and reduced creatinine clearance were associated with reduced survival.; Together, these studies make a meaningful contribution toward identification of predictors of important clinical outcomes in SSc. In addition to examining the role of a novel therapeutic approach to end-stage pulmonary dysfunction, our observations may provide opportunity to intervene prior to development of irreversible organ damage, and offer insights into pathogenesis of SSc. |
