Stimulatory Autoantibodies to the PDGF Receptor in Systemic Sclerosis

Silvia Svegliati Baroni, Ph.D., Mariarosaria Santillo, Ph.D., Federica Bevilacqua, M.D., Michele Luchetti, M.D., Tatiana Spadoni, B.Sc., Matteo Mancini, B.Sc., Paolo Fraticelli, M.D., Paola Sambo, M.D., Ada Funaro, Ph.D., Andrius Kazlauskas, Ph.D., Enrico V. Avvedimento, M.D., Ph.D., and Armando Gabrielli, M.D.

ABSTRACT

Background Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression.

Methods We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR or chains or the same cells expressing PDGFR or . Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments.

Results Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen–gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts.

Conclusions Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.

Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia

Marilyn J. Manco-Johnson, M.D., Thomas C. Abshire, M.D., Amy D. Shapiro, M.D., Brenda Riske, M.S., M.B.A., M.P.A., Michele R. Hacker, Sc.D., Ray Kilcoyne, M.D., J. David Ingram, M.D., Michael L. Manco-Johnson, M.D., Sharon Funk, B.Sc., P.T., Linda Jacobson, B.S., Leonard A. Valentino, M.D., W. Keith Hoots, M.D., George R. Buchanan, M.D., Donna DiMichele, M.D., Michael Recht, M.D., Ph.D., Deborah Brown, M.D., Cindy Leissinger, M.D., Shirley Bleak, M.S.N., Alan Cohen, M.D., Prasad Mathew, M.D., Alison Matsunaga, M.D., Desiree Medeiros, M.D., Diane Nugent, M.D., Gregory A. Thomas, M.D., Alexis A. Thompson, M.D., Kevin McRedmond, M.D., J. Michael Soucie, Ph.D., Harlan Austin, Ph.D., and Bruce L. Evatt, M.D.

ABSTRACT

Background Effective ways to prevent arthropathy in severe hemophilia are unknown.

Methods We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).

Results Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.

Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov] .)

Surgical versus Nonsurgical Therapy for Lumbar Spinal Stenosis

James N. Weinstein, D.O., M.S., Tor D. Tosteson, Sc.D., Jon D. Lurie, M.D., M.S., Anna N.A. Tosteson, Sc.D., Emily Blood, M.S., Brett Hanscom, M.S., Harry Herkowitz, M.D., Frank Cammisa, M.D., Todd Albert, M.D., Scott D. Boden, M.D., Alan Hilibrand, M.D., Harley Goldberg, D.O., Sigurd Berven, M.D., Howard An, M.D., for the SPORT Investigators

ABSTRACT

Background Surgery for spinal stenosis is widely performed, but its effectiveness as compared with nonsurgical treatment has not been shown in controlled trials.

Methods Surgical candidates with a history of at least 12 weeks of symptoms and spinal stenosis without spondylolisthesis (as confirmed on imaging) were enrolled in either a randomized cohort or an observational cohort at 13 U.S. spine clinics. Treatment was decompressive surgery or usual nonsurgical care. The primary outcomes were measures of bodily pain and physical function on the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) and the modified Oswestry Disability Index at 6 weeks, 3 months, 6 months, and 1 and 2 years.

Results A total of 289 patients were enrolled in the randomized cohort, and 365 patients were enrolled in the observational cohort. At 2 years, 67% of patients who were randomly assigned to surgery had undergone surgery, whereas 43% of those who were randomly assigned to receive nonsurgical care had also undergone surgery. Despite the high level of nonadherence, the intention-to-treat analysis of the randomized cohort showed a significant treatment effect favoring surgery on the SF-36 scale for bodily pain, with a mean difference in change from baseline of 7.8 (95% confidence interval, 1.5 to 14.1); however, there was no significant difference in scores on physical function or on the Oswestry Disability Index. The as-treated analysis, which combined both cohorts and was adjusted for potential confounders, showed a significant advantage for surgery by 3 months for all primary outcomes; these changes remained significant at 2 years.

Conclusions In the combined as-treated analysis, patients who underwent surgery showed significantly more improvement in all primary outcomes than did patients who were treated nonsurgically. (ClinicalTrials.gov number, NCT00000411 [ClinicalTrials.gov] .)