CHICAGO—Promising therapeutic targets for rheumatic diseases were the focus of a plenary session here at the ACR/ARHP 2011 Annual Meeting in November. [Editor’s note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
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Explore This IssueApril 2012
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Presenters discussed discoveries and treatments for systemic sclerosis, rheumatoid arthritis (RA), vasculitis, and Behçet’s disease.
Rituximab for ANCA-Associated Vasculitis
John H. Stone, MD, MPH, director of clinical rheumatology at Massachusetts General Hospital in Boston, focused on results from the RAVE trial, which is evaluating rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Traditionally, cyclophosphamide and glucocorticoids have been the mainstay of treatment for these patients. Results published in 2010 focused on six-month results from the RAVE trial and showed that rituximab was not inferior to cyclophosphamide (CYC) for remission induction.1 Dr. Stone’s presentation focused on six to 18 months of follow-up data from the RAVE trial.
Nearly 200 patients with severe Wegener’s granulomatosis or microscopic polyangiitis, all of whom were ANCA positive, received one to three pulses of methylprednisolone. The patients were then randomized to receive rituximab infusions and CYC placebo for three to six months or rituximab placebo infusions and CYC for three to six months. After six months, the two randomized groups received a placebo for 12 to 15 months or azathioprine for 12 to 15 months.
“Let me emphasize, for 12 to 15 months, following the six-month outcome, patients in the rituximab group were on no medication after they were tapered off prednisone,” Dr. Stone said.
Investigators found that a single course of rituximab was just as effective as 18 months of CYC and azathioprine. “Relapses were more common in patients who were PR3-ANCA positive, had Wegener’s, and had relapsing disease at baseline,” Dr. Stone said. The risk for severe flare with rituximab appears low as long as B cells remain depleted and ANCA remains negative, Dr. Stone said.
“We hope ongoing mechanistic studies will enable us to predict who’s at risk for disease flare and when that disease will occur,” he said.
JAK2 in Systemic Sclerosis
Janus kinase 2 (JAK2) inhibitors can serve as a possible treatment for fibrotic diseases, said Clara Dees, PhD, a researcher in the department of medicine 3, rheumatology and immunology, at the University of Erlangen in Nuremberg, Germany. She explained that activated JAK2 is implicated in myeloproliferative diseases and that JAK2 inhibitors are currently under evaluation in clinical trials.
Dr. Dees is involved in the study of JAK2 signaling in active systemic sclerosis patients. This research has found that JAK2 signaling is indeed active in these patients and reduces collagen expression. “JAK2 is persistently active in fibroblasts. Inhibition of JAK2 reduces the intrinsic activation of systemic sclerosis fibroblasts,” Dr. Dees said.
A mouse model of skin fibrosis showed that JAK2 injections led to increased dermal thickness, increased collagen content, and increased myofibroblast numbers, Dr. Dees said. “However, treatment with a selective JAK2 inhibitor almost completely prevented the development of fibrosis and decreased dermal thickening,” she said. This kind of treatment could be used for early inflammatory stages, she added.
The inhibition of JAK2 prevents fibrosis in inflammatory as well as noninflammatory models of fibrosis, Dr. Dees concluded. “Inhibition of JAK2 reduces the basal synthesis of collagen selectively in systemic sclerosis fibroblasts, but not in control fibroblasts,” she said.
An IRF5 Variant and Systemic Sclerosis
A functional variant of the gene interferon regulatory factor 5 (IRF5) for the treatment of systemic sclerosis was discussed during a presentation from Shervin Assassi, MD, assistant professor of medicine in the division of rheumatology at the University of Texas Health Science Center in Houston. He presented a study investigating the impact of non–major histocompatibility complex susceptibility loci on survival and severity of interstitial lung disease in systemic sclerosis patients. New treatments are especially important in systemic sclerosis, where morbidity and mortality rates are higher than most other rheumatic diseases, Dr. Assassi said.
The study population was 1,443 patients with systemic sclerosis divided into a discovery cohort (914 patients) and a replication cohort (529 patients).
Investigators found that only one single-nucleotide polymorphism (SNP) in the IRF5 gene—rs4728142—was associated with patient survival. Even after investigators adjusted their analysis for disease duration and other factors, the prominence of rs4728142 with survival was clear.
“In this case, the minor allele has a frequency of 49%, which makes it potentially suitable for biomarker development,” Dr. Assassi said.
“The minor allele of a SNP in the IRF5 promoter region is associated with lower IRF5 transcript levels and is predictive of better survival and milder interstitial lung disease in patients with systemic sclerosis,” Dr. Assassi said. “This provides further support for the importance of genes involved in the type I interferon pathway in the pathogenesis of systemic sclerosis and has potentially important implications for biomarker development and the identification of therapeutic targets.”
This particular allele also might be used with scleroderma renal crisis, the severity of gastrointestinal involvement, and pulmonary hypertension, Dr. Assassi said.
Behçet’s Disease Targets
Yohei Kirino, MD, PhD, a fellow in the inflammatory disease section of the medical genetics branch at the National Human Genome Research Institute in Bethesda, Md., discussed a genome-wide analysis of imputed genotypes that identified CCR1, CCR3, and STAT4 as novel candidate risk loci in Behçet’s disease.
Treating RA Patients with Rheumavax
Ranjeny Thomas, MBBS WA, MD WA, of the Diamantina Institute at Princess Alexandra Hospital at the University of Queensland in Brisbane, Australia, presented evidence regarding Rheumavax for the treatment of patients with RA. Rheumavax is a vaccine derived from the patient’s blood, and involves autologous dendritic cells exposed to citrullinated peptides.
The research Dr. Thomas presented found that Rheumavax was safe. Investigators did not observe any major adverse events. The results that the researchers observed were in patients with anticitrullinated protein antibody–treated early RA.
“There’s potential for further development of strategies targeting dendritic cells and cit-peptide in specific HLA-DR groups,” Dr. Thomas said. “The tolerance biomarkers suggest improvement in immune hyperregulation.”
Vanessa Caceres is a freelance medical writer in Bradenton, Fla.