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In the non-rheumatology journals: Yet more promise for interferon-free treatment of hepatitis C. Also, stem cells and meniscectomy, and more insights into the link between scleroderma and cancer.
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV InfectionNew England Journal of Medicine, January 16, 2014
Once-daily treatment with two direct-acting antiviral agents, oral daclatasvir (DCV) plus sofosbuvir (SOF, Sovaldi), has yielded high rates of sustained virologic response among patients with genotype 1, 2 or 3 hepatitis C virus (HCV) infection, even those who previously did not respond to protease inhibitors.
The combination has high cure rates even in patients with poor response to other treatments.
A total of 211 patients were randomized into treatment with DCV plus SOF, with or without ribavirin (RBV). The primary end point was sustained virologic response (HCV RNA <25 IU/mL) 12 weeks after the end of therapy.
In the 211-patient randomized trial of DCV plus SOF with or without ribavirin (RBV), 98% of patients with genotype 1 infection and 91% with genotype 2 or 3 met the primary end point:sustained virologic response (HCV RNA <25 IU/mL) 12 weeks after the end of therapy. Response rates were similar with or without RBV.
Daclatasvir is an HCV NS5A replication complex inhibitor, and sofosbuvir inhibits nucleotide analog HCV NS5B polymerase.
Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1New England Journal of Medicine, January 16, 2014
In a phase 2b study, peginterferon-free regimens with and without ribavirin (RBV) were effective in patients with hepatitis C virus (HCV) genotype 1 infection, with sustained virologic responses (SVR) of 83 to 100%, although small numbers limited the power of the study.
Five hundred and seventy-one patients were randomly assigned to 14 treatment subgroups, of the protease inhibitor ABT-450 with ritonavir (Norvir), combined with the NS5A inhibitor ABT-267, or the nonnucleoside polymerase inhibitor ABT-333, or both, for 8, 12, or 24 weeks. All the subgroups but one also received ribavirin.
The primary endpoint was SVR at 24 weeks after the end of treatment. Among those who received treatment for 12 weeks, 95% (p=0.24) reached the primary endpoint.
The rate of response was consistently high, similar in both untreated and treatment-refractory patients, and similar in those with and without host IL28B non-CC genotype, HCV genotype 1a, black race, and high baseline HCV RNA levels.
Adult Human Mesenchymal Stem Cells Delivered via Intra-Articular Injection to the Knee Following Partial Medial Meniscectomy: A Randomized, Double-Blind, Controlled StudyThe Journal of Bone & Joint Surgery, January 15, 2014
Osteoarthritic patients who received an injection of mesenchymal stem cells after partial medial meniscectomy had a greater reduction in pain after six weeks and two years than a control group who received a placebo injection. They also had a greater increase in meniscal volume. No ectopic tissue or important safety issues were identified.
This was the first randomized, controlled trial to evaluate the safety and clinical outcome of stem cells injected into the knee. Of 55 patients, 18 received an injection of 50 × 106 stem cells, 18 received three times that number, and 19 in the control group received a hyaluronic acid vehicle.
Allogenic mesenchymal stem cells do not have adverse immune effects. The adult human mesenchymal stem cells were derived from bone-marrow aspirates obtained from unrelated, unmatched donors, and cultured ex vivo. The supplier paid for the study.
Can Cancer Trigger Autoimmunity?Science, January 10, 2014
Association of the Autoimmune Disease Scleroderma with an Immunologic Response to CancerScience, January 10, 2014
Scleroderma may be triggered by proteins that are mutated in cancer. A study from Johns Hopkins compared patients with autoantibodies to RNA polymerase III subunit (RBC1), in whom scleroderma and cancer appear more or less concurrently, and others with autoantibodies to topoisomerase 1 (TOP1) or centromere protein B (CENPB), in whom scleroderma usually predates the onset of cancer by a decade or more.
They sequenced tissue from tumor and blood samples of 16 scleroderma patients with cancer. Half had autoantibodies to RPC1 and the other 8 had autoantibodies to TOP1 or CENPB instead.
RPC1 is encoded by the gene polymerase III polypeptide A (POLR3A). TOP1 and CENPB are encoded by the genes TOP1 and CENPB
Blood and tumor samples from six of eight patients with RPC1 autoantibodies had mutations or loss of heterozygosity in POLR3A, the gene that encodes RPC1. None of the eight patients without RPC1 autoantibodies had alterations in this gene, or in the genes that encode TOP1 and CENPB. They also had less severe scleroderma and cancer was delayed by a mean of 14 years compared to the six with gene alterations.
All the anti-RPC1 antibodies recognized both wild-type and mutated RPC1. This suggests that the humoral immune response does not directly target the area of the mutation. But some patients with POLR3A mutations had T cells that reacted to RPC1 protein fragments produced by the mutated gene. So scleroderma may be caused by both a humoral and T-cell cross-reaction to the POLR3A mutation associated with cancer.