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      High mobility group box-1 protein as a tumor necrosis factor-independent therapeutic target in rheumatoid arthritis

      editorial
      Author(s): 1 ,
      Publication date (Electronic):
      Journal: Arthritis Research & Therapy
      Publisher: BioMed Central

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          Abstract

          Rheumatoid arthritis (RA) remains a prevalent disease worldwide that causes significant morbidity and mortality despite recent therapeutics. High mobility group box-1 (HMGB1) protein, originally appreciated as an intranuclear DNA binding protein, has been implicated as an integral mediator in the pathogenesis of animal arthritides and RA disease in humans. Our current understanding of HMGB1 has promoted the development of targeting therapies that have improved outcomes in animal models of inflammation. In the previous issue of Arthritis Research & Therapy, Sundberg and colleagues address, for the first time in a prospective cohort study, whether HMGB1 expression is dependent upon tumor necrosis factor activity in patients with RA.

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          HMG-1 as a late mediator of endotoxin lethality in mice.

          H. Wang, O Bloom, M. Zhang … (1999)
          Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
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            Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group.

            R Maini, E W St Clair, F Breedveld … (1999)
            Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate. In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.
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              Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity.

              Ya-Jun Li, Kevin J. Tracey, A-C Aveberger … (2003)
              Extracellular high mobility group box chromosomal protein 1 (HMGB-1) is a recently identified, endogenous, potent tumor necrosis factor- and interleukin-1 (IL-1)-inducing protein detectable in inflamed synovia in both human and experimental disease. In the present study, we examined clinical effects in collagen-induced arthritis (CIA) using therapeutic administration of neutralizing HMGB-1 antibodies or truncated HMGB-1-derived A-box protein, a specific, competitive antagonist of HMGB-1. CIA was induced in DBA/1j mice or dark agouti rats, and animals were examined daily for signs of arthritis. Treatment with polyclonal anti-HMGB-1 antibodies or the A-box protein was initiated at the onset of disease and was administered intraperitoneally twice daily for 7 days. Animals were killed 8 days after initiation of therapy, and immunohistochemical analysis of synovial tissue specimens was performed. Systemic administration of anti-HMGB-1 antibodies or A-box protein significantly reduced the mean arthritis score, the disease-induced weight loss, and the histologic severity of arthritis. Beneficial effects were observed in both mice and rats. Immunohistochemical analysis revealed pronounced synovial IL-1beta expression and articular cartilage destruction in vehicle-treated mice. Both these features were significantly less manifested in animals treated with anti-HMGB-1 antibodies or A-box protein. Counteracting extracellular HMGB-1 with either neutralizing antibodies or a specific HMGB-1 antagonist may offer a new method for the successful treatment of arthritis. Inflammation and tissue destruction were suppressed in CIA after HMGB-1 blockade.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Arthritis Res Ther
                Title: Arthritis Research & Therapy
                Publisher: BioMed Central
                ISSN (Print): 1478-6354
                ISSN (Electronic): 1478-6362
                Publication date (Print): 2008
                Publication date (Electronic): 2 June 2008
                Volume: 10
                Issue: 3
                Page: 111
                Affiliations
                [1 ]Department of Emergency Medicine and The Feinstein Institute for Medical Research, North Shore University Hospital, Community Drive, Manhasset, NY 11030, USA
                Article
                Publisher ID: ar2427
                DOI: 10.1186/ar2427
                PMC ID: 2483447
                PubMed ID: 18557992
                SO-VID: 3d3c65af-0ddf-4168-8a7a-2be73972968b
                Copyright © Copyright © 2008 BioMed Central Ltd
                History
                Categories
                Subject: Editorial

                ScienceOpen disciplines: Orthopedics
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                ScienceOpen disciplines: Orthopedics

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