Research presented this week at the American College of Rheumatology Annual Scientific Meeting in Chicago has demonstrated that a vaccine designed to re-educate the immune system is safe and feasible in the treatment of rheumatoid arthritis.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
"RA is caused by an aberrant response that can be triggered by disease-specific antigens, or proteins," says lead investigator Ranjeny Thomas, MBBS MD; professor of rheumatology at The University of Queensland Diamantina Institute. "Current treatments attempt to reduce the joint destruction associated with this disease by targeting the inflammation that is a consequence of this immune response. However, non-specific suppression of inflammation may increase infection, and drugs may be toxic to vital organs."
Dr. Thomas'' team recently completed a study looking at the feasibility and safety of using a vaccine, called RheumavaxÂ®, to reduce the way a person''s immune system reacts towards the disease antigens thought to cause RA.
"Approximately 70 to 80 percent of RA patients make antibodies towards RA-specific antigens called citrullinated peptides, which are identifiable with a blood test," explains Dr. Thomas. "While antigen-specific immune tolerance is a major goal for RA prevention and treatment, early trials failed to show a response, and the strategy was abandoned when biologic therapy was spectacularly successful. We reasoned the problem might be solved if the dendritic cells that normally educate the immune system towards these antigens were modified with a drug that would promote immune tolerance."
And, with that thought in mind, Dr. Thomas'' team designed Rheumavax using drug-modified dendritic cells (generated from a person''s own blood) and citrullinated peptide antigens, to suppress specific RA immune reactivity (or restore immune tolerance) - leaving broader immunity towards infections intact.
Once the vaccine was developed, the researchers identified 29 people with RA (predominately female with an average age of 56) who had suffered from the disease for an average of 5.5 years, and who were treated with at least one disease modifying anti-rheumatic drug (commonly called DMARDs).
These participants were placed into three groups. The first group of nine received 1 million Rheumavax dendritic cells, the second group of nine received 5 million, and the third (the control group) of 11 received their usual DMARDS. The cells were given once, through an injection into the thigh.
Participants were evaluated monthly for six months, and the researchers looked for safety issues, immune tolerance and changes in RA activity.
Overall, Rheumavax was well tolerated at both dosages and did not cause any skin reactions, allergic reactions, infections, or immediate disease flares. Some side effects were noted, but were all minor. These included headache, anemia, decrease in white blood cells, and altered liver function tests.
Additionally, the researchers found that those participants with lower levels of disease activity before receiving Rheumavax continued to have low disease activity, and improvements occurred after receiving Rheumavax in patients who started with higher levels of disease activity. Participants receiving Rheumavax also had improvements in blood inflammatory markers and glucose tolerance.
"This study shows that a new approach to re-educate the immune system towards RA-specific antigens using dendritic cells can be safe, says Dr. Thomas. "Similar strategies could now be developed and tested for RA prevention and treatment using this concept."
The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.rheumatology.org/education
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Editor''s Notes: Ranjeny Thomas, MBBS MD, will present this research during the ACR Annual Scientific Meeting at McCormick Place Convention Center at 11:45 AM on Tuesday, November 8 in Room W375b.
Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover the ACR''s Simple Tasks campaign, which highlights the severity of rheumatic diseases and the importance of early and appropriate referral to a rheumatologist
Presentation Number: 2430
Feasibility, Safety and Clinical Effects of a Single Intradermal Administration of Autologous Tolerising Dendritic Cells Exposed to Citrullinated Peptides in Patients with Rheumatoid Arthritis
Ranjeny Thomas (Univ of Queensland, Brisbane, Australia)
Shayna Street (Univ of Queensland, Brisbane, Australia)
Nishta Ramnoruth (Univ of Queensland, Brisbane, Australia)
Helen Pahau (Univ of Queensland, Brisbane, Australia)
Soi Law (Univ of Queensland, Brisbane, Australia)
Marion Brunck (Univ of Queensland, Brisbane, Australia)
Claire Hyde (Univ of Queensland, Brisbane, Australia)
Brendan O''Sullivan (Univ of Queensland, Brisbane, Australia)
Christelle Capini (Univ of Queensland, Brisbane, Australia)
Ai Tran (Univ of Queensland, Brisbane, Australia)
Jennifer Ng (Univ of Queensland, Brisbane, Australia)
Sanjoy Paul (Univ of Queensland, Brisbane, Australia)
Background/Purpose: Bone marrow-derived dendritic cells modified with the irreversible NF-kappaB inhibitor, Bay11-7082 (Bay-DCs), exposed to arthritogenic antigen, transfer antigen-specific suppression of inflammatory arthritis in mice, through induction of regulatory T cells. We carried out a phase I clinical trial of autologous peripheral blood (PB) Bay-DCs exposed to citrullinated peptide antigens (known as Rheumavax) in HLA-DR shared epitope (SE)+ anti-citrullinated peptide antibody (ACPA)+ rheumatoid arthritis (RA) patients. The aims of this phase I first-in-man study were to demonstrate feasibility and safety of autologous peripheral blood (PB) DC immunotherapy, and to describe its clinical and immune effects.
Method: Bay-DCs were generated from 250ml PB under good laboratory practice (GLP) conditions after purification of PB mononuclear cells by density sedimentation, and PB monocytes by elutriation, then culture in the presence of RPMI, 10% human serum, 400U/ml GM-CSF and 800U/ml IL-4 and 2.5 uM Bay11-7082 for 60h. During the final 18h, cells were pulsed with a mixture of four citrullinated peptide antigens (cit-vimentin 447-455, cit-fibrinogen beta chain 433-441, cit-fibrinogen alpha chain 717-725, cit-collagen type II 1237-1249). Rheumavax was administered intradermally once to each group of 9 RA patients on usual disease modifying drugs (DMARDs) in 2 progressive vaccine dose levels (total of 18 vaccinated subjects) in an escalating dose regimen. Group 1 received 1 million DCs and group 2 received 5 million DCs on day 1 of study. Open label control group of 11 patients received usual DMARDs. The primary outcomes were 1. clinical, and 2. laboratory measures of safety and 3. citrullinated peptide-specific tolerance; the secondary outcome was clinical response. Patients were evaluated at baseline, monthly for 3 months and finally at 6 months.
Result: We recruited 29 SE+ ACPA+ patients with RA, including 18 females, with mean age 56 (range 38-76), mean disease duration of 5.4 (range 1-10) years, and treated with at least 1 DMARD, to the study. All Bay-DC cultures were sterile. Rheumavax was well-tolerated at both doses and did not provoke local skin reactions, lymphadenopathy, allergic reactions, infections or immediate disease flares. Adverse events were all grade 1 (of 4) severity and included headache (2), and laboratory evidence of anemia (3), lymphopenia (3), leukopenia (3) and elevated alkaline phosphatase (2) or AST (1). DAS scores decreased below 2.5, sometimes for prolonged periods, in 7/9 Rheumavax recipients who commenced the trial with DAS4vCRP>2.5. DAS scores were stable in 7/9 Rheumavax patients who commenced the trial with DAS4vCRP<2.5. Systemic effects of Rheumavax were demonstrated by reductions in CRP, ESR and the homeostatic model of insulin resistance (HOMA-IR). Immune tolerance outcomes will be discussed.
Conclusion: These data demonstrate the feasibility and safety of a single intradermal administration of autologous tolerising dendritic cells exposed to citrullinated peptides in RA patients.
Disclosure: R. Thomas, None; S. Street, None; N. Ramnoruth, None; H. Pahau, None; S. Law, None; M. Brunck, None; C. Hyde, None; B. O''Sullivan, None; C. Capini, None; A. Tran, None; J. Ng, None; S. Paul, None.