T-cell agents in the treatment of rheumatoid arthritis: 2012 update.
|Author:||Solomon, Gary E.|
|Publication:||Name: Bulletin of the NYU Hospital for Joint Diseases Publisher: J. Michael Ryan Publishing Co. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 J. Michael Ryan Publishing Co. ISSN: 1936-9719|
|Issue:||Date: July, 2012 Source Volume: 70 Source Issue: 3|
Abatacept is a selective T-cell co-stimulator blocker. It blocks
the activation of T cells by interrupting the interaction between the
CD28 ligand on the T cell and the CD80 and CD86 ligand on the antigen
presenting cell. This "second" signal is necessary for T cell
activation in addition to the "first signal," which is the
interaction between the T-cell receptor and the MHC-antigen complex on
the antigen presenting cell. "Upstream" blockade of T cell
activation has profound effects on "downstream" events
including the production of the cytokines TNF, IL-1, and IL-6, and
Abatacept is currently approved for reducing signs and symptoms, inducing a major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderate to severe rheumatoid arthritis. It may be used as monotherapy or in combination with non-biologic DMARDS. Currently, abatacept is available both as an infusion and as a self-administered subcutaneous injection. For the infusible form, loading doses are given on weeks 0, 2, and 4 followed by monthly dosing. The dosing is weight based with three dose stratifications for weights less than 60 kg, between 60 and 100 kg, and greater than 100 kg. The subcutaneous form is given as a fixed dose of 125 mg per week irrespective of weight. This article will review the peer reviewed publications and abstracts relating to abatacept that were published in 2011 and 2012.
A subcutaneous preparation of abatacept was approved by the FDA in August 2011. In a phase IIIB clinical trial, the subcutaneous dose was as effective as the intravenous dose, and the safety profile was comparable. Immunogenicity was low, and injection site reactions were both rare and mild. In this study, all patients received IV loading with a single dose of 10 mg/kg. While the official approved label requires a single intravenous loading dose (based on weight), it is being widely used without the loading dose. (1)
The ATTUNE study evaluated the consequences of switching patients who were on long-term intravenous abatacept to subcutaneous therapy. In this study, there was no loss of efficacy following the switch; indeed in this study of 123 patients, no patients discontinued drug due to loss of efficacy following the switch. One patient discontinued secondary to an adverse reaction, and two patients had mild injection site reactions but continued therapy. There was no increase in immunogenicity seen following the switch. (2)
Immunogenicity was further studied in the ALLOW trial. In this study, a 3 month interruption of therapy, followed by re-introduction of drug did not result in a statistically significant difference in immunogenicity compared with a group of patients who received continuous drug therapy. There were no safety differences between the two groups, and in patients who flared following drug withdrawal, efficacy was re-established when the drug was resumed. (3)
Other Indications for Abatacept
In a 6 month multicenter, randomized, double blinded, placebo controlled, phase II study, 170 patients with psoriatic arthritis were treated with abatacept at doses of 3 mg/kg, 10 mg/kg, or 30 mg/kg with loading doses on days 1 and 15 followed by monthly infusion. The primary endpoint of an ACR20 was 19% in the placebo group and 33%, 48%, and 42% in the Abatacept treated groups. All groups showed an improvement in MRI, HAQ, and SF-36 with the greatest improvement seen in the 10 mg/kg group. The safety profile of the three groups was similar. (4)
This same patient population was followed in a 6 month open label extension study, and benefits were sustained throughout the treatment period. (5)
In a small open label study, abatacept given for 6 months failed to meaningfully improve disease activity, function, or other disease parameters. (6) These results are consistent with a previous study that failed to demonstrate a clinical response in patients with ankylosing spondylitis. (7)
Type 1 Diabetes Mellitus
In a multi-center study of patients with recently diagnosed insulin dependent diabetes mellitus, patients were randomized to receive abatacept at a dose of 10 mg per kg, or placebo infusion for a 24 month period. The primary outcome measured was the baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) of serum c-peptide level after a mixed-meal tolerance test at 2 year follow-up. The AUC was 59% higher (95% CI 6.1-112) with abatacept than with placebo. There was an average of 9.6 months' delay in c-peptide reduction with abatacept. There were few infusion related reactions, and there was no increase in infection or neutropenia between the treatment and the placebo groups. (8)
Adult-onset Still's Disease
In a single case report, abatacept was effective in treating adult-onset Still's disease, with the patient in remission after 35 months of therapy. (9) A second case report also documented efficacy in a patient who had failed previous treatment with anti-TNF and anti-IL-1 therapy. (10)
In a single case report, abatacept produced both clinical improvement and normalization of laboratory parameters in a patient who had failed to respond to methotrexate, TNF inhibitors, steroid, immunoabsorption, plasmapheresis, and IL- inhibition. (11)
Crohn's Disease and Ulcerative Colitis
Four placebo-controlled trials failed to reveal any efficacy in the treatment of moderate-to-severe CD or UC. (12)
Comparative Efficacy and Safety Compared to Other Biologic Agents, Switching Biologic Agents
In an open label extension of the ATTEST trial, patients treated with either abatacept, infliximab, or placebos for one year were switched to abatacept for year two. Of 431 patients assigned abatacept, 79.8% remained on the drug through year 2. At years 1 and 2, 19.7% and 26.1% of abatacept treated patients achieved DAS 28 remission (< 2.6) while 13.3 and 28.6% of infliximab-to-abatacept patients achieved DAS-28 remission. (13)
Higher remission rates were achieved in patients with early RA treated with abatacept, compared to those with long standing RA (> 10 years). DAS28-CRP remission was seen in 35.2% of patients with early disease at year 1 vs. 19.4% of patients with long standing disease. At year 3, the results were 46.0% vs. 30.9%. This study provided support for the concept of treating biologic naive patients with inadequate response to MTX earlier in their disease course. (14)
In a patient cohort (DANBIO) with > 90% TNF failures, a good-or-moderate EULAR response rate was achieved in patients treated with either abatacept or tocilizumab. (15)
In a head-to-head study (AMPLE) looking at 646 biologic-naive patients with RA, abatacept was compared to adalimumab. ACR responses for the two groups were comparable at 4 weeks and 52 weeks. Both drugs exhibited a similar time course for onset of action and similar inhibition of radiographic progression. There were no significant safety differences between the two groups. An important feature of this study was the fact that in both groups, the patients were on background methotrexate. (16)
Basic Science, Mechanism of Action
Macrophages and cytokine stimulated T cells (Tck) were mixed in the presence of abatacept or control Ig with and without TLR ligands. Abatacept reduced production of TNF by macrophages. Tck and TLR ligands were synergistic in their induction of the production of proinflammatory cytokines by macrophages, most notably IL12p70. Production of this cytokine was reduced in the presence of abatacept. This study strongly suggests that the biologic effects of abatacept extend beyond antigen specific T cell mediated effector function. (17)
Further evidence of the broader effects of abatacept is provided by a study in which immunohistochemical analysis of synovium was performed in patients treated with either methotrexate or methotrexate plus abatacept. Expression of MMP-3, CD8, CD4, CD8, CD20, CD80, and CD86 was significantly decreased in the synovium of patients treated with abatacept versus the methotrexate control. These finding indicate inhibition of not only T cells, but B cells and macrophages. (18)
Data from a French registry (Orencia and Rheumatoid arthritis--ORA) showed that CCP positivity was associated with EULAR clinical response and with a higher abatacept retention rate at 6 months. A EULAR response was obtained in 59.1% of the 558 patients in the registry (good 20.4% and moderate 38.7%). (19)
In a cost-effectiveness study where the endpoint was remission or low disease activity, the use of abatacept as a second line agent following failure of a TNF agent (either etanercept, adalimumab, or infliximab) regimens that used abatacept as the second agent were more cost effective than those that use rituximab as the second agent. (20)
Psoriasiform lesions were reported in three patients with rheumatoid arthritis who were treated with abatacept. Previously, this observation had been confined to patients receiving anti-TNF agents. The mechanism underlying this observation remains unclear. (21)
Abatacept, methotrexate, and rituxan inhibit the antibody response to vaccination with A/H1N1. This may have clinical implications and booster vaccinations may be required for high risk individuals. (22)
Abatacept can be safely used in patients with hepatitis B if antiviral prophylaxis for hepatitis B is given concurrently. (23)
T-cell based therapy for rheumatoid arthritis, as well as other forms of arthritis, continues to be promising. (24) Abatacept is an effective therapy for psoriatic arthritis, and may be effective for musculoskeletal manifestations of SLE. (25) It is unlikely that ABA will be an effective agent for axial spondyloarthropathies, Crohn's disease, or ulcerative colitis. Preliminary data suggest that it may be an effective agent if used early in Type I diabetes mellitus.
Registry data suggests that the efficacy and safety of ABA is comparable to other biologic agents. The availability of a subcutaneous version of the drug offers a new treatment option to patients and physicians who prefer injectable biologics. For some patients, initial treatment with ABA rather than an anti-TNF agent would be reasonable. The low immunogenicity of abatacept offers advantages over more immunogenic molecules for the treatment of a chronic disease like rheumatoid arthritis.
The biologic effects of abatacept seem to extend beyond inhibition of T cell effector functions and include inhibition of TNF generation as well as macrophage and B cell function.
The cumulative data regarding the efficacy and safety of abatacept strongly supports its early use in the treatment of rheumatoid arthritis. For patients who fail to have an adequate response to methotrexate, the addition of abatacept as the first biologic agent is a viable strategy. It would also be appropriate to switch a patient who had an inadequate response to an anti-TNF agent to abatacept as the second biologic agent.
The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.
(1.) Genovese MC, Covarrubias A, Leon G, et al. Subcutaneous abatacept versus intravenous abatacept: A phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum. 2011 Oct;63(10):2854-64.
(2.) Keystone EC, Kremer JM, Russell A, et al. Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from the phase IIIb ATTUNE study. Ann Rheum Dis. 2012 Jun;71(6):857-61.
(3.) Kaine J, Gladstein G, Strusberg I, et al. Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase IIIb ALLOW study). Ann Rheum Dis. 2012 Jan;71(1):38-44.
(4.) Mease P, Genovese M, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: results of a six month multi-center, randomized, double blind, placebo-controlled, phase II trial. Arthritis Rheum. 2011 Apr;63(4)939-48.
(5.) Mease P, Genovese M, et al. Abatacept in the treatment of psoriatic arthritis: 12 month results of a phase II study. Presented at the annual meeting of the American College of Rheumatology, 2010, abstract 1919.
(6.) Lekpa FK, Farrenq V, Canoui-Poitrine F, et al. Lack of efficacy of abatacept in axial spondyloarthropathies refractory to tumor-necrosis-factor inhibition. Joint Bone Spine. 2012 Jan;79(1):47-50.
(7.) Song IH, Heldmann F, Rudwaleit M, et al. Treatment of active ankylosing spondylitis with abatacept: an open-label, 24 week pilot study. Ann Rheum Dis. 2011 Jun;70(6):1108-10.
(8.) Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent onset type 1 diabetes: a randomized, double-blind, placebo-controlled trial. Lancet. 2011 Jul;378(9789):412-9.
(9.) Ostrowski RA, Tehrani R, Kadanoff R. Refractory adult-onset still disease successfully treated with abatacept. J Clin Rheumatol. 2011 Sep;17(6):315-7.
(10.) Quartuccio L, Maset M, De Vita S. Efficacy of abatacept in a refractory case of adult-onset Still's disease. Clin Exp Rheumatol. 2010 Mar-Apr;28(2):265-7.
(11.) Fuji W, Kohno M, Ishino H, et al. The rapid efficacy of abatacpt in a patient with rheumatoid vasculitis. Mod Rheumatol. 2012 Aug;22(4):630-4.
(12.) Sandborn WJ, Colombel JF, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology. 2012 Jul;143(1):62-9.e4. Epub 2012 Apr 12.
(13.) Schiff M, Keiserman M, Codding C, et al. Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept; openlabel extension of the ATTEST study. Ann Rheum Dis. 2011 Nov;70(11):2003-7. Epub 2011 Sep 12.
(14.) Yazici Y, Moniz Reed D, Klem C, et al. Greater remission rates in patients with early versus long-standing disease in biologicnaive rheumatoid arthritis patients treated with abatacept: a post hoc analysis of randomized clinical trial data. Clin Exp Rheumatol. 2011 May-Jun;29(3):494-9.
(15.) Leffers HC, Ostergaard M, Glintborg Bet al. Efficacy of abatacept and tocilizumab n patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry. Ann Rheum Dis. 2011 Jul;70(7):1216-22.
(16.) Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: one year results from the AMPLE study. Eular 2012: Abstract OP0022.
(17.) Wenink MH, Santegoets KC, Platt AM, et al. Abatacept modulates proinflammatory macrophage responses upon cytokine -activated T cell and Toll-like receptor ligand stimulation. Ann Rheum Dis. 2012 Jan;71(1):80-3.
(18.) Kanbe K, Chiba J, Nakamura A. Immunhistological analysis of synovium treated with abatacept in rheumatoid arthritis. Rheumatol Int. 2012 Jan 3. [Epub ahead of print].
(19.) Gottenberg JE, Ravaud P, Cantagrel A, et al. Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the "Orencia and Rheumatoid Arthritis" registry. Ann Rheum Dis. 2012 May 21. [Epub ahead of print].
(20.) Puolakka K, Blafield H, Kauppi M, et al. cost-effectiveness of sequential biologic strategies for the treatment of moderate to severe rheumatoid arthritis in Finalnd. Open Rheumatol J. 2012;(6):38-43.
(21.) Konsta M, Rallis E, Karameris A, et al. Psoriasiform lesions appearing in three patients with rheumatoid arthritis during therapeutic administration of abatacept, a selective inhibitor of T-cell costimulation. J Eur Acad Dermatol Venereol. 2012 Feb;26(2):257-8.
(22.) Adler S, Krivine A, Weix J, et al. Protective effect of A/H1N1 vaccination in immune mediated disease--a prospective controlled vaccination study. Rheumatology (Oxford). 2012 Apr;51(4):695-700.
(23.) Kim PS, Ho GY, Prete PE, et al. Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B. Arthritis Care Res (Hoboken). 2012 Aug;4(8):1265-8.
(24.) Solomon GE. T cell agents in the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2010;68(3):162-5.
(25.) Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter,exploratory, phase IIb, randomized, double blind, placebo controlled trial. Arthritis Rheum. 2010 Oct;62(10):3077-87.
Gary E. Solomon, M.D., is Clinical Associate Professor, Division of Rheumatology, Department of Medicine, NYU Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York.
Correspondence: Gary E. Solomon, M.D., NYU Hospital for Joint Diseases, 301 East 17th Street, New York, New York 10003; gary. email@example.com.
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