SANTA MONICA, CALIF.—The future of rheumatoid arthritis treatment should involve targeting subclinical disease and reversing immune dysregulation, Paul Emery, MA, MD, said here on May 18 at the California Rheumatology Alliance 9th Annual Medical and Scientific Meeting.
Predicting Treatment Response
To target treatments, it will be important to better predict synovitis, since synovitis predicts erosions in individual joints, said Dr. Emery, professor of rheumatology and head of the academic unit of musculoskeletal disease at the University of Leeds in Leeds, U.K. “I think we’ll have sophisticated imaging at onset so you could visualize what you’re getting very easily,” he said.
Another important development will be predicting treatment response, Dr. Emery said, noting that unsuccessful methotrexate (MTX) treatment isn’t a benign event because during the period of treatment, irreversible damage can happen. He said there also could be an effect making the acute disease less responsive to therapy. Predictors would help determine which patients should receive a more aggressive treatment response before damage occurs, he said.
Dr. Emery cited a study that sought to identify whether interleukin (IL) 7 titers in serum could identify which patients with inflammatory joint symptoms would evolve toward RA.1 The study included 250 patients with inflammatory joint symptoms and 80 healthy controls. RA progression was monitored over the span of five years. Findings showed that, in patients with undifferentiated RA, low IL-7 levels at onset of symptoms will predict regression to more severe disease and can serve as a diagnostic biomarker, Dr. Emery said.
Predicting B-cell responses may also help in treatment, he said, citing a study showing the importance of B-cell depletion as a biomarker.2 The researchers tested the B-cell levels of patients who were already being treated with rituximab. If their B cells were depleted, they were given standard therapy. If patients still had B cells, they were randomized to either standard therapy with placebo or standard therapy with an extra infusion of rituximab. The patients who were treated a second time not only depleted, they also had better clinical responses.
Higher Remission Rates
Another prediction: Higher remission rates will become standard. “In the future, if you’re not getting 70% remission rate with in your new patients, you’re not treating your patients very well. That’s what you’re going to be told,” Dr. Emery said.
He also predicted that, in the U.K., rheumatologists will eventually be asked by the government to publish patient-reported outcomes and remission rates. “If you’re able to get remission rates up, you’ll get patients in [for treatment] very early indeed,” he said.
Stopping therapy, he said, will become a goal for RA treatment. “When I meet patients, the common thing they say to me, is, ‘How long am I going to be taking the drug for?’ ” Dr. Emery recalled. “If you say, ‘for the rest of your life,’ it’s not the most encouraging thing to a patient. And so the question is, ‘How can we possibly have transient use of drugs?’ ”
The first step, he says, is to get to patients early in the course of their disease. The second is getting them to a normal maintenance of function and quality of life with normal immunology. Achieving the latter will likely involve more aggressive treatment early in the course of disease.
“In the future, we’re going to be using TNF [tumor necrosis factor] inhibition early but not late,” he said. “I don’t think TNF inhibition is a great drug late, partly for the reason I said about MTX, the incremental benefit is less, there is already structural damage, and there is a limit to what you can achieve because the amount of inflammation that is mediated by TNF actually reduces over time.”
Dr. Emery presented data from the COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis) study, which compared the impact of MTX alone with MTX in combination with etanercept. The study showed that, after one year, about 50% of patients treated with etanercept plus MTX were able to achieve remission, compared with 28% treated with MTX alone.
He also noted that the BeST trial, showed that the ability to discontinue combination therapy was better achieved in patients who received biologics as initial therapy.3
During his presentation, Dr. Emery also asked the questions: What happens when you give a biologic later in disease? Can you stop it? To answer them, he showed data from two studies. One study was PRESERVE [Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis]. The bottom line of this study, he said, is that patients who start biologic treatment late don’t maintain the response well when etanercept is stopped, but they do better when the dose is halved.
The second, the CERTAIN study, showed that when patients who started treatment late stopped taking adalimumab, most of them relapsed.4
“The message is very clear: You can stop a biologic if you start it early, but it’s very difficult to stop it if you start it late,” he said.
Prevention
According to Dr. Emery, another major advance in RA will be preventing the disease altogether. “I say that without a shadow of a doubt because the data is already there,” he said.
To illustrate his point, he referred to EULAR recommendations published in 2012 that identified these RA risk factors:5
- Environmental/lifestyle factors;
- Genetic risk;
- Systemic autoimmunity;
- Arthralgia-nonspecific symptoms; and
- Undifferentiated arthritis.
According to Dr. Emery, these risk factors will help in determining which patients to treat. “If you look at systemic autoimmunity, we know that multiple antibodies become positive, especially just before presentation, and they actually go on increasing unless you treat the patients. There’s already an autoantibody storm just prior to treating them,” he said.
Population screening of biomarkers, however, is not cost effective because not all people with risk factors will develop RA. He and colleagues, therefore, are currently conducting a series of studies to learn which factors signal a greater likelihood of disease progression.
To illustrate his point about the effectiveness of early awareness and treatment, Dr. Emery referenced one study, the ADJUST trial, which showed that of patients with pre-RA symptoms, those who received abatacept had no X-ray progression at six months while those on placebo progressed in a linear fashion.6
Dr. Emery ended his presentation by explaining that a palindrome is a good metaphor for the future of RA treatment strategies. “A therapy strategy based on pathogenesis is a palindromic shift, and that’s because [at the end of treatment] you’ll see the return to normal,” he said.
Stephanie Cajigal is a medical journalist based in California.
References
- Goëb V, Aegerter P, Villeneuve E, et al. Reduced IL-7 serum titres are associated with progression towards rheumatoid arthritis in less than 6 months inflammatory arthritis. Ann Rheum Dis. 2011;70(Suppl 2):A2.
- Vital EM, Dass S, Rawstron AC, et al. Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. Arthritis Rheum. 2010;62:1273-1279.
- Weisman MH. Progress toward the cure of rheumatoid arthritis? The BeSt study. Arthritis Rheum. 2005;52:3326-3332.
- Smolen JS, Emery P, Ferraccioli G, et al. Maintenance of remission in rheumatoid arthritis patients with low-moderate disease activity following withdrawal of certolizumab pegol treatment: Week 52 results from the CERTAIN study. Ann Rheum Dis. 2012;71(Suppl 3):361.
- Gerlag DM, Raza K, van Baarsen LG, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: Report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis. 2012;71:638-641.
- Emery P, Durez P, Dougados M, et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: A clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis. 2010;69:510-516.
