This is Part One of a two-part series on early arthritis clinics.
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Explore This IssueMay 2008
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Early arthritis clinics (EACs) and the huge research databases amassed over the past 20 to 30 years in Europe and other countries have vastly improved physicians’ understanding and treatment of the early stages of rheumatoid arthritis (RA).
The pioneering EACs, many of which are in Europe, were established by rheumatologists seeking an earlier intervention in RA. The EACs were largely responsible for current criteria used to predict persistent RA in early, undifferentiated arthritic patients, and for the advent of new treatments that enhance patient outcomes.
RA patients were first studied in the late 1950s with population-based studies in Bath, U.K., and in the 1960s from cohorts in Middlesex, U.K., and Memphis, Tenn. As a result, research published in the 1980s demonstrated early structural erosion and the long-term consequences of RA. At that time, treatment guidelines for the initial therapy of RA called for nonsteroidal anti-inflammatory drugs, with disease-modifying antirheumatic drugs (DMARDs) prescribed much later, often after early destruction had already occurred.
Although today’s EACs vary in their definition of “early” RA (some restrict selection to patients symptomatic for three or less months, while others allow patients with symptoms for up to two years), they have universally adopted improved diagnostic and imaging techniques—and, most importantly, the use of DMARDs earlier in the course of disease.
Beginnings in Birmingham
One of the first EACs was founded in 1983 at Queen Elizabeth Hospital, Birmingham, U.K., by Paul Bacon, MD, at that time the Arthritis Research Campaign (ARC) professor of rheumatology at the University of Birmingham. His goal was to identify factors to predict which patients with early synovitis would go on to develop RA. The Birmingham clinic had ceased operation in the mid 1980s, but then Paul Emery, MD, arrived and restarted it. Dr. Emery is currently the ARC professor of rheumatology at the University of Leeds, U.K., and director of the Leeds EAC, which he formed in 1994.
The goals of the early EACs were important because “one would like to focus therapy on those patients who are going to develop RA while sparing the half of early arthritis patients who get better spontaneously from the risks of therapy,” says Karim Raza, MD, the current director of the Birmingham EAC, now located at City Hospital Birmingham. “Much of the work carried out in this early arthritis clinic was done in collaboration with Mike Salmon, PhD, and Dr. Emery, who made important contributions in the field of genetic predictors of disease outcome.”
The first Birmingham EAC recruited patients with symptoms up to six months’ duration by actively approaching and encouraging primary care physicians to refer appropriate patients. Today’s Birmingham EAC has changed its focus to patients with symptom duration of three months or less.
“The great successes of our early arthritic clinics have been that we have been able to identify very specific predictors of the development of RA in patients with early synovitis and have identified, for the first time, that the first few weeks after the onset of symptoms represent a pathologically distinct phase in the development of RA,” says Dr. Raza.
For example, the Birmingham group noted that a combination of anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor in patients with three months’ or less symptom duration has a high specificity for development of persistent RA.1 These findings were later validated by the Austrian group led by Josef S. Smolen, MD, chair of the division of rheumatology at the Medical University of Vienna in Austria and chair of the second department of medicine at the Center for Rheumatic Diseases at Hietzing Hospital in Vienna. The Birmingham researchers later demonstrated that early RA is characterized by a distinct and transient synovial fluid cytokine profile.2 Dr. Raza notes that these observations need to be reproduced in additional cohorts before being incorporated into predictive algorithms.
While the Birmingham EAC flourished, additional clinics began to emerge in other countries. In 1993, the department of rheumatology of the Leiden University Medical Center in The Netherlands established the Leiden EAC, “because we wanted to study the natural course of arthritis and identify prognostic markers for disease by well-organized follow-up schemes of all patients,” says Tom Huizinga, MD, professor of rheumatology at Leiden University Medical Center and director of the Leiden EAC.
The Leiden EAC’s earliest challenge was to contact all general practitioners in the area for referrals of patients with symptom duration of less than two years. Now, with a centralized database of over 2,000 patients, Dr. Huizinga says his group has demonstrated that patient outcome can be improved by rapid treatment initiation. Additionally, “an enormous amount of data have been gathered to better understand the pathogenesis and thereby establish better treatment schedules.”
While some of the earliest EACs were confined to clinical research units, in the 1990s EACS began to emerge as part of general rheumatology services worldwide, according to research by Mark A. Quinn, MBChB, MRCP, and Dr. Emery.3
Much of the movement towards EACs in the 1990s is credited to work by Dr. Emery early in that decade. He was a founder of the Early Rheumatoid Arthritis Study in 1986, and later the Leeds Early Arthritis Project and Yorkshire Early Arthritis Register. His goal has been the prevention of damage by changing the course of RA. He says the most difficult aspect of that early work was patient recruitment and uncertainty about whether patients would get better in the short term. Happily, their short-term improvement has carried into the long term as well.
The Leeds EAC defines “early” RA patients as those with symptom duration of less than one year, but “ideally three months,” Dr. Emery says. Patients are seen within two weeks of referral.
The Challenge: Getting Primary Care Referrals
Because there were initial difficulties in getting the cooperation of local general practitioners to refer early suspected cases of RA, the Leeds EAC team contacted local physicians to re-educate them to the importance of early treatment.
Dr. Emery, along with colleagues from The Netherlands, France, Germany, Austria, and the United States, authored a review article that discussed evidence-based development of a clinical guide for early referral recommendations.4 The article advises rapid referral to a rheumatologist if the patient has three or more swollen joints, metatarsophalangeal/metacar-pophalangeal involvement, and morning stiffness lasting 30 minutes or more.
The Austrian rheumatologist contributing to that review was Dr. Smolen, who, along with his associate, Klaus Machold, MD, associate professor in rheumatology at the University of Vienna, started Vienna’s Früharthritis-Ambulanzen EAC in 1996 to provide early treatment and to establish guidelines for fast decision making regarding DMARDs. “This meant we had to reduce the time lag from first telephone contact with the clinic to the actual appointment with the rheumatologists in our clinics,” says Dr. Smolen. “It also meant we needed to reduce the delay in which patients went to a physician because of their joint problems.”
To accomplish this, the doctors devised an information campaign for both physicians and the lay public. “We spoke to representatives of the social security organizations and the president of the chamber of physicians, who liked and supported our initiative,” he says. “We held press conferences for the mass media in order to reach the public. We wrote a series of educational articles on RA and the importance to recognize it early, and these were published in the journal of the chamber of physicians.”
To be eligible for the Früharthritis-Ambulanzen, patient symptoms should not exceed three months, “since this time frame appears to constitute a window of opportunity,” he says. “Obviously we also see patients with longer-term early arthritis, but these go the more regular path.”
Another challenge, adds Dr. Smolen, “is the lack of diagnostic or classification criteria” for early RA, a topic he and coauthors addressed in an Arthritis & Rheumatism article, in which they discussed the need for and controversy surrounding criteria for early RA.5
At the 2006 ACR Annual Scientific Meeting, the Leiden EAC group presented their suggested criteria, which they prefer to call “a prediction rule.” Based on their study of 1,700 RA patients with recent-onset disease, they say the prediction rule for persistent RA should include nine clinical variables: gender, age, localization of symptoms, morning stiffness, tender and swollen joint count, C-reactive protein, rheumatoid factor, and anti-CCP antibodies.
During the past 10 years, the Austrian group has learned that about 10% of patients with less than three months’ symptom duration already have erosions, “indicating that there may be a period of asymptomatic but already aggressive pre-arthritis,” says Dr. Smolen. Studies by his group have shown significant differences in all aspects of improvement with earlier treatment, but early DMARD therapy alone “is not sufficient in most patients to halt progression of the disease,” he says.
Among the newest medications in the RA treatment armamentarium, the biologic response modifiers can reduce inflammation and structural damage. Three of these drugs work by blocking the activity of tumor necrosis factor (TNF)–alpha molecules, while another works by blocking interleukin-1. However, since more than 40% of RA patients fare well on traditional DMARDs, in Europe biologics are not used until there has been an inadequate response to at least two conventional DMARDs.
On the other hand, the Behandel Strategieë (BeSt study)—including 508 Dutch patients with early RA and led by investigators from Leiden University—demonstrated that individuals treated very early with the DMARD metrotrexate plus the biologic infliximab experienced disease remission.6 Results of this study have also been published in Arthritis & Rheumatism7 and Annals of Internal Medicine.8
“It is likely that there will be a subgroup of patients with very early RA who will turn out to benefit from the very rapid introduction of anti-TNF therapy,” says Dr. Raza.
Dr. Smolen notes that, “if patients are still active after three months of traditional DMARD therapy plus steroids, we should consider adding a biological agent.”
Whatever the future may hold for diagnosis and treatment, EACs have been instrumental, especially over the past 20 years, in providing better outcomes for rheumatoid arthritis patients. Patient studies have provided data to investigate RA from inception to later stages, resulting in valuable information leading to improved treatment for early RA patients.
Sue Pondrom is a medical journalist based in San Diego.
- Raza K, Breese M, Nightingale P, et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol. 2005;32(2):231-238.
- Raza K, Falciani F, Curnow SJ, et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7:R784-R795.
- Quinn MA, Emery P. Are early arthritis clinics necessary? Best Pract Res Clin Rheumatol. 2005;19(1):1-17.
- Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS. Early referral recommendation for newly diagnosed rheumatoid arthritis: eEidence based development of a clinical guide. Ann Rheum Dis. 2002;61(4):290-297.
- Aletaha D, Ward MM, Machold KP, et al. Remission and active disease in rheumatoid arthritis: Defining criteria for disease activity states. Arthritis Rheum. 2005;52:2625-2636.
- Van Der Kooij SM, Van Der Bijl AE, Allaart CF, et al. Remission induction in early rheumatoid arthritis (RA) with initial infliximab and methotrexate therapy: The disease course after IFX discontinuation in the best trial. ACR Annual Scientific Meeting 2006; presentation 658.
- Wessels JA, van der Kooij SM, le Cessie S, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 2007;56(6):1765-1775.
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis. Ann Intern Med. 2007;146:406-415.