Dutch rheumatologist Piet L. van Riel, MD, PhD, still recalls his resistance in 1980 when he was required to spend time in the rheumatology department as part of his internal medicine training at the Radboud University Medical Centre in Nijmegen, the Netherlands. “I didn’t want to go the rheumatology department,” says Dr. van Riel from his home in Nijmegen. “In fact, in the beginning, I was more interested in becoming a hematologist. I had the idea that rheumatology patients had many complaints and that you couldn’t do a lot to help them – there were no adequate treatments at that time – and so I thought it was not going to be very stimulating there.” What he found was just the opposite: he became interested in the possibilities for clinical research afforded by long-term contact with rheumatology patients.
Until that point, Dr. van Riel had been fully intending to pursue a career in hematology. He had already spent several months at the Royal Marsden Hospital Institute of Cancer Research in London working on cell apheresis during his third year in medical school. “What most attracted me at that time about hematology was that it was a combination of doing research in the laboratory and having clinical contact with patients,” he says. “That was a nice way of combining research and patient care.” As it turns out, Dr. van Riel’s career in rheumatology during the last three decades has interwoven both of those important components, combining clinical and laboratory research and care for patients, and has included collaborations with many of the world’s top researchers.
Mentors and Early Work
Two key people in the rheumatology department at Radboud University catalyzed Dr. van Riel’s initial research efforts in rheumatology: Leo van de Putte, MD, PhD, and Professor Frank W.J. Gribnau MD, PhD. At their invitation, he began work on a randomized clinical trial comparing oral gold versus parenteral gold, which became his PhD thesis.
It was during his work with this study that the idea for what was later to become the Disease Activity Score (DAS) began. To explore a possible correlation between therapeutic response, adverse reactions, and genetic susceptibility, the research team performed HLA typing on the 52 study participants. In the process of defining categorizations for responders and non-responders, Dr. van Riel recalls that his mentor Dr. Gribnau drew his attention to a paper describing the Mallya Index.1
“I remodeled that index for our population,” he explains. “I found out that if you combined the percentage of change in disease activity, using this index, with the degree of disease activity attained, you could come up with a correlation between genetic markers and response markers.”2
When Less Can Be More
The oral versus parenteral gold trial was a small study, and Dr. van Riel wanted to investigate whether the disease activity index could be improved by studying a larger patient population for a longer period of time. (The follow-up on the smaller trial was only one year.) The team at Radboud was interested in starting investigations on a larger cohort of patients with early rheumatoid arthritis and following them intensively every month for a longer period.
Work began on this project in 1987, when Désirée van der Heijde, MD, PhD, now professor of rheumatology at University Hospital Maastricht in the Netherlands and a renowned outcomes researcher, was a PhD candidate under Dr. van Riel’s supervision. Dr. van der Heijde recalls the time as very exciting: “We started with a database with a lot of numbers and figures and had to find out how to construct a combined disease activity score and then do all the analysis. At each step in the research, we had to define how to do that step, and then the next step.”
She recalls many long hours spent in front of the computer screen with statistician Martin van‘t Hof, PhD, to develop the DAS, which was always discussed and supervised by Dr. van Riel. Dr. van Riel, who was what the Dutch call a “promotor,” or supervisor of her PhD thesis, was “always available for discussions” about the work, she says. The first DAS included the Ritchie articular index, the 44 swollen-joint count, the erythrocyte sedimentation rate, and an assessment of the patient’s general health using a visual analog scale, and was developed during Dr. van der Heijde’s PhD work.3,4 She later to moved to another medical center after she had completed her rheumatology training at Radboud.
Since that time, the DAS has been extensively validated and has undergone several refinements. Dr. van Riel continued on to develop the DAS28, which uses 28 joint counts to monitor disease activity.
Dr. van Riel also worked hard to promote the DAS concept as a tool for assessing disease progression in trials and clinical practice. The DAS28 continues to be used as an instrument for monitoring treatment with DMARDs and biologicals. “If you ask 10 people to comment on Piet van Riel,” says Robert Landewé, MD, associate professor of rheumatology and clinical rheumatologist at the University Hospital in Maastricht and consultant rheumatologist at the Atrium Hospital in Heerlen, “I’m sure that 10 out of 10 will come up with [the association of] the Disease Activity Score, which was invented by Désirée van der Heijde under his supervision,” he says. “The fact is that he has promoted the Disease Activity Score as the measure of choice in the EULAR [European League Against Rheumatism] community, and proposed that EULAR adopt response criteria analogous to the ACR response criteria.”
Interestingly, the Dutch population presented certain limitations that the investigators turned to their advantage. From James F. Fries, MD, professor of medicine at Stanford University School of Medicine (Calif.), and others working with longitudinal patient databases, Dr. van Riel learned that it is important to collect data, to quantify the amount of response and the amount of disease activity. “But, I also learned that it was not possible to do that [on the same large scale] in the Netherlands,” he says, “because we are a very small country and we have fewer patients.”
His solution? “It’s better to do the same kind of research (collecting data and following patients long-term) but to do it more intensely,” says Dr. van Riel. A national characteristic which facilitated this idea, he explains, is that patients in the Netherlands do not move around as much as their counterparts in the United States. “They will continue to visit you [the rheumatologist] for many, many years. We have patients who have been in our study for 20 to 25 years and have not moved,” he says. “So the advantage is that you can do more precise assessments and you can get a lot more information than if you combine patients in your study from many different centers.” The latter approach, notes Dr. van Riel, can introduce “a lot of noise and variation” into statistical analyses, because patients at different centers will be assessed by different teams of physicians and nurses.
It Takes a Team
Another influence on Dr. van Riel’s thinking about assessment was Howard A. Bird, MD, professor of pharmacological rheumatology at Leeds University in the U.K., who wrote a book about multidisciplinary care of rheumatoid arthritis patients. Dr. van Riel and his colleagues adopted Bird’s approach, which relied on utilization of a nurse-specialist for patient education and clinical assessments, easing the burden on rheumatologists to conduct assessments for their studies. This made collection of data easier, and also motivated patients, says Dr. van Riel, because they benefited from the counseling that nurses delivered.
The approach was not uniformly embraced by his colleagues, however. In the beginning, not all rheumatologists liked the multidisciplinary approach. “They felt, ‘I am responsible for my patients and they should discuss all their problems with me,’” he notes wryly.
It took some time for the approach to be accepted. Dr. van der Heijde notes that the approach “was indeed new at that time. More and more centers are now doing this, but at that time there were very few.” Dr. Landewé agrees: “Initiating that early RA cohort with the help of research nurses was very innovative and unprecedented in those days.”
Dr. van Riel’s approach to research is also collaborative, notes Pilar Barrera, MD, PhD, of the rheumatology department at Radboud University Medical Centre. “He is a collaborator, and he’s a thinker, but he’s also someone who lets other people think about what should be done,” says Dr. Barrera. “We have many weekly meeting moments in which people from several disciplines come together. Together – rheumatologists, biomedical scientists, laboratory researchers – we make, I think, the perfect team.”
Career
1978–Graduates from Catholic University of Nijmegen.
1985–Completes internal medicine training at St. Radboud Ziekenhuis in Nijmegen.
1986–Completes rheumatology training at Academic Hospital in Nijmegen.
1987–Accepts position as associate professor of rheumatology at University Hospital in Nijmegen.
1987–Work on the Disease Activity Score begins.
1993–Becomes duty head of rheumatology and director of the clinical research unit at University Hospital.
1997–Becomes professor of rheumatology at the University Hospital.
2003–Accepts position as head of rheumatology at University Medical Centre St. Radboud.
Free Time is Limited
Dr. van Riel has authored more than 250 scientific articles, and served as Chairman of the EULAR Standing Committee for International Clinical Studies including Therapeutic Trials from 1999–2004. As the chair of the Dutch Society of Rheumatology, he has accomplished much important work in the Netherlands in that capacity, according to Dr. Landewé. His own research and publications, as well as travel to medical meetings and guest lectureships worldwide (he recently returned from a trip to Japan) leave little time for relaxation. “The free time is always limited,” he laughs, “but I do like to work in the garden, when possible. On Saturday mornings I run with a group of people, and at least once during the week as well.” He also participates in the yearly Zevenheuvelenloop (Seven Hills) 15k run in his hometown of Nijmegen.
Dr. van Riel, his wife, and three daughters (one still lives at home) like to relax at home during the holidays. They also enjoy travel to Canada and the United States – especially California, where he appreciates the relaxation of driving in the wide-open spaces of the West – a real contrast, he says, to the heavy traffic on the European continent.
Contributions and Assessment Barriers
Asked about his contributions to the field of rheumatology outcome measures, Dr. van Riel tellingly uses the pronoun “we” and not “I” to characterize his work. He believes he and his colleagues were “a little bit lucky” to have begun their work on assessments in the mid 1980s. When new treatments for RA, especially the biologicals, became available in the mid 1990s, there was more of a need for an instrument to evaluate different treatments. “So, we were lucky that we developed those instruments and that, later on, treatments became available that needed an instrument to assess the response to those treatments,” he says. “This allowed the ability to titrate doses in your patients.”
Dr. Landewé lauds his colleague’s modesty: “I believe he has done very good work in determining the relationship between disease activity, function, and radiographic damage. Under his guidance and supervision, a lot of longitudinal statistics have been incorporated into the field of rheumatology.”
The development of the DAS and other assessments also converged with efforts on the international level to standardize assessments. Before the 1980s, Dr. van Riel notes, “every rheumatologist was assessing patients in their own way, and publishing in different ways. Therefore, you couldn’t compare results of the different trials with each other.” Another serendipitous occurrence was the growing level of patient involvement in their treatments. Dr. van Riel recalls a marked change in the 1980s when patients became interested in knowing “the exact details of their medical story – their response to treatments and how their disease was progressing.”
Philosophical about Acceptance
Dr. van Riel notes that assessment instruments are not used by practicing rheumatologists as much as he would like. “You know, when we developed this instrument and published it and talked about it at conferences, I thought, ‘That’s it: We have shown that it is worthwhile to assess patients in this way, so everybody should do it .… And that was 15 years ago!” he says.
Dr. van Riel says he has realized that it takes “a long, long time” to convince colleagues about the usefulness of these measures. He concedes that time may be the biggest barrier. “Incorporating this kind of assessment in your outpatient clinic routine means you have to prioritize and rearrange the way you perform patient examinations,” he says.
By all accounts, Dr. van Riel has been quietly but unswervingly dedicating himself to the principles of assessment in RA – and will continue to do so. Dr. van Riel is a person of commitment, says Dr. Barrera, who considers him not only her mentor but her friend. “He’s kept to his idea that measuring gives an improvement in the way to treat patients,” she says. “To measure is to know – and that’s something he introduced.”
Gretchen Henkel is writing the “Metrics in Rheumatology” series.
References
- Mallya RK, Mace BE. The assessment of disease activity in rheumatoid arthritis using a multivariate analysis. Rheumatol and Rehabil. 1981;20:14-20.
- van Riel PLCM, Reekers P, van de Putte LBA, Gribnau FWJ. Association of HLA antigens, toxic reactions and therapeutic response to auranofin and aurothioglucose in patients with rheumatoid arthritis. Tissue Antigens. 1983;22:194-199.
- van der Heijde DMFM, van ‘t Hof MA, van Riel PLCM, et al. Judging disease activity in clinical practice in rheumatoid arthritis. Ann Rheum Dis. 1990; 49:916-920.
- van der Heijde DMFM, van ‘t Hof MA, van Riel PLCM, et al. Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis. 1992; 51:177-181.
