Metrics in Rheumatology: Focus on Harold E. (Hal) Paulus, MD

Editor’s note: We just learned that Dr. Hal Paulus passed away on April 5, 2019. We are reposting this story today in his memory and will share additional information as we learn it.

Read his obituary.

Dr. Paulus

From his seminal work demonstrating the role of lymphocytes in rheumatoid arthritis (RA) to the development of a composite index for individual improvement in RA to his work with the Food and Drug Administration (FDA) Arthritis Advisory Committee developing guidelines to test new drugs, the contributions of Harold E. (“Hal”) Paulus, MD, have both paralleled and shaped the maturation of modern rheumatology.

Now professor of medicine, emeritus, in the division of rheumatology, department of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, Dr. Paulus continues to work and expand his powerful legacy in multiple domains. He collaborates nationally and internationally with a variety of metrics and outcomes initiatives, serves on the institutional review board for his institution, oversees the annual Carl M. Pearson Memorial Symposium (which he established in honor of one of his mentors), and continues to guide the division’s junior faculty in their research efforts.

Use All Your Skills

When Dr. Paulus became a physician in the mid-1950s, clinicians had no effective treatments for their patients with rheumatic disease. And yet, the challenge of treating these patients was appealing to Dr. Paulus, because, as he says, “You really have to use all your skills as an internal medicine physician.”

After 10 years in private practice as a family medicine physician in Minnesota, Dr. Paulus recognized that a generalist would no longer to be able to provide optimal care to many patients. He began investigating rheumatology programs and chose UCLA.

Dr. Paulus completed an internal medicine residency under Leo Fred, MD, at the Wadsworth VA Medical Center, and then—encouraged by Carl Pearson, MD, the founding chief of rheumatology at UCLA—applied for the rheumatology fellowship program with John Calabro, MD, at the Wadsworth VA Medical Center (see timeline below). “Dr. Pearson suggested that I train with Ronald Okun, MD, a clinical pharmacologist at Cedars Sinai Medical Center, in order to fill the role of ‘clinical pharmacologist’ for his large NIH [National Institutes of Health] program project grant to study the pharmacology and clinical pharmacology of drugs for chronic rheumatologic diseases,” recalls Dr. Paulus.

New Concept of Autoimmunity

As a medical student, Dr. Paulus had been intrigued by lectures on the then–relatively new concept of autoimmunity and had taken an elective in rheumatology. That fascination took hold as he learned the basics of inflammation and immunity from Michael Whitehouse, PhD, an experimental pharmacologist Dr. Pearson had also recruited to UCLA. Dr. Pearson had developed a rat model of adjuvant arthritis, which Dr. Whitehouse had transferred by infusing animals with lymphocytes from diseased rats and then studying the effects of potential drugs on various types of induced inflammation. Dr. Paulus became interested in studying the effects of nonsteroidal antiinflammatory drugs on several types of induced inflammation in patients with RA.

Those mechanistic studies led Dr. Paulus in the early 1970s to investigate the involvement of lymphocytes in RA, systemic lupus erythematosus (SLE), dermatomyositis, and scleroderma, first in a case report of thoracic duct lymphocyte drainage (TDD) published in 1973.¹ In a 1977 study, he and his coinvestigators documented significant improvement in grip strength, ring size, duration of morning stiffness, and number of tender joints in their RA study participants who underwent TDD.² Reinfusion of unlabeled or 51Cr-labeled lymphocytes resulted in transient exacerbation of disease activity in three of the study subjects. These studies validated the hypothesis that these lymphocytes played a critical role in the chronic inflammatory disease process and helped form the basis for subsequent basic research.

Dr. Paulus’ work with Dr. Whitehouse yielded more fruitful collaborations. A book chapter they cowrote on classification of potential treatments for chronic inflammatory diseases such as RA and SLE was “another key paper in my development,” notes Dr. Paulus. In logical, elegantly clear prose, the chapter introduced the concept “that a Prime Cause initiates tissue injury, which is magnified by mediators produced by the host in response to the tissue injury, followed by the nonspecific, normal protective inflammatory response that attempts to heal the injured tissue.”³

On the Trail Toward Treatments

Concomitant with his investigations into and writings about the mechanisms of chronic inflammation, Dr. Paulus was volunteered by Dr. Pearson to serve on an ad hoc committee being set up to advise the FDA on clinical trial guidelines for arthritis treatments. Dr. Paulus was co-author of a working draft for clinical testing guidelines and became a pivotal force in the dawning disease-modifying antirheumatic drug (DMARD) era.⁴

“Hal Paulus was able to carefully communicate what we knew, what we didn’t know, what we needed to do better, what we needed to define, and then took steps to move things forward in the context of clinical research, trials, and training,” says Michael B. Brenner, MD, Theodore B. Bayles professor of medicine at Harvard Medical School, and chief, Division of Rheumatology, Immunology and Allergy at Brigham and Women’s Hospital in Boston, who began his UCLA rheumatology fellowship in 1978.

Defining the Specialty

Dr. Paulus was able to merge his clinical, teaching, and research skills throughout his tenure at UCLA and led by example. “Hal Paulus was defining the specialty of academic rheumatology before it was formalized [the first ABIM Subspecialty Board in Rheumatology was given in 1972],” continues Dr. Brenner. “He has played a big role in shaping the specialty by defining how to do clinical trials, conducting clinical trials, and training generations of academic and practicing rheumatologists.”

Robert F. Ashman, MD, professor emeritus of medicine and microbiology, University of Iowa Medical School in Iowa City, trained with Dr. Paulus as a rheumatology fellow at UCLA in 1972 and went on as a faculty member until 1980. “Hal was one of my most influential mentors,” he recalls. “I coveted his wonderful patient assessment skills and tried hard to learn them. Their core was common sense. That quality also determined his success in designing clinical studies so that they would actually permit conclusions and allow comparisons to other studies. He had a dry sense of humor and a mischievous grin. That was one of the ways he communicated his unmistakable sense of enjoyment of being a clinical rheumatologist.”

Daniel E. Furst, MD, the Carl M. Pearson professor of rheumatology, Department of Medicine, Division of Rheumatology, at the David Geffen School of Medicine at UCLA has collaborated with Hal Paulus since the early 1970s. He recalls participating during his fellowship in Dr. Paulus’ seminal studies on TDD in RA patients (“as a gopher,” he says). As noted earlier, those studies which helped to establish the importance of the immune system response in RA. “He has done some exceptional things,” says Dr. Furst. He values the high standard that Dr. Paulus set, of being rigorous about clinical trials. And, “on a clinical basis,” adds Dr. Furst, “he just has an incredible feel. He is the one who taught me to see, when you walk in the room, when a patient is sick. He has a very logical approach to differential diagnosis.”

Early in their affiliation, Drs. Furst and Paulus found their interests aligned when it came to pharmacological studies. After his fellowship at UCLA, Dr. Furst then proceeded to the University of California, San Francisco—on the advice of Dr. Paulus—to acquire additional fellowship training in clinical pharmacology. The two collaborated in the development of FDA guidelines for studying DMARDs in RA. And, it was Dr. Paulus who recruited Dr. Furst back to UCLA from Virginia Mason Institute in Seattle as the first Carl M. Pearson professor of rheumatology.

Dedicated to the Greater Good

Dr. Paulus is known for his singular dedication to scientific rigor, often manifested in a generous yet reserved manner. The background work for the composite index for estimating improvement in individual RA patients, Dr. Paulus noted, was the series of foundational studies done by the Cooperating Clinics in the 1960s through the 1980s evaluating drugs such as cyclophosphamide, azathioprine, and methotrexate for use as DMARDs. Even though the resulting proposed composite index is generally known as “the Paulus criteria,” Dr. Paulus does not label it as such in conversation, and credits John Ward’s leadership of the Cooperative Systematic Studies of Rheumatic Diseases group for moving the work forward.⁵

Dr. Ashman recalls that Dr. Paulus “had a knack for choosing questions to investigate that would have a practical impact on practice. I suspect that is why he continues to be a collaborator valued by clinical investigators all over the world, as his recent bibliography demonstrates.”

The Paulus criteria have been used by various investigators (such as Maini et al in their first studies of infliximab, the anti–tumor necrosis factor agent⁶) to evaluate the effectiveness of biological drugs for RA. In 1995, an international committee effort led by David Felson, MD, MPH, professor of medicine and epidemiology at Boston University School of Medicine, and principal investigator of the NIH-funded Boston University Multidisciplinary Clinical Research Center, refined the index, resulting in the ACR Definition of Improvement in RA.⁷

Dr. Paulus was a member of that international panel and is, according to Dr. Felson, “a great person to have on a committee. He almost always has very valuable insights to problems, and doesn’t say anything unless it’s useful.” Dr. Felson also notes that Dr. Paulus was “open to any and all possibilities”—a quality Dr. Felson appreciated, in view of the fact that Dr. Paulus had already proposed his own definition of improvement in RA. “He could have been an unrelenting advocate for his own definitions, but he wasn’t at all.”

Continuing Guidance

Dr. Paulus ostensibly retired in 2000, the year that Dinesh Khanna, MD, now assistant professor, Division of Rheumatology, David Geffen School of Medicine, UCLA, began his fellowship at UCLA. “Retirement” entailed cessation of clinic duties, but Dr. Paulus has continued to come to the office nearly every day. In the intervening 10 years, says Dr. Furst, Dr. Paulus has become “sort of the go-to person for junior faculty and fellows.” Dr. Khanna and other junior faculty have been the beneficiaries of Dr. Paulus’ “open door policy.”

Dr. Khanna feels fortunate that one of the pioneers in clinical trial design has made himself available for consultation. “He helps you to clarify exactly what you are trying to ask [in a clinical trial],” notes Dr. Khanna. “Then, he helps you to think about a trial design from the standpoint of feasibility to validation of outcome measures. And his grantsmanship is exceptional in providing all kinds of useful, unbiased comments to help applications flow well.”

Dr. Khanna is one of several in the division who’ve attained their NIH K23 Young Investigators Awards under the purview of Dr. Paulus, in addition to their other mentors. Dr. Paulus has been a contributing author on a number of Dr. Khanna’s studies and is now contributing to work on the development of indices for scleroderma and Raynaud’s phenomenon.

Veena Ranganath, MD, assistant clinical professor, Division of Rheumatology, David Geffen School of Medicine, another K23 Young Investigator in the Division, has collaborated with Dr. Paulus and other members of the Western Consortium of Practicing Rheumatologists in a study comparing composite measures of disease activity in early seropositive RA patients.⁸ She finds Dr. Paulus’ method of mentoring very empowering. “He looks out for your best interests,” she notes. “He cultivates you to become an inquisitive researcher with integrity and enthusiasm, based on a foundation of solid science.”

Dr. Khanna appreciates Dr. Paulus’ selfless approach: “He’s a very thoughtful, soft-spoken gentleman. He doesn’t say much at meetings, but when he does, he hits the nail on the head.” Dr. Furst seconds that impression. Dr. Paulus, he notes, “is the person who will sit in the background saying nothing. But when he speaks, everybody will listen, because he changes the whole tone or direction of the discussion.”

The guidance also comes in the form of written commentary. Former fellows and current colleagues alike remarked about the ubiquitous “red pen.” “You can depend, whenever you send something to him for review, that it will be covered in little red writing,” laughs Dr. Furst.

“Dr. Paulus always looks to create the strongest research product,” says Dr. Ranganath. She, too, is familiar with the red pen, and says, “It only shows love!”

References

1. Paulus HE, Machleder H, Bangert R, et al. A case report: Thoracic duct lymphocyte drainage in rheumatoid arthritis. Clinical Immunol Immunopathol. 1973;1:173-181.
2. Paulus HE, Machleder H, Levine S, et al. Lymphocyte involvement in rheumatoid arthritis. Arthritis Rheum. 1977;20:1249-1262.
3. Paulus HE and Whitehouse MW. Drugs for chronic inflammatory disease. In: Rubin AA, Ed. Search for New Drugs. New York: Dekker; 1971:1-114.
4. FDA Ad Hoc Advisory Committee. Non-steroidal, anti-inflammatory drug clinical testing guideline, working draft. Drug Research Reports. 1971;14.
5. Paulus HE, Egger MJ, Ward JR, et al. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum. 1990;33: 477-484.
6. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552-1563.
7. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-735.
8. Ranganath VK, Yoon J, Khanna D, et al. Comparison of composite measures of disease activity in an early seropositive rheumatoid arthritis cohort. Ann Rheum Dis. 2007;66:1633-1640.

Editor’s note: Originally published November 2010