About PRCSG

The Pediatric Rheumatology Collaborative Study Group (PRCSG), founded in 1973, is a consortium of over 90 academic clinical pediatric rheumatology centers in the United States, Canada, and Puerto Rico. The chief aim of the PRCSG is to conduct high quality clinical trials of therapeutic agents in children with rheumatic diseases.

Daniel Lovell, MD, MPH has been the Chairman of the PRCSG since 1991. Hermine Brunner, MD, MSc has been the Scientific Director of the group since 2006, succeeding Edward H. Giannini, MSc, DrPH, who had been the Scientific Director of the group since 1976.

The PRCSG is governed by a set of  Bylaws that are overseen by an Advisory Council (AC).  The chief functions of the Advisory Council are to provide leadership and guidance for the PRCSG in the following areas: identification and facilitation of research areas most likely to be successful and clinically useful; seeking of funded support for the groups research efforts; management and quality assurance of the PRCSG’s membership, its scientific studies, statistical analyses, databases generated, and publications. Membership of the Council consists of the Chairman, Dan Lovell, MD, MPH; Scientific Director, Hermine Brunner, MD, MSc; Principal Investigators of the PRCSG; Representatives from Childhood Arthritis and Rheumatology Research Alliance (CARRA), Food and Drug Association (FDA),  and National Institutes of Health (NIH), as well as established clinical investigators and junior investigator.

A centralized Coordinating Center certified by International Organization for Standardization (ISO) 9001:2008 facilitates and manages all administrative, financial, regulatory and scientific matters related to the PRCSG. To see a Description of Services, click here.

The PRCSG has completed, or is currently in the process of conducting, a total of more than 45 trials in children with juvenile idiopathic arthritis (JIA), systemic lupus erythematosus, vasculitis and familial mediterranean fever. In addition, the PRCSG has performed and published many studies on methodological issues and secondary analyses of trial databases. The PRCSG has performed the vast majority of  trials of medications for JIA in North America since 1977.

Drugs previously tested include:

  • Abatacept
  • Adalimumab
  • Anakinra
  • Canakinumab
  • Certolizumab Pegol
  • D-penicillamine
  • Etanercept
  • Golimumab
  • Hydroxychloroquine
  • Infliximab
  • Intravenous immunoglobulin
  • Methotrexate
  • Naproxen/Esomeprazole
  • NSAIDs and selective COX2 inhibitors
  • Rilonacept
  • Tocilizumab
  • Tofacitinib

Except for the earliest of these studies (tolmetin sodium in the treatment of JIA), Dr. Giannini, Dr. Lovell, and more recently Dr. Brunner have served as the designers and coordinators for all of the studies. Numerous secondary analyses that used data generated in the initial studies have provided meaningful answers to important clinical questions. These investigators developed and validated the currently accepted measure of clinical response used in clinical trials involving children with JIA. This definition of clinical response was successfully utilized in the trial of the TNF-a blocker, etanercept, in children with severe JIA.

These same investigators also designed and performed the validation study of the Childhood Myositis Assessment Scale and have been actively involved in the definition of core sets of outcome measures and definitions of improvement for children with Juvenile Idiopathic Inflammatory Myopathies. Recently, the PRCSG, in collaboration with the Pediatric Rheumatology InterNational Trials Organization (PRINTO) and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed a preliminary definition of clinical remission for children with JIA.

PRINTO, CARRA and the PRCSG are working together to advance research and treatments for children with rheumatic diseases. To foster this relationship, a collaborative agreement exists with PRINTO.

 

Brief History of the Pediatric Rheumatology Collaborative Study Group

Prior to the 1970’s the pharmacotherapeutic options for children and adolescents with rheumatic diseases were extremely limited.  Drugs that were available, albeit off-label, had not undergone the rigorous blinded, controlled trials that are required today in order to obtain a label for use in JRA.  Most of the evidence of drug efficacy and safety that was available came from anecdotal reports, small case series, or extrapolations from trials in adults with rheumatic diseases.  Indeed, knowledge of the short and long-term risks of these agents in children was virtually non-existent as was any type of pharmacologic guidelines to aid the physician as to when to start these agents, how long a drug should be given before concluding it was or was not effective, what the probability of a beneficial effect was, and what the appropriate sequence of treatment should be as the disease course progressed.

In the early 1970s newer non-steroidal anti-inflammatory drugs (NSAIDs) began to be approved for treatment of adults with rheumatoid arthritis (adult RA).  A small core group of pediatric rheumatologist soon realized that something had to be done to assure that promising new drugs were tested and possibly labeled for use in children.  Further, they realized a standardized system of classification of the rheumatic diseases of childhood was needed which would allow them to speak to each other about patients using a common nomenclature.  The group was led by Dr. Earl J. Brewer of Texas Children’s Hospital in Houston who, in the 1968, had conducted a placebo controlled study which showed indomethacin was far superior to acetaminophen in reducing high fever in children.  Others in this small group of concerned physicians included John Baum, Virgil Hansen, Chester W. Fink, Joseph E. Levinson, and Jane Schaller.    They soon were joined in their plea to study drugs in children by others in the field including Jerry Jacobs, Ralph Wedgwood, Jack Bass, Balu Athreya, and Jack Miller.

In 1972 McNeil Laboratories which was in the process of testing a new NSAID, tolmetin sodium (Tolectin®) for use in adult RA.   Drs. Brewer and Wedgwood were contacted by Dr. Stanley Gottlieb of McNeil who was in charge of drug development for children.  This is generally considered the official launch of pediatric rheumatology into the systematic study of anti-inflammatory and anti-rheumatic drugs in children.  If such studies were to be done and held to scrutiny by the FDA, a more formalized consortium of investigators would have to be in place.  In 1973 Dr. Brewer, along with this group of colleagues, officially formed the Pediatric Rheumatology Collaborative Study Group (PRCSG) whose chief goal was to conduct scientifically valid studies of promising new anti-inflammatory and disease modifying agents in children in order that they may be labeled for use in pediatric patients.  Dr. Brewer was named the first Chairman of the group and is considered its founding father.  Just 4 years later the PRCSG published its first study (Levinson JE, Baum J, Brewer EJ, Fink C, Hanson V, Schaller J:  Comparison of tolmetin and aspirin in the treatment of juvenile rheumatoid arthritis. J Pediatr 1977, 91:799-804).

Despite this early success other companies in the process of developing NSAIDs had little enthusiasm for conducting studies in children, perhaps due to the limited market.  Only through the direct encouragement of Dr. John Harter of the FDA did companies become aware that if drugs were to be tested and approved for use in adults, they should also be tested and, if appropriate, marketed for children.  Very quickly thereafter companies looked to the PRCSG to conduct trials of a host of new NSAIDs.  Dr. Brewer soon recognized the need for the group to form a Coordinating Center that would oversee the design and progress of the studies, retrieve, manage and report the data, and assure compliance with applicable regulatory affairs.  In 1976 Dr. Edward Giannini, an epidemiologist and biostatistician, was named the Senior Scientist for the group and founded the PRCSG Coordinating Center at Texas Children’s Hospital.  An Advisory Council was formed to oversee the direction and operation of the growing consortium, and Bylaws were adopted that served to govern membership requirements, overall operation and delineate authorship guidelines.

Between 1976 and 1982 the PRCSG conducted six more studies of NSAIDs while refining and sharpening its methodologies, communications, and standardization of reporting.  While progress was being made during the 1980’s in the development and testing of the first line NSAIDs, diseases modifying anti-rheumatic drugs (DMARDs) known as second line agents were being tested in adult RA.  D- The leadership of the PRCSG recognized the need for systematic, blinded, controlled trials of all these agents in children and urged the NIH and FDA to assist them in convincing industrial sponsors to facilitate such trials.  They also were quick to realize that many hundreds of patients would be needed to conduct these trials in a statistical valid manner.  The answer was to collaborate with investigators outside of North America in order to gain access to more potential subjects, fully realizing that the logistics, regulatory affairs and diplomatic relationships would likely be difficult.  But a potential answer was at hand.

The United States and the Soviet Union had signed the Cooperation in Medical Science and Public Health Agreement on May 23, 1972 in Moscow.  With the aid and cooperation of the National Institutes of Health, a long and productive collaboration between the PRCSG and the Ministry of Health in Moscow soon began.  Despite the difficulties, blinded, controlled trials of all four of these agents were successfully completed and published by 1992.  The standout drug proved to be methotrexate.   As a result, methotrexate became recognized as the second line agent of first choice for many years thereafter, while the other drugs showed no more efficacy than placebo and rapidly disappeared from usage in JIA.  Since those studies were completed, an array of other agents with a variety of mechanisms of action have been tested in JIA by the PRCSG, but few play a substantial role in the therapeutic armamentarium of JIA at present (see link to publications below).

During this productive period, Dr. Brewer announced his retirement in 1988 and Dr. Dan Lovell, who had been trained by Dr. Brewer, was elected to become the new Chairman of the PRCSG, with Dr. Giannini remaining as the Senior Scientist.  The Coordinating Center was moved from Texas Children’s Hospital to Cincinnati Children’s Hospital in 1990.

Due to dramatic increases in technology and an in-depth understanding of the underlying mechanism of the inflammatory process central to JIA, a new class of agents had become available by the early 1990’s.  Since these new molecules, many of which were monoclonal antibodies, were directed against specific inflammatory mediators, they became known as ‘immune response modifiers’ or, more simply, ‘biologicals’.   The first was an anti-TNF agent named etanercept (Enbrel®) which underwent trial by the PRCSG using a newly developed randomized, withdrawal design.  The efficacy and short-term safety of this agent proved to be remarkable and by March of 2000 the results were published in the New England Journal of Medicine.  Soon afterwards the drug was approved for use in JIA by the FDA, the first biological to be approved for children.

In 1996 pediatric rheumatology leaders from 14 different European countries came together to form the Pediatric Rheumatology International Trials Organization (PRINTO).  Since that time PRINTO has grown to include 44 different countries around the world.  Professor Alberto Martini at Gaslini Hospital in Genoa, Italy has served as the Chairman of PRINTO since its inception and Dr. Nicola Ruperto, who spent 1 ½ years training with Dr. Giannini in Cincinnati, has been the Senior Scientist and remains in that position today.  An alliance was quickly formed with the PRCSG and the two groups have now performed trials that have led to FDA approval for children of numerous biologicals, and worked collaboratively on various methodological papers to improve further the ascertainment of a patient’s disease state and activity, advanced the efficiency and user-friendliness of new and innovative study designs, and streamlined the standardization of data collection, management and reporting (for details please see publications).

Leadership of the PRCSG has been remarkably stable throughout the 40 years of its existence.  Dr. Dan Lovell has remained Chairman of the group since his election in 1989.  Dr. Giannini announced his retirement as Senior Scientist in 2006 after 30 years of service, and still serves as an advisor to the Advisory Council.  The name of the position was changed to Scientific Director in 2006 and Dr. Hermine Brunner was elected to fulfill the role and remains in that position today.