Pediatric Rheumatology Online Journal

Vol 2, No. 2 (108-113)  2004

http://www.pedrheumonlinejournal.org

 

special article

 

International Netwoks in Pediatric Rheumatology: The Example of PRINTO

 

Nicolino Ruperto, Alberto Martini

Department of Pediatrics, University of Genoa, and IRCCS G Gaslini, Genoa, Italy

 

Correspondence:

Pediatric Rheumatology International Trials Organization (PRINTO)

IRCCS G. Gaslini 

Pediatria II

Largo Gaslini, 5

16147 Genova

ITALY

Tel: +39-010-382854 or +39-010-3393425

Fax +39-010-393324 or +39-010-3393619

E-mail: albertomartini@ospedale-gaslini.ge.it or nicolaruperto@ospedale-gaslini.ge.it

http://www.printo.it or www.pediatric-rheumatology.printo.it

 

 

The pediatric rheumatic diseases (PRD) are rare conditions associated with substantial morbidity with consequences on the quality of life as well as monetary costs. Many studies on the impact and outcome of PRD have shown that this group of diseases is associated with significant morbidity and therefore should be the target of intense research aimed at finding new, more effective therapies. However, in the past it has always been very difficult to perform controlled trials in PRD for two main reasons: a) the rarity of the diseases and therefore the need to perform large international studies in order to gather sufficient patients to obtain clinically and statistically significant results in a relatively short-time; b) the difficulty in securing funding since the pharmaceutical industry has little interest in the small pediatric market.

This picture changed substantially in recent years because of two main events: 1) the organization of large international networks for clinical trials in PRD; 2) the approval of the pediatric rule by the FDA.

 

The Pediatric Rheumatology Collaborative Study Group (PRCSG)

Collaborative research in pediatric rheumatology was pioneered by the PRCSG, founded by Dr Earl Brewer, and led in the following years by Edward H. Giannini, and Daniel J. Lovell. The PRCSG performed fundamental methodological studies for the performance of clinical trials and conducted controlled studies on non-steroidal anti-inflammatory drugs (NSAID) therapy in JIA. The PRCSG shaped the current treatment of JIA by demonstrating the ineffectiveness of penicillamine, hydroxychloroquine (1) and auranofin (2) as well as  the efficacy of low-dose methotrexate (MTX) (3).

 

Pediatric Rheumatology International Trials Organization (PRINTO)

PRINTO was founded in 1996 on the initiative of Alberto Martini and Nicolino Ruperto and initially included 14 European countries. PRINTO has grown to include 43 countries with more than 170 pediatric rheumatology centers world wide. PRINTO and the PRCSG have  worked closely together in various international collaborative projects.

PRINTO is composed of academic clinical centers actively engaged in the care of children with PRD. PRINTO has four main vertical structures: the Advisory Council that provides leadership and guidance for PRINTO research activities; the International Coordinating Center in Genoa, Italy whose main task is to facilitate the flow of logistic and scientific details needed to design, launch and manage multi-centered, multi-national, collaborative studies; the National Coordinating Centers (one per country) whose tasks are to facilitate the participation of the greatest possible number of individual centers and  to provide the translation of all the forms to be completed by the parents/patients; and finally the individual centers that constitute the main support structure to obtain a critical mass of data for on-going and future research.  

 

The ACR pediatric 30 definition of improvement for JIA

Until the mid-1990’s, the assessment of clinical response in JIA was not standardized. Multiple outcome measures were utilized and various trials used different endpoints. Some of these endpoints had low validity characteristics and were insensitive to change, some were redundant, and some were non-reliable. Additionally, there was little consensus about the amount of change in endpoints which signifies clinically important improvement or worsening. This lack of standardization led to inefficient trials that required larger than necessary sample sizes, an increased risk of statistical error, possible reporting bias, multiple or ambiguous interpretations of the results, and an inability to compare multiple therapies using meta-analytic techniques.

Under the guidance of E.H. Giannini, the main aim of this first combined effort conducted by the PRCSG and PRINTO was to develop a standardized core set of measures and a definition of improvement for the evaluation of response to therapy in JRA. This work led to the publication of the preliminary definition of improvement for JIA (4; 5). This definition has been adopted by the Food and Drug Administration (FDA) as the primary outcome for all clinical trials involving children with JIA, and is officially recognized as the American College of Rheumatology (ACR) pediatric 30 definition of improvement (6).

 

The Methotrexate trial in JIA.

After the trial published by Giannini et al (3), MTX became the first choice disease-modifying-agent for polyarticular course JIA. For children who did not respond to 10 mg/m2/week some pediatric rheumatologists in the 1990’s used higher dose MTX, up to 30 mg/m2/week (7), but no randomized trial has ever confirmed this hypothesis. Since the definition of the optimal dosage of MTX in term of efficacy and safety is central to disease management, PRINTO, supported by the European Union (Contract BMH4 983531), conducted a randomized open label standard-of-care trial to evaluate the MTX efficacy and safety profile in intermediate versus higher dose for polyarticular course JIA patients who failed to improve on standard dose MTX. The trial, now in press (8), has showed that the plateau of efficacy of MTX in JIA is reached with the parenteral administration of 15 mg/m2/week and that further increase in dosage is not associated with any additional therapeutic benefit.

 

The quality of life project for the PRD

PRINTO is composed of many nations with different languages and cultures. One goal was therefore to have common instruments to measure functional ability and quality of life translated into the different languages and validated in the different cultures. Due to the European Union (Contract BMH4 983531), PRINTO has been able to cross culturally adapt and validate two childhood questionnaires. Both the Childhood Health Assessment Questionnaire (CHAQ) for functional ability assessment and the Child Health Questionnaire (CHQ) for the health related quality of life assessment were adapted and validated. The project led to the enrollment of 6,644 subjects (3,235 patients with JIA, and 3,409 healthy children) with the validated version of the CHAQ and CHQ now available for 32 different countries (9). The CHAQ is now the functional assessment tool used for all trials in JIA.

 

Disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM)

With a second grant from the European Union (contract n° QLG1-CT-2000-00514) PRINTO has been able to propose validated core sets for the evaluation of disease activity and damage (10) and also definitions of improvement to be used in future clinical trials in JSLE and JDM (paper in preparation). A total of 295 patients with JDM and 556 patients with JSLE were collected from 41 countries.

 

A website for families of children with pediatric rheumatic diseases

           The actual large availability of the use of the internet allows families to access medical information quickly and easily, but this information is often not standardized and may be inaccurate and unreliable. To overcome this problem PRINTO, in collaboration with the Paediatric Rheumatology European Society (PRES), supported by the European Union (contract 2001CVG4-808), has just finished a project with the goal to prepare a website, directed to families and health professionals, containing consensus defined information about PRD (in the format of frequently asked questions), the list of pediatric rheumatology centers, and the list of family help associations. All information is available in the languages of all the countries belonging to the PRINTO (www.pediatric-rheumatology.printo.it) (manuscript in preparation).

 

Research Training in pediatric rheumatology

Good collaborative clinical research requires qualified people around the world able to conduct studies in a standardized fashion (11). PRINTO, with another grant from the European Union (Contract no AML/B7-311/97/0666/II-0246-FI), has set up a research training programme in pediatric rheumatology, to support mainly Latin America recipients (Argentina, Brazil, Chile, Costa Rica, Cuba, or Mexico). For the 24 Latin American recipients the course will take place in Genoa, Italy; Paris, France; Utrecth, the Netherlands; Goteborg, Sweden; and London, England. Also, in order to coordinate and optimize the conduct of collaborative international studies, four other European trained recipients from Genoa will spend some months in Buenos Aires in Argentina, Mexico as well as Rio de Janeiro and Botucatu,  Brasil.

 

The Pediatric Rule

Fundamental to the conduct of controlled clinical trial in PRD has been the adoption, by the United States Food and Drug Administration (FDA) in 1998, of the so called “pediatric rule” by which manufacturers of products likely to be used in children have to study the safety and the efficacy of these products in the relevant pediatric population. Due to this very important legislative initiative, the number of requests for clinical trials in the last few years has greatly increased. The benefits of the pediatric rule for pediatric rheumatology were demonstrated when the FDA approved a biologic agent (etanercept) for use in JRA (12) after a PRCSG study. In addition, three biologic agent trials are currently being studied by members of the PRINTO and PRCSG networks. A similar legislation on pediatric drugs will hopefully be adopted in the next future by the European Medical Evaluation Agency (EMEA).

 

Conclusions

These four recent advances in pediatric rheumatology---the adoption of adequate legislative measures (pediatric rule), the creation of big international trial networks such as PRINTO and PRCSG, the definition of internationally recognized and standardized outcome measures and definitions of improvement, and the cross-cultural adaptation and validation of quality of life instruments---have created the foundation for a critical advance in the assessment of the efficacy of new treatments for the PRD. Children with rheumatic diseases now have the same rights that adults have to be treated with drugs whose safety and efficacy have been properly assessed and evaluated.

 

Reference List

      1.   Brewer EJ, Giannini EH, Kuzmina N, Alekseev L. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis: Results of the U.S.A. - U.S.S.R double-blind, placebo controlled trial. N Engl J Med 1986;314:1269-1276.

      2.   Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Wallin B, for the Pediatric Rheumatology Collaborative Study Group. Auranofin in the treatment of juvenile rheumatoid arthritis. Results of the U.S.A. - U.S.S.R. double-blind, placebo controlled cooperative trial. Arthritis Rheum 1990;33:466-476.

      3.   Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. N Engl J Med 1992;326:1043-1049.

      4.   Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40(7):1202-1209.

      5.   Ruperto N, Ravelli A, Falcini F, Lepore L, De Sanctis R, Zulian F et al. Performance of the preliminary definition of improvement in juvenile chronic arthritis patients treated with methotrexate. Ann Rheum Dis 1998;57(1):38-41.

      6.   Albornoz MA. ACR formally adopts improvement criteria for juvenile arthritis (ACR Pediatric 30). ACR News 2002;21(7):3.

      7.   Wallace CA, Sherry DD. Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis. J Rheumatol 1992;19:1604-1607.

      8.   Ruperto N, Murray KJ, Gerloni V, Wulffraat N, Oliveira S, Falcini F et al. A randomized trial of parenteral methotrexate in intermediate versus higher doses in children with juvenile idiopathic arthritis who failed standard dose. Arthritis Rheum 2004;in press.

      9.   Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado-West L et al. Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clin Exp Rheumatol 2001;19(4):S1-S9.

    10.   Ruperto N, Ravelli A, Murray KJ, Lovell DJ, Andersson-Gare B, Feldman BM et al. Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology (Oxford) 2003;42(12):1452-1459.

    11.   Hirsch R. Pediatric rheumatology: a call to action. Curr Opin Rheumatol 2004;15:571.

    12.   Lovell DJ, Giannini EH, Reiff A, Cawkwell D, Silverman ED, Nocton JJ et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 2000;342(11):763-769.