|
Stockholm; Sweden, 12-15 June 2002
The PRES meeting this year was attached to the 3rd Annual European Congress of Rheumatology (EULAR) with several joint pediatric and adult sessions.
Hereditary episodic fever syndromes:
A special opening session was dedicated to inherited childhood episodic fever syndromes, discussing both clinical and basic science aspects. Dan Kastner (USA) discussed the molecular basis for these syndromes, discovered only during the last decade. In most of these syndromes the genetic defect results in a pro-inflammatory state. Dr. Kastner dubbed these syndromes as auto-inflammatory. Two of the diseases, Familial Mediterranean Fever (FMF) and hyperimmunoglobulin IgD (HIDS) syndrome have a autosomal recessive mode of transmission. The other three syndromes, Muckle-Wells syndrome (MWS), tumor necrosis factor associated periodic syndrome (TRAPS) and familial cold urticaria (FCU) have an dominant mode of transmission. The causes of periodicity and the environmental stimuli of attacks are unclear, besides cold that triggers episodes of FCU.
There is evidence that the pyrin protein, deficient in FMF, plays a role in the regulation of apoptosis and in the activation of IL-1. It is hypothesized that polymorphonuclear cells deficient in pyrin do not undergo apoptosis resulting in excessive IL-1 production and a massive inflammatory response to various stimuli. The protein cryopyrin may play a similar role in MWS and FCU.
Anne-Marie Prieur (France) briefly introduced new data on the genetic basis of the chronic infantile neurological, cutaneous and articular (CINCA) syndrome. She found that the defect on chromosome 1 was on the same gene as in MWS and CFU, although the specific mutations were different. This data is preliminary and needs further elaboration.
Seza Ozen (Turkey) gave an update on FMF. She emphasized the limitations of current genetic testing, noting that many patients with FMF phenotype lack homozygote mutations. This phenomenon is particularly common in regions with a low prevalence of FMF. Another unanswered question is whether to treat asymptomatic patients with homozygote mutations. This question is related to the problem of identifying patients with a high risk of developing amyloidosis.
Michael McDermott (UK) elaborated on the TRAPS syndrome. In this syndrome the physiologic shedding of TNF receptors from cell membranes is defective resulting in continuous TNF stimulation. The soluble TNF-receptor, Etanercept, has been used to treat patients with TRAPS, although the long-term effect is still unclear.
Joost Frenkel (Netherlands) discussed the pathogenesis of HIDS. Mevalonic acid plays a role in the RAS molecule pathway of inflammation. This excess in mevalonic acid, derived from the deficiency in mevalonate kinase, causes excessive production of the pro-inflammatory cytokine IL-1β. An animal model revealed that the lack of isoprenoid, the end product of the mevalonate enzyme pathway, was the cause of excessive IL-1β production.
Treatment of juvenile arthritis (JA):
Many studies regarding the treatment of JA were presented. Nicola Ruperto (Italy) presented the first PRINTO multinational drug study comparing parenteral administration of medium-dose methotrexate (MTX) (15 mg/m2/week) vs. high-dose MTX (30 mg/m2/week) in patients with polyarticular JA who failed to respond to 6 months of standard MTX (8-12 mg/m2/week). Twenty countries participated in the study that took 4 years to complete. Six hundred and thirty-three patients were enrolled in the standard dose MTX screening phase.
Based on the ACR Pediatric 30 standard, 72% of the patients were considered responders. Of the 145 non-responders, 80 patients were randomized to receive medium or high-dose MTX (40 in each group). After a further 6 months of treatment, 60% of the patients in both groups responded to therapy. There were no significant toxicity differences between the groups. The authors concluded that in patients who fail to respond to standard low-dose MTX, it is appropriate to switch to medium-dose MTX. Due to the study protocol it was impossible to answer the question whether similar response rates would have been achieved if standard dose MTX would have been continued for a further 6 months. The importance of a multinational study with a strong coordinating center was demonstrated in this complex study which needed a large sample size.
As in many recent meetings, studies of biologic agents, mainly anti-TNF agents, were prominently presented. Horneff (Germany) from the German Pediatric Rheumatology Registry reported their experience of the use of etanercept. The registry includes 158 patients treated with etanercept; 104 were followed for at least 3 months. Overall they reported a similar efficacy and safety profile to previous etanercept studies. However, patients with systemic JA responded less often than patients with polyarticular JA. Fifty-six percent of the patients with systemic JA had an ACR Pediatric 30 response while only 25% had a 50% response. Five of the patients developed uveitis during etanercept treatment. However, it is still premature to determine whether uveitis may represent an adverse reaction to Etanercept or is only part of the natural course of disease.
Smaller non-controlled series reported on the efficacy of biologic agents in other pediatric rheumatic diseases, including ankylosing spondylitis, dermatomyositis and even CINCA. A pilot study of the use of the humanized anti-TNF agent Adalimumab in JA was reported. Studies of IL-1 antagonists (Anakinra) in children have not yet been described.
Another session reviewed the current experience of autologous stem-cell transplantation (ASCT) in the few severe patients with JA unresponsive to other therapies. Allan Tyndall (Switzerland) reported on 31 patients with JA who underwent ASCT. Earlier series reported a 10% mortality rate, mainly due to the macrophage activation syndrome. Several changes in the protocol were made to prevent or to minimize the effect of the syndrome. Prior to ASCT, patients are treated aggressively with steroids to suppress inflammation. If macrophage activation syndrome is suspected after ASCT, cyclosporin is added immediately. Since these changes were enacted there were no reported mortalities. The efficacy of ASCT in this series was complete remission in 50% of the patients and significant improvement in most of the remaining patients.
Transition from pediatric to adult care:
One of the most fascinating joint sessions dealt with the issues of transition of adolescents from pediatric rheumatology to adult rheumatology care. The session chair, Anne-Marie Prieur (France), engaged the audience in a lively discussion. The specific life issues facing an adolescent with chronic disease were addressed. The issues include self-esteem, education, vocation, and relationships. Long-term studies of adults who had JA were presented. One study found that the proportion of patients with JA who had a job or were married was lower than matched healthy controls. Questions as to the timing, criteria as well as the best method to transfer patients were discussed. There was no consensus although most discussants thought that transition should be individually tailored for each patient and family. A multidisciplinary clinic with both adult and pediatric rheumatologists was proposed for the year of transition.
Inflammatory myopathies, Lyme disease, study groups:
A joint session reviewed issues related to the pathogenesis, clinical and therapeutic aspects of inflammatory myopathies. Lundberg (Sweden) discussed the pathogenesis, stressing the increased expression of pro-inflammatory cytokines by endothelial cells. These cytokines represent evidence of Class I MHC molecule expression on myocytes. Each of these cytokines may present a specific target for future treatment strategies.
Brian Feldman (Canada) discussed the common and differing clinical expressions of myositis in adults and children. One of the major points raised was the lack of evidence-based medicine for the treatment of myositis other than the use of steroids.
A joint session was dedicated to Lyme borreliosis. Pathogenesis, clinical expression and diagnostic issues were discussed. The importance of demonstration of borrelia in the synovium or synovial fluid was emphasized since the common serologic tests are often inaccurate. The future lies in finding an effective vaccination. The current vaccine is effective in 75% of U.S. residents who have received 3 doses but is less effective in Europe.
Several sessions were dedicated to the various PRES study groups including scleroderma, hereditary episodic fever syndromes, dermatomyositis, vasculitis and development of clinical guidelines for rheumatic diseases. These groups discussed the establishment and practicalities of organizing registries for these rare disease as well as collaborative international research projects.
Yosef Uziel, MD, MSc, and Philip J. Hashkes, MD, MSc
Meir Medical Center, Kfar-Saba and Sieff Hospital, Safed, Israel