Conference Scene. 15th Paediatric Rheumatology European Society Congress. Future Rheumatology

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1 15th Paediatric Rheumatology European Society Congress SJ Vastert, Joost F Swart & Berent J Prakken Author for correspondence: Department of Paediatric Immunology, Wilhelmina Children s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands Tel.: Fax: b.vastert@umcutrecht.nl 15th Paediatric Rheumatology European Society Congress, London, UK, September 2008 Pediatric rheumatology has developed rapidly over the last decade. This has lead to remarkable improvements in diagnosis, classification and treatment of juvenile autoimmune diseases. Correspondingly, it has brought about important new challenges for the next decade, such as better understanding of the immune pathology of pediatric rheumatologic diseases, the improvement of current targeted therapies and the longterm consequences of the disease. This renewed focus was evident at the 15th Congress of the Paediatric Rheumatology European Society, held at the University College of London, UK, and organized by Professor Patricia Woo and colleagues. A total of 590 participants from 49 countries participated in a program that included four plenary sessions and 12 parallel sessions, and over 270 poster presentations. For the eighth time in succession, the main meeting was preceded by a young investigator meeting (YIM). Young researchers (less than 40 years of age) from all over Europe gathered in the Institute of Child Health on September 13th, 2008, to present their research in an informal, vivid and highly motivating setting. The scientific sessions in the main congress and YIM addressed a broad variety of clinical and more basic research topics. Here, we will discuss some of the most eyecatching communications presented during the main congress and YIM, all related to the three aforementioned main challenges, namely mechanisms of diseases, improvement of treatment and long-term consequences of disease. By no means do we aim to provide a complete overview of the conference. Mechanisms of disease: systemic juvenile idiopathic arthritis In the last year, important steps forward have been made in the field of autoinflammatory diseases. The increased understanding of the role of IL 1 in the pathogenesis of autoinflammatory diseases has lead to the realization that systemic juvenile idiopathic arthritis (SoJIA) shares many features that resemble autoinflammation. Indeed, pivotal work from various groups has determined that in SoJIA, next to IL 6, the IL 1 cascade plays an important role. Several reports during the conference contributed important information to the puzzle of SoJIA pathogenesis. Anemia is a prominent finding in SoJIA, and has been attributed to various factors, such as the chronic inflammation and the effects of IL 6. Another mechanism was pointed out by Alexei Grom from Cincinnati (OH, USA). He demonstrated that gene-expression studies of peripheral blood mononuclear cells (PBMC) of SoJIA patients reveal a strong erythropoiesis signature [1]. This signature is associated with an expansion of CD34 + progenitor cells, suggesting that the underlying mechanism of the anemia in SoJIA is not decreased erythrocyte production due to chronic inflammation, but hemophagocytosis. When comparing PBMC gene-expression data of SoJIA patients with anemia with patients with other types of JIA and anemia, after unsupervised hierarchical clustering, all SoJIA patients with anemia showed homogenous clustering. An increased number of CD34 + progenitor cells were seen in the SoJIA patients only, and not in the other types of JIA. This adds to previous findings and suggests subclinical macro phage activation syndrome to be present in SoJIA patients with severe anemia. These findings lead to a debate on how this relates to earlier findings by Cazzola and colleagues, that severe anaemia in SoJIA can be treated with high-dose (intravenous) iron therapy [2]. In addition to IL 1, another related cytokine attracts attention in SoJIA, namely IL 18 [3,4]. SoJIA patients display very high levels of IL 18, which is known to drive natural killer (NK) cell function. Paradoxically, most SoJIA patients show decreased numbers of cytotoxic NK cells, and defective functioning of NK cells in cellmediated killing assays. Comparing active SoJIA patients to severely affected polyarticular JIA patients and healthy controls, Wilco de Jager (UMC Utrecht, the Netherlands) found similar NK cell receptor phenotypes in all Future Rheumatology part of / Future Medicine Future Rheumatol. (2008) 3(6), ISSN

2 Vastert, Swart & Prakken groups, but decreased IL 18-mediated effector functions (IFN γ production, perforin expression and granule-mediated lysis of target cells) only in the SoJIA patients. He was able to pinpoint a selective phosphorylation defect of the IL 18Rβ chain. Future research will demonstrate whether this defect is either a reversible tolerogenic effect due to the high circulating IL 18 levels, or due to, for example, genetic defects in the IL 18 receptor. Mechanisms of disease: regulation of the immune response Oligoarticular JIA is the first human autoimmune disease in which evidence was found for a role of FOXP3 + regulatory T cells (T reg ) [5]. Studies from various groups are bringing about more insight into the role and function of these cells in JIA. Halima Moncrieffe (Great Ormond Street Hospital, London, UK) presented data on CD39 + T reg. CD39 belongs to a family of ectoenzymes that convert pro inflammatory ATP into ADP and AMP. Ultimately, this leads to an increase in the anti-inflammatory molecule adenosine, which exerts its effects on a variety of cells (T cells, monocytes and so on). In fact, adenosine is thought to be responsible (at least in part) for the anti-inflammatory effects of methotrexate (MTX), still the most widely used diseasemodifying drug in juvenile arthritis. Moncrieffe demonstrates CD39 expression on a variety of mononuclear cells, both in healthy controls and in JIA patients. Increased CD39 expression is seen in synovial-fluid-derived mononuclear cells. Interestingly, a proportion of Foxp3 + T reg also express CD39. This suggests that conversion of ATP into adenosine pre cursors might be one of the effector mechanisms of T reg. Another question is whether commonly used drugs in JIA, such as MTX and etanercept, may exert their action through influencing the T reg compartment. A study on the change in the immune repertoire before MTX treatment is started and following withdrawal demonstrates that this is probably not the case, as this did not lead to an effect on the amount or function of CD4 + FoxP3 + T reg (Vastert, Utrecht, the Netherlands). Instead, MTX appears to exert its anti-inflammatory effects by affecting effector T cell populations and T cell responses to a regulatory autoantigen in JIA, human heat shock protein 60. Th17 cells are the other side of the coin of adaptive immune regulation in JIA, as data from experimental models point to a causative role of these IL 17-producing cells in auto immunity. Indeed, several groups at the conference reported on Th17 cells in (juvenile) arthritis. Ralph Lippe from the University of Muenster, Germany, communicated work on CREM α in mice in this respect. CREM α is a transcriptional repressor and is able to bind to the IL 2 promoter, thereby decreasing transcription of IL 2. In systemic lupus erythematosus (SLE) patients, for example, CREM α appears to be over expressed, possibly contributing to the auto immune response. Lippe overexpressed CREM α under control of the T cell-specific promoter in mice to levels similar to that in SLE patients. He found in a contact dermatitis model more severe disease activity in CREM α transgenic mice, compared with wild-type mice. Moreover, transgenic CREM α mice showed increased T cell proliferation, and especially an increased Th17 response compared with wild-type mice. This needs to be further explored. Kiran Nistala (Great Ormond Street Hospital, London, UK) elaborated on previous findings on a reciprocal relation between Th17 cells and CD4 + FOXP3 + T reg in the synovial fluid of JIA patients. The balance between the regulatory T cell and Th17 populations is possibly related to the development into either an extended polyarticular course of the disease or a persistent oligo-articular course. Nistala demonstrated that CCR6-sorted cells from synovial fluid contain both the classical CD4 + IL 17 + cells, as well as IL 17 + IFN γ + double-positive CD4 + T cells. The latter might be even more inflammatory. Mesenchymal stem cells in arthritis Owing to their immune regulatory and regenerative capacity, mesenchymal stem cells (MSCs) have gained much interest over the past 5 years, first in the field of transplantation, but now also in the field of immune regulation. In a keynote lecture, Professor Dazzi from Imperial College, London, UK, discussed MSC transplantation and hematopoietic stem cell transplantation as cellular therapies for the future. MSCs are multipotent bone marrow cells able to differentiate in vitro and in vivo into tissues of mesenchymal origin. Dazzi reviewed experimental data on MSC therapy, which exerts nonspecific, nonselective and reversible inhibitory or regulatory effects on cell proliferation, and activation-induced cell death. Their inhibitory effect is independent of MHC1 presentation, which broadens their possibilities in clinical use. Clinical studies, mainly in graft versus host disease are promising, although there remain many important questions to answer before it can be translated into therapy for arthritis or other autoimmune 518 Future Rheumatol. (2008) 3(6)

3 15th Paediatric Rheumatology European Society Congress diseases. Joost Swart (VU Medical Center, Amsterdam, The Netherlands) presented new data on the use of MSC infusions in an arthritis mouse model (proteoglycan-induced arthritis). He injected mice with either one or two doses of MSC in either the knee (intra-articularly) or intra-peritoneally, and noted a significant beneficial effect of MSC on arthritis. Interestingly, even a local injection in one joint had systemic anti-inflammatory effect on other joints. The effect was related to dose and not frequency of injections. These are promising results for future avenues of therapy. Developments in treatment: a new look at steroids? Johannes Roth (University of Muenster, Germany) provided new insight on the regulatory, anti-inflammatory effects induced by glucocorticoids in macrophages. After activation of human monocytes for 16 h with glucocorticoids, using an Affymetrix (CA, USA) chip-array he found 102 upregulated and 45 downregulated genes. These genes could be arranged into five functional groups, of which the most interesting appeared to be the stimulation of migration to the site of inflammation and a reduction in apoptosis via the MAPK pathway. Roth s data point to a role of the adenosine/a3ar/erk pathway as a novel pathway responsible for gluco corticoid-mediated survival of anti-inflammatory monocytes. Developments in treatment: biologicals At the conference, new data were presented on the use of various biologicals in JIA. Nicola Ruperto (University of Genova, Italy) presented data on behalf of the Paediatric Rheumatology INternational Trials Organisation (PRINTO) on the long-term efficacy and safety of infliximab plus MTX for the treatment of polyarticular JIA. This study was an open-label extension of a previous randomized trial, which, amongst other things, demonstrated that after 1 year of infliximab plus MTX treatment, clinical benefits in the group who used 3 mg/kg infliximab were as good as the group who used 6 mg/kg every 4 weeks. After 1 year of randomized therapy, patients were eligible to enter an open-label extension continuing for 3 more years, starting with 3 mg/kg with a possible increase in dose to 6 mg/kg. Treatment in the extension study resulted in a 91.7% achievement of the ACR30 response, and 50% ACR90 response after 4 years of therapy. The most important side effect of the continued use of infliximab in combination with MTX was the occurrence of anti-infliximab antibodies in 36% of patients, resulting in infusion reactions in more than half of the concerned patients. Ruperto and colleagues concluded that infliximab plus MTX was a safe and effective treatment for polyarticular JIA. Heinrike Schmeling and colleagues from the Hospital for Sick Children in Toronto, Canada, presented a poster about JIA patients switching from etanercept to adalimumab, either due to inefficacy (66%), the occurrence of uveitis under etanercept therapy (16%) or intolerance (9%). Although the number of patients in this study was low (n = 33), they observed only minor improvement in the pediatric ACR criteria. This was confirmed in a study of Salmaso and colleagues from the Gaetano Pini Institute in Milan, Italy, where 60 JIA patients switched from one anti-tnf agent to another (etanercept, infliximab or adalimumab). They demonstrated that failure of an anti-tnf therapy in patients with JIA does not preclude a response to a second anti-tnf agent of a different class. There were multiple reports of different anti- IL 1β agents, mainly used in SoJIA. Nicola Ruperto, on behalf of PRINTO, reported findings on a Phase II trial of canakinumab, a longacting anti-il1β agent, to evaluate preliminary dosing, safety and efficacy profile in SoJIA patients. This study includes 19 patients in an open label, dose escalation fashion. Patients received a single subcutaneous injection in a dose range of mg/kg, followed by an observation period and re-dosing upon relapse. Responses were measured using ACR pediatric criteria. The response rate to ACR Pedi 50 at day 15 of treatment was almost 60% (11 out of 19 patients), while the time to relapse varied from 23 to more than 200 days. One serious adverse event was documented (gastric bleeding). They conclude that canakinumb is a promising, longacting agent for SoJIA patients. Pierre Quartier and colleagues from Hôpital Necker-Enfants Malades, Paris, France, communicated findings of a randomized, double-blind, placebo-controlled trial of anakinra in SoJIA patients. Two groups received either a placebo or anakinra in daily subcutaneous injections for 1 month. The anakinra group had a significant, improved ACR Pedi 30 response (eight out of 12 patients), compared with the placebo (one out of 12 patients). After 1 month, all patients were treated in an open-label extension with anakinra. Of the patients receiving placebo in the first month, nine out of ten responded to anakinra at month 2. Before month 12, eight out of 22 patients discontinued anakinra, mainly 519

4 Vastert, Swart & Prakken due to lack of efficacy (n = 4) or adverse events (n = 2). This study demonstrates that anakinra is effective in SoJIA, but some patients do relapse within the first year of treatment. A new development is the use of anakinra as primary treatment of SoJIA. Nico Wulffraat (UMC Utrecht, the Netherlands) demonstrated that the use of anakinra in corticosteroid-naive SoJIA patients lead to a dramatic improvement within 3 days of treatment. Follow-up at 3 weeks showed persistent remission in six out of seven patients without the use of steroids. Wulffraat proposes a randomized, controlled trial to define the place of anakinra as a second-line treatment, immediately after nonresponsiveness to nonsteroidal anti-inflammatory drugs. Shumpei Yokota and colleagues from the Yokohama University in Japan reported on the long-term safety and efficacy of tocilizumab, a blocking antibody to the IL 6R, in children with systemic JIA. They treated 67 patients with a median duration of 146 weeks. ACR Pedi 70 criteria were achieved in 93% in week 96 of treatment. Treatment with tocilizumab was accompanied by major adverse events in a minority of patients (serious infections were reported at a rate of 10.7 per 100 patient-years). Nine out of 67 patients discontinued therapy, either for adverse events (n = 4), development of anti-tocilizumab antibodies (n = 4) or lack of efficacy (n = 1). Long-term consequences Thus, altogether, various new treatment options have lead to a clear improvement in the prognosis of children with JIA and other inflammatory diseases. However, this comes with a price, as was highlighted at the conference. Both the keynote presentation of Taunton Southwood from the Institute of Child Health in Birmingham, UK, and the poster presentation of Mette Tarkiainen from Helsinki, Finland, stressed the importance of proper postmarketing studies on safety and outcomes in children with JIA treated with anti-tnf α agents. Nowadays, the sum of JIA patients recruited to biologic registries approaches the number of patients necessary to pick up rare serious adverse events, at least for etanercept. The most important adverse events so far appear to be of infectious origin. Very interesting in that respect was the keynote lecture of Michael Levin from Imperial College, London. He spoke about the effect of anti-tnf agents on mycobacterial immunity, and raised several important issues. The time to infection, for example, in anti-tnf-treated patients is suggestive for reactivation of latent infection rather than the occurrence of a new mycobacterial infection. Second, the formation of granuloma appears to be defective in anti-tnf treated patients. This is likely to be related to a failure in the interferon γ/il 12/ TNF α pathway, which is critical to resistance to mycobacteria. Thus, despite the clear and undisputable success of improved treatment available today, we must be very aware of long-term consequences for patients with JIA, not only as direct or indirect side effects of treatment. In addition, there must be a growing awareness of the possible increased risks patients have in the very longterm, for example, in the development of cardiovascular complications (Rae Yeung, Toronto, Canada). It is therefore appropriate to end this summary with the opening statement of Sir Gordon Duff (Florey Professor of Molecular Medicine, University of Sheffield, UK). While Executive summary Key conclusions Hemophagocytosis seems to be one of the mechanisms of anemia encountered in systemic onset juvenile idiopathic arthritis (JIA). Next to IL-1, IL-18 seems to also be a key cytokine in the pathogenesis of systemic onset juvenile idiopathic arthritis. IL-1b agents are effective in many patients with systemic onset juvenile idiopathic arthritis. Long-acting agents provide significant treatment advantages. The anti-inflammatory molecule adenosine seems to be involved in the function of regulatory T cells in juvenile idiopathic arthritis as well as in the anti-inflammatory pathways induced by glucocorticoids. Switching from one anti-tnf agent to another does not yield improvement in most JIA patients. The interferon-g/il-12/tnf-b pathway seems to be critical in granuloma formation in and resistance to mycobacterial infections. Unresolved issues Long-term consequences of treatment and disease. Future perspective: aims for further work Further unraveling immune mechanisms of disease. Improvement of targeted therapies. Proper postmarketing studies on new therapies. 520 Future Rheumatol. (2008) 3(6)

5 15th Paediatric Rheumatology European Society Congress discussing, amongst others, the failure of the infamous London TGN142 trial, he concluded that notwithstanding the great efforts both by academia and pharmaceutical companies we are still unable to develop a safe and effective medicine that can cure arthritis. This is the ultimate challenge for pediatric rheumatology in the 21st Century. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Bibliography 1. Fall N, Barnes M, Thornton S et al.: Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum. 56, (2007). 2. Cazzola M, Ponchio L, De Benedetti F et al.: Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood 87, (1996). 3. de Jager W, Hoppenreijs EP, Wulffraat NM et al.: Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann. Rheum. Dis. 66, (2007). 4. Gattorno M, Piccini A, Lasiglie D et al.: The pattern of response to anti-interleukin 1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 58, (2008). 5. de Kleer IM, Wedderburn LR, Taams LS et al.: CD4 + CD25 bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J. Immunol. 172, (2004). Affiliations SJ Vastert Department of Paediatric Immunology, Wilhelmina Children s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Tel.: ; Fax: ; b.vastert@umcutrecht.nl Joost F Swart Department of Paediatrics, VU Medical Venter, Postbus 7057, 1007 MB Amsterdam, the Netherlands Berent J Prakken Department of Paediatric Immunology, Wilhelmina Children s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands