Mesenchymal stem cell therapy in proteoglycan induced arthritis.

OBJECTIVES: To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA). METHODS: MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs. RESULTS: Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA. CONCLUSIONS: MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis.

Transition of rheumatologic care, from teenager to adult: which health assessment questionnaire can be best used?

OBJECTIVES: Transition of care for adolescents includes a transfer from paediatric to adult health care. This requires a transfer of specific measurements, which evaluate disease profiles such as functional ability. One of the most common measurements is the Health Assessment Questionnaire (HAQ). METHODS: Results of the Childhood HAQ (CHAQ) and HAQ were compared among adolescents diagnosed with rheumatic diseases involving the musculoskeletal system. All adolescents had recently dealt with or would in the near future be dealing with transition. RESULTS: Overall results of both questionnaires were comparable; intra-class correlation for consistency (ICC) was 0.95 (95% confidence interval 0.93-0.97). For a smooth transfer from CHAQ to HAQ, both correlation and agreement are required. Agreement between both questionnaires was not found. Described by limits of agreement, results of HAQ can differ from CHAQ as much as 0.95. CONCLUSIONS: Despite strong correlations for consistency, lack of agreement was found in the results of CHAQ and HAQ. If correlation persists over time, this study suggests evaluating both the childhood and adult version of the HAQ during the transition period. When transfer into adulthood is completed, comparison to earlier tests at younger age is available and reliable.

Current educational status of paediatric rheumatology in Europe: the results of PReS survey.

OBJECTIVES: To understand the status of education and problems in paediatric rheumatology practice in Europe, through a survey. METHODS: A 26-item questionnaire was conducted during the 14th Congress of the Paediatric Rheumatology European Society in Istanbul, 2007. Physicians who were practicing or studying within the field of paediatric rheumatology for at least one year were included in the survey. RESULTS: One hundred and twenty eight physicians, 79 paediatric rheumatologists (including 5 paediatric immunologists and 10 paediatric nephrologists), 34 paediatric rheumatology fellows and 15 adult rheumatologists completed the survey. The physicians were from: Europe 95 (81.9%), South America 12 (10.4%), Middle East 5 (4.3%), Asia 2 (1.7%), Africa 2 (1.7%). The duration of training for paediatric rheumatology ranged between 1-5 years (mean: 3.12+/-1.11). Sixty physicians scored their education as unsatisfactory and among those, 48 physicians were from Europe. Physicians reported good skills in the following items; intraarticular injections (83.3%); soft tissue injections (47.6%); evaluation of radiographs (67.5%); whereas competence in the evaluation of computed tomography/magnetic resonance imaging (30.5%); and musculoskeletal sonography (16.7%) was much lower. A need for improved basic science and rotations among relevant fields were specifically expressed. CONCLUSION: Being a relatively new speciality in the realm of paediatrics, paediatric rheumatology education at the European level needs to be further discussed, revised and uniformed.

Exercise therapy in juvenile idiopathic arthritis: a Cochrane Review.

BACKGROUND: Exercise therapy is considered an important component of the treatment of arthritis. The efficacy of exercise therapy has been reviewed in adults with rheumatoid arthritis but not in children with juvenile idiopathic arthritis (JIA). OBJECTIVES: To assess the effects of exercise therapy on functional ability, quality of life and aerobic capacity in children with JIA. METHODS: Several electronic databases were searched up to October 2007 and references were tracked. The selection criteria were randomized controlled trials (RCTs) of exercise treatment in JIA. As for data collection and analysis, potentially relevant references were evaluated and all data were extracted by two review authors working independently. RESULTS: Three out of 16 identified studies met the inclusion criteria, with a total of 212 participants. All the included studies fulfilled at least seven of 10 methodological criteria. The outcome data of the following measures were homogenous and were pooled in a meta-analysis: functional ability (N=198; weighted mean difference [WMD] -0.07, 95% CI -0.22 to 0.08), quality of life (CHQ-PhS: N=115; WMD -3.96, 95% CI -8.91 to 1.00) and aerobic capacity (N=124; WMD 0.04, 95% CI -0.11 to 0.19). The results suggest that the outcome measures all favoured the exercise therapy but none were statistically significant. None of the studies reported negative effects of the exercise therapy. CONCLUSIONS: Overall, based on ''silver-level'' evidence there was no clinically important or statistically significant evidence that exercise therapy can improve functional ability, quality of life, aerobic capacity or pain. The included and excluded studies were all consistent about the adverse effects of exercise therapy; no short-term detrimental effects of exercise therapy were found in any study. Both included and excluded studies showed that exercise does not exacerbate arthritis. Although the short-term effects look promising, the long-term effect of exercise therapy remains unclear.

Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis.

OBJECTIVE: Osteopenia is a common complication of juvenile idiopathic arthritis (JIA). In adults, low bone density and increased fracture risk are associated with low vitamin K status of bone. The vitamin K-dependent protein osteocalcin plays an important role in bone metabolism. Its activity depends upon post-translational carboxylation in which vitamin K is an essential co-factor. Hence, vitamin K deficiency leads to under-carboxylated (i.e., inactive) osteocalcin (ucOC). Little is known about the vitamin K status and bone health in children with juvenile idiopathic arthritis (JIA). We studied the vitamin K status of bone and its association with bone mass properties in children with JIA compared to healthy children. METHODS: We performed a cross sectional study in 55 children with JIA and 54 healthy controls between 6-18 years of age. Bone markers, ultrasound bone mass properties and vitamin K status of bone were determined. RESULTS: Overall, no differences in vitamin K status of bone were found between the study groups. Among children with JIA, a high ratio of ucOC/cOC indicating low vitamin K status was associated with low bone ultrasound parameters, whereas children with a high vitamin K status had markedly higher bone properties. This association was independent of physical activity, age, gender and BMI. CONCLUSION: These results suggest that vitamin K may be one of multiple risk factors for low bone mass in children with JIA, in addition to other recognized determinants of bone mass. The question remains whether JIA patients would benefit from increased dietary vitamin K intake.

Exercise therapy in juvenile idiopathic arthritis.

BACKGROUND: Exercise therapy is considered an important component of the treatment of arthritis. The efficacy of exercise therapy has been reviewed in adults with rheumatoid arthritis but not in children with juvenile idiopathic arthritis (JIA). OBJECTIVES: To assess the effects of exercise therapy on functional ability, quality of life and aerobic capacity in children with JIA. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (The Cochrane Library), MEDLINE (January 1966 to April 2007), CINAHL (January 1982 to April 2007), EMBASE (January 1966 to October 2007), PEDro (January 1966 to October 2007), SportDiscus (January 1966 to October 2007), Google Scholar (to October 2007), AMED (Allied and Alternative Medicine) (January 1985 to October 2007), Health Technologies Assessment database (January 1988 to October 2007), ISI Web Science Index to Scientific and Technical Proceedings (January 1966 to October 2007) and the Chartered Society of Physiotherapy website (http://www.cps.uk.org) were searched and references tracked. SELECTION CRITERIA: Randomised controlled trials (RCTs) of exercise treatment in JIA. DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data were extracted by two review authors working independently. MAIN RESULTS: Three out of 16 identified studies met the inclusion criteria, with a total of 212 participants. All the included studies fulfilled at least seven of 10 methodological criteria. The outcome data of the following measures were homogenous and were pooled in a meta-analysis: functional ability (n = 198; WMD -0.07, 95% CI -0.22 to 0.08), quality of life (CHQ-PhS: n = 115; WMD -3.96, 95% CI -8.91 to 1.00) and aerobic capacity (n = 124; WMD 0.04, 95% CI -0.11 to 0.19). The results suggest that the outcome measures all favoured the exercise therapy but none were statistically significant. None of the studies reported negative effects of the exercise therapy. AUTHORS' CONCLUSIONS: Overall, based on 'silver-level' evidence (www.cochranemsk.org) there was no clinically important or statistically significant evidence that exercise therapy can improve functional ability, quality of life, aerobic capacity or pain. The low number of available RCTs limits the generalisability. The included and excluded studies were all consistent about the adverse effects of exercise therapy; no short-term detrimental effects of exercise therapy were found in any study. Both included and excluded studies showed that exercise does not exacerbate arthritis. The large heterogeneity in outcome measures, as seen in this review, emphasises the need for a standardised assessment or a core set of functional and physical outcome measurements suited for health research to generate evidence about the possible benefits of exercise therapy for patients with JIA. Although the short-term effects look promising, the long-term effect of exercise therapy remains unclear.

Calcinosis in juvenile dermatomyositis: a possible role for the vitamin K-dependent protein matrix Gla protein.

OBJECTIVES: The aims of the present study were to investigate whether the calcification inhibitor matrix Gla protein (MGP) is expressed in muscle biopsies of patients with juvenile dermatomyositis (JDM), and whether different forms of MGP are differentially expressed in JDM patients with and without subcutaneous calcifications. METHODS: Muscle tissue from six JDM patients (three without calcinosis, two with calcinosis and one recently diagnosed patient), four patients with muscular dystrophy, three patients with IBM and five normal histological control subjects was used for immunohistochemistry staining using novel antibodies to different conformations of MGP. RESULTS: In the JDM patients, all forms of MGP [non-carboxylated MGP (ucMGP), carboxylated MGP (cMGP), non-phosphorylated MGP (serMGP) and phosphorylated MGP (pserMGP)] were more intensely stained in the perifascicular compared with the central muscle fibres. In addition, these MGP species were demonstrated in the pathological muscle fibres of IBM and dystrophy patients, but hardly in normal histological muscle tissue. In JDM patients with calcifications, only pserMGP was increased compared with those without calcifications. All forms of MGP were also found in various staining intensities in the microvasculature and macrophages of normal histological and disease biopsies. CONCLUSIONS: MGP was expressed at the site of muscle damage in JDM patients as well as in patients with muscular dystrophy and IBM. The difference in staining intensity of pserMGP appeared to distinguish between JDM patients with and without calcifications, whereas cMGP, the other functional form, was equally expressed.

Current perspectives of autologous stem cell transplantation for severe Juvenile Idiopathic Arthritis.

The majority of children with Juvenile Idiopathic Arthritis can nowadays be treated adequately. However despite the use of combinations of antirheumatic drugs, corticosteroids and the newer so called biologicals (blocking the TNF, Interleukin 1 or Interleukin 6 pathways) a proportion of children with arthritis remain resistant also to these therapies and suffer from a very severe, debilitating and potentially fatal disease. For such children autologous stem cell transplantation (ASCT) is successfully performed since 1997. Here we describe the long term outcome of the initial cohort of children with resistant Juvenile Idiopathic arthritis, treated with ASCT. The initial cohort of children was treated with a conditioning regimen containing Cyclophosphamide, anti thymocyte globulins and low dose Total Body irradiation. Overall favourable responses were seen, with a drug free remission rate of 50-55 %. In the more recent years late relapses were noted with lower percentages for drug free long term outcome. Special emphasis is given on 2 cases showing very late relapses, occurring after 7 and 9 years. The observed relapses are often less severe compared to the situation before SCT and can be treated successfully with conventional drugs in the majority of cases. More recently, ASCT was performed in 4 JIA children with a fludarabin containing regimen in stead of low dose TBI. With a 4 to 5 year follow up, these 4 patients are all in drug free full remission. Allogeneic transplant with an HLA matched family donor was reported in 2 JIA cases. Follow up of 1 and 3 year is sofar show clinical disease remission and tapering of medition. In conclusion, given the favourable long term outcome, SCT remains a valuable treatment option for children with drug resistant JIA.

Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study.

BACKGROUND: The increase in the prevalence of allergic diseases in countries with a so-called western lifestyle may be due to a decrease in exposure to infectious agents in early life. OBJECTIVE: To establish the effect of Bacille-Calmette-Guerin (BCG) vaccination in 6-week-old high-risk infants in a prospective single-blind, randomized, placebo-controlled trial on the prevalence of allergic disease at the age of 4 and 18 months. METHODS: Subjects were 121 predominantly Caucasian high-risk newborns, having either a mother, or both a father and at least one sibling with past or present allergic disease. BCG or placebo was administered at the age of 6 weeks, and repeated once when both a post-vaccination scar and a positive TB skin test were absent at the age of 4 months. RESULTS: At the age of 18 months, the prevalence of allergic disease was not significantly different between the two groups. A trend towards less eczema (P=0.07) and significantly less use of medication for eczema was shown in the BCG group compared with the placebo group (P=0.04). CONCLUSION: A single (or once repeated) BCG vaccination in 6-week-old high-risk Caucasian infants was not associated with a 50% reduction in the prevalence of allergic disease. However, there could be a smaller beneficial effect of BCG, especially because a trend towards less eczema and significantly less use of medication for eczema was shown. For definite proof, a larger study should be carried out.

Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial.

OBJECTIVE: To assess the safety and efficacy of intensive immunosuppression followed by T cell-depleted autologous hematopoietic stem cell transplantation (ASCT) for induction of disease remission in children with refractory progressive juvenile idiopathic arthritis (JIA). METHODS: Twenty-two patients with progressive refractory JIA were followed up over a median period of 80 months after pretreatment with intensive immunosuppression followed by ASCT in a multicenter, prospective, phase II clinical trial. Hematopoietic stem cells were harvested from the patients' bone marrow, depleted of T cells, and kept frozen until used for ASCT. Pretreatment of patients consisted of a combination of antithymocyte globulin, cyclophosphamide, and low-dose total body irradiation. Patients were followed up for ASCT-related complications, recovery of hematologic and immune system parameters, and disease outcomes. RESULTS: Reconstitution of hematologic values to normal range was rapid. Recovery of immune system parameters, especially normalization of CD4+, CD45RA+ naive T cells, was delayed, occurring at >/=6 months after ASCT. The prolonged period of immune deficiency resulted in a large number of viral infections and may have contributed to the development of macrophage activation syndrome (MAS), leading to death, in 2 patients. After ASCT, 8 of the 20 evaluable patients reached complete clinical remission of their JIA, 7 were partial responders, and 5 experienced a relapse of their disease (occurring 7 years after ASCT in 1 patient). Later during followup, 2 of the patients whose disease relapsed died from infections that developed after restarting immunosuppressive medication. CONCLUSION: Intensive immunosuppression followed by ASCT resulted in sustained complete remission or marked improvement in 15 of 22 patients with progressive refractory JIA. The procedure, however, is associated with significant morbidity and risk of mortality due to prolonged and severe depression of T cell immunity. After fatal complications due to MAS were observed in some patients, the protocol was amended in 1999, to ensure less profound depletion of T cells, better control of systemic disease before transplantation, antiviral prophylaxis after transplantation, and slow tapering of corticosteroids. Following these protocol modifications, no additional ASCT-related deaths were observed among the 11 patients who received the modified treatment.

[The basic biomedical subjects are of undiminished importance in the training of medical doctors]. / De biomedische basisvakken zijn onverminderd van belang voor de artsopleiding.

The contemporary physician is not merely a professional who is trained in the recognition of clinical syndromes and the application of evidence-based medicine. A good understanding of the basic biomedical sciences is necessary to comprehend what is wrong with a patient and what form of treatment is the most appropriate, especially if a disease manifests itself in an unfamiliar way.

Comparison of behavior modification with and without swaddling as interventions for excessive crying.

OBJECTIVE: To test the hypothesis that swaddling is an effective method to reduce crying, we compared a standardized approach of regularity and stimulus reduction with the same approach supplemented with swaddling. STUDY DESIGN: Healthcare nurses coached 398 excessively crying infants up to 12 weeks of age for 3 months. Outcome measurements were crying as measured by Barr's 24-hour diary and parental perception of crying. RESULTS: Crying decreased by 42% in both groups after the first intervention week. Swaddling had no added benefit in the total group. Young infants (1-7 weeks of age at randomization) benefited significantly more from swaddling as shown by a larger decrease of crying over the total intervention period. Older infants (8-13 weeks of age at randomization) showed a significantly greater decrease in crying when offered the standardized approach without swaddling. The actual difference in crying time was 10 minutes. CONCLUSION: For older babies, swaddling did not bring any benefit when added to regularity and stimuli reduction in baby care, although swaddling was a beneficial supplementation in excessively crying infants <8 weeks of age.

How fatigue is related to other somatic symptoms.

AIMS: To assess the relation between fatigue and somatic symptoms in healthy adolescents and adolescents with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). METHODS: Seventy two adolescents with CFS were compared within a cross-sectional study design with 167 healthy controls. Fatigue and somatic complaints were measured using self-report questionnaires, respectively the subscale subjective fatigue of the Checklist Individual Strength (CIS-20) and the Children's Somatization Inventory. RESULTS: Healthy adolescents reported the same somatic symptoms as adolescents with CFS/ME, but with a lower score of severity. The top 10 somatic complaints were the same: low energy, headache, heaviness in arms/legs, dizziness, sore muscles, hot/cold spells, weakness in body parts, pain in joints, nausea/upset stomach, back pain. There was a clear positive relation between log somatic symptoms and fatigue (linear regression coefficient: 0.041 points log somatic complaints per score point fatigue, 95% CI 0.033 to 0.049) which did not depend on disease status. CONCLUSIONS: Results suggest a continuum with a gradual transition from fatigue with associated symptoms in healthy adolescents to the symptom complex of CFS/ME.

Chronic fatigue syndrome and health control in adolescents and parents.

AIMS: To explore the locus of health control in adolescents with chronic fatigue syndrome (CFS) and their parents in comparison with healthy adolescents and their parents. METHODS: In this cross-sectional study 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was applied to all participants. RESULTS: There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS (OR = 0.39, 95% CI 0.25 to 0.61). Internal health control of the parents was also protective (OR fathers: 0.57 (95% CI 0.38 to 0.87); OR mothers: 0.74 (95% CI 0.50 to 1.09)). The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13. CONCLUSIONS: In comparison with healthy adolescents, adolescents with CFS and their parents show less internal health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies such as cognitive behaviour therapy, for which health behaviour is the main focus.

Is chronic fatigue syndrome a connective tissue disorder? A cross-sectional study in adolescents.

OBJECTIVES: To investigate whether constitutional laxity of the connective tissues is more frequently present in adolescents with chronic fatigue syndrome (CFS) than in healthy controls. Increased joint hypermobility in patients with CFS has been previously described, as has lower blood pressure in fatigued individuals, which raises the question of whether constitutional laxity is a possible biological predisposing factor for CFS. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-two adolescents with CFS (according to the criteria of the Centers for Disease Control and Prevention) referred to a tertiary hospital and 167 healthy controls. METHODS: The 32 adolescents with CFS were examined extensively regarding collagen-related parameters: joint mobility, blood pressure, arterial stiffness and arterial wall thickness, skin extensibility, and degradation products of collagen metabolism. Possible confounding factors (age, gender, height, weight, physical activity, muscle strength, diet, alcohol consumption, and cigarette smoking) were also measured. The results were compared with findings in 167 healthy adolescents who underwent the same examinations. RESULTS: Joint mobility, Beighton score, and collagen biochemistry, all indicators of connective tissue abnormality, were equal for both groups. Systolic blood pressure, however, was remarkably lower in patients with CFS (117.3 vs. 129.7 mm Hg; adjusted difference: -13.5 mm Hg; 95% confidence interval [CI]: -19.1, -7.0). Skin extensibility was higher in adolescents with CFS (mean z score: 0.5 vs. 0.1 SD; adjusted difference: 0.3 SD; 95% CI: 0.1, 0.5). Arterial stiffness, expressed as common carotid distension, was lower in adolescents with CFS, indicating stiffer arteries (670 vs 820 mum; adjusted difference: -110 mum; 95% CI: -220, -10). All analyses were adjusted for age, gender, body mass index, and physical activity. Additionally, arterial stiffness was adjusted for lumen diameter and pulse pressure. CONCLUSIONS: These findings do not consistently point in the same direction of an abnormality in connective tissue. Patients with CFS did have lower blood pressure and more extensible skin but lacked the most important parameter indicating constitutional laxity, ie, joint hypermobility. Moreover, the collagen metabolism measured by crosslinks and hydroxyproline in urine, mainly reflecting bone resorption, was not different. The unexpected finding of stiffer arteries in patients with CFS warrants additional investigation.

Flow cytometric determination of FcgammaRIIa (CD32) polymorphism.

A guanine to adenine point mutation results in an arginine (R) to histidine (H) substitution in FcgammaRIIa at residue 131 that strongly impacts receptor function. This FcgammaRIIa polymorphism is mostly typed by allele-specific polymerase chain reactions (PCR) or in functional assays, dependent on ligand binding. Both types of methods are laborious, time consuming, and not readily available in routine laboratories. We generated a panel of human antibodies against FcgammaRII, and one of them, MDE-9, selectively recognized the FcgammaRIIa-H131 allotype. MDE-9 was applicable to detect FcgammaRIIa-H131 in both flow cytometry and immunohistochemistry. MDE-9 was used to develop an FcgammaRIIa allotyping method based on flow cytometry. In a "single-tube assay", FITC-labeled MDE-9 (specific for FcgammaRIIa-H131) and Cy3-labeled mAb 41H16 (specific for FcgammaRIIa-R131) were added to 50 mul samples of whole blood. The results of flow cytometric FcgammaRIIa allotyping correlated completely with PCR genotyping. This novel allotyping assay should facilitate the screening of patients in a routine diagnostic setting. In addition, a combination of MDE-9 and 41H16 can be used in FcgammaRIIa-H/H131 homozygous individuals to detect FcgammaRIIa and FcgammaRIIb surface expression on monocytes. This is an important application of these antibodies because, to this day, no antibodies were available to specifically study the surface expression of FcgammaRIIb.

Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity.

OBJECTIVE: To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA). DESIGN: Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation. RESULTS: Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%). CONCLUSIONS: ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.

Safety of anti-TNFalpha therapy in children with juvenile idiopathic arthritis.

Anti-TNFalpha agents are frequently used in the treatment of severe JIA. Etanercept, a fully human soluble recombinant tumour necrosis factor p75 receptor Fc fusion protein, has been registered for the treatment of polyarticular course JIA patients who fail to respond to or do not tolerate methotrexate (MTX). Infliximab, a chimeric human-mouse monoclonal antibody to TNFalpha, is expected to be registered soon for JIA and Crohn's disease (CD) in children. As in adults, both agents are effective in controlling inflammation and inhibiting the progression of joint destruction. Despite this good clinical efficacy, the physician must remain alert for potential side effects, especially after prolonged use. This review gives an overview of the reported adverse events.