Immune ablation and stem-cell therapy in autoimmune disease: Immune ablation and stem-cell therapy in autoimmune disease - Clinical experience

In the past 5 years, around 350 patients have received haematopoietic stem cell (HSC) transplantation for an autoimmune disease, with 275 of these registered in an international data base in Basel under the auspices of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation(EBMT). Most patients had either a progressive form of multiple sclerosis (MS; n = 88) or scleroderma (now called systemic sclerosis; n = 55). Other diseases were rheumatoid arthritis (Ra n = 40), juvenile idiopathic arthritis (JIA; n = 30), systemic lupus erythematosus (SLE; n = 20), idiopathic thrombocytopenic purpura (ITP; n = 7) and others. The procedure-related mortality was around 9%, with between-disease differences, being higher in systemic sclerosis and JIA and lower in RA (one death only). Benefit has been seen in around two-thirds of cases. No one regimen was clearly superior to another, with a trend toward more infectious complications with more intense regimens. Prospective, controlled randomized trials are indicated and being planned.     

A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population

Recently, we reported that genetic polymorphisms within the human IL18 gene were associated with disease susceptibility to adult-onset Still's disease (AOSD), which is characterized by extraordinarily high serum levels of IL-18. Because high serum IL-18 induction has also been observed in the systemic type of juvenile idiopathic arthritis (JIA), we investigated whether similar genetic skewing is present in this disease. Three haplotypes, S01, S02, and S03, composed of 13 genetic polymorphisms covering two distinct promoter regions, were determined for 33 JIA patients, including 17 with systemic JIA, 10 with polyarthritis, and 6 with oligoarthritis. Haplotypes were also analyzed for 28 AOSD patients, 164 rheumatoid arthritis (RA) patients, 102 patients with collagen diseases, and 173 healthy control subjects. The frequency of individuals carrying a diplotype configuration (a combination of two haplotypes) of S01/S01 was significantly higher in the JIA patients, including all subgroups, than in the healthy controls (P = 0.0045, Fischer exact probability test; odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.55–8.14). In patients with systemic JIA, its frequency did not differ statistically from that of normal controls. Nevertheless, it is possible that haplotype S01 is associated with the phenotype of high IL-18 production in systemic JIA because the patients carrying S01/S01 showed significantly higher serum IL-18 levels compared with patients with other diplotype configurations (P = 0.017, Mann-Whitney U test). We confirmed that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects (P = 0.011, OR = 3.45, 95% CI = 1.42–8.36). Furthermore, the RA patients were also more predisposed to have S01/S01 (P = 0.018, OR = 2.00, 95% CI = 1.14–3.50) than the healthy control subjects, whereas the patients with collagen diseases did not. In summary, the diplotype configuration of S01/S01 was associated with susceptibility to JIA as well as AOSD and RA, and linked to significantly higher IL-18 production in systemic JIA. Possession of the diplotype configuration of S01/S01 would be one of the genetic risk factors for susceptibility to arthritis in the Japanese population.     

TNF promoter ?308 A/G and ?238 A/G polymorphisms and juvenile idiopathic arthritis: a meta-analysis

The aim of this study was to determine whether the tumor necrosis factor (TNF) promoter polymorphisms confer susceptibility to juvenile idiopathic arthritis (JIA). A meta-analysis was conducted on the A allele of the TNF -308 A/G and -238 A/G polymorphisms. The nine comparison studies including 1,132 JIA patients and 1,663 controls were included in the meta-analysis and consisted of 7 European, 1 Mexican, and 1 Turkish population. No association was found between JIA and the TNF -308 A allele and the TNF -238 A allele (odds ratio [OR] = 1.211, 95 % confidence interval [CI] = 0.917-1.598, P = 0.177; OR = 1.135, 95 % CI = 0.603-1.861, P = 0.615, respectively). Stratification by ethnicity did not show the association of the TNF -308 and -238 polymorphisms with JIA in Europeans. Mexicans were found to have lower prevalences of A alleles (2.9, 4.1 %) of the TNF -308 A/G and -238 A/G polymorphisms than any other population studied, and the Turkish population the highest (31.2, 26.9 %). This meta-analysis shows no association between the A alleles of the TNF -308 A/G or -238 A/G polymorphisms and JIA in Europeans, but that the prevalences of these alleles are ethnicity dependent.     

Genetic epidemiology: Juvenile idiopathic arthritis genetics - What's new? What's next?

Studies have established the magnitude of the genetic basis of juvenile idiopathic arthritis (JIA). JIA is a complex genetic condition and the genes that influence susceptibility are actively being sought. A candidate gene approach is being used by several groups. MHC-, cytokine- and T-cell-related genes have all been positively associated with JIA. Here we review some of the latest genetic data, and discuss ways in which JIA genetic research might proceed.     

Juvenile idiopathic arthritis genetics - what's new? What's next?

Studies have established the magnitude of the genetic basis of juvenile idiopathic arthritis (JIA). JIA is a complex genetic condition and the genes that influence susceptibility are actively being sought. A candidate gene approach is being used by several groups. MHC-, cytokine- and T-cell-related genes have all been positively associated with JIA. Here we review some of the latest genetic data, and discuss ways in which JIA genetic research might proceed.     

Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index > or =2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-gamma (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.     

Circulating and synovial antibody profiling of juvenile arthritis patients by nucleic acid programmable protein arrays

Introduction

Juvenile idiopathic arthritis (JIA) is a heterogeneous disease characterized by chronic joint inflammation of unknown cause in children. JIA is an autoimmune disease and small numbers of autoantibodies have been reported in JIA patients. The identification of antibody markers could improve the existing clinical management of patients.

Methods

A pilot study was performed on the application of a high-throughput platform, the nucleic acid programmable protein array (NAPPA), to assess the levels of antibodies present in the systemic circulation and synovial joint of a small cohort of juvenile arthritis patients. Plasma and synovial fluid from 10 JIA patients was screened for antibodies against 768 proteins on NAPPAs.

Results

Quantitative reproducibility of NAPPAs was demonstrated with > 0.95 intra-array and inter-array correlations. A strong correlation was also observed for the levels of antibodies between plasma and synovial fluid across the study cohort (r = 0.96). Differences in the levels of 18 antibodies were revealed between sample types across all patients. Patients were segregated into two clinical subtypes with distinct antibody signatures by unsupervised hierarchical cluster analysis.

Conclusion

The NAPPAs provide a high-throughput quantitatively reproducible platform to screen for disease-specific autoantibodies at the proteome level on a microscope slide. The strong correlation between the circulating antibody levels and those of the inflamed joint represents a novel finding and provides confidence to use plasma for discovery of autoantibodies in JIA, thus circumventing the challenges associated with joint aspiration. We expect that autoantibody profiling of JIA patients on NAPPAs could yield antibody markers that can act as criteria to stratify patients, predict outcomes and understand disease etiology at the molecular level.     

Juvenile Idiopathic Arthritis-Associated Uveitis: A Nationwide Population-Based Study in Taiwan

Objective

The incidence and prevalence of juvenile idiopathic arthritis (JIA) vary widely across the world but data in East Asia is lacking. Uveitis is a serious cause of morbidity in JIA. This study aimed to analyze the incidence and prevalence of JIA, and the characteristics of JIA-associated uveitis in Taiwan.

Methods

A population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. Each patient was individually tracked from 1999 to 2009 to identify the diagnosis of JIA and uveitis using the International Classification of Diseases diagnostic codes. Multivariate logistic regression was used to determine the risk factors and complications of uveitis in patients with JIA.

Results

The study cohort had 2636 cases of JIA and included juvenile rheumatoid arthritis (57.7%), enthesitis-related arthritis (ERA) (39.2%), and psoriatic arthritis (3.1%). The average annual incidence of JIA and JIA-associated uveitis were 4.93 (range, 3.93–6.23) and 0.25 (range, 0.12–0.37) cases per 100,000 population, respectively. The average period prevalence of JIA was 33.8 cases per 100,000 population. Uveitis occurred in 4.7% of patients with JIA, while JIA-associated uveitis was complicated by cataract (11.2%) and glaucoma (24.8%). Enthesitis-related arthritis was significantly associated with uveitis (OR: 3.47; 95% CI: 2.24–5.37) (p<0.0001). Uveitis diagnosed before JIA was the most significant risk factor for complications of glaucoma or cataract (OR: 3.54; 95% CI: 1.44–8.72) (p = 0.006).

Conclusions

The incidence of JIA is low but that of JIA-associated uveitis is increasing. Higher percentage of males in patients with ERA and the strong association between ERA and uveitis are unique for children with JIA in Taiwan. Uveitis diagnosed before arthritis is an important risk factor for complications. Continuous ophthalmologic follow-up is needed for children with JIA or uveitis of unknown etiology.     

Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium

Abstract

Juvenile idiopathic arthritis (JIA) is the most common form of chronic rheumatic disease affecting children worldwide, with some features similar to adult rheumatoid arthritis (RA). In the present study, we aim at investigating novel markers that will allow in the future for tailored, more personalized treatment strategies. Hence, taking notice of several reports proving the role of local acidosis as a causal link between inflammatory diseases and related pain, and the involvement of several carbonic anhydrases (CA, EC 4.2.1.1) isoforms in articular diseases, we evaluated in JIA patients the expression of these metalloenzymes. We identified that JIA patients show high levels of active CA IX and XII isoforms. Our results represent the first evidence of the identification of these enzymes as potential therapeutic targets and development of novel innovative therapies for arthritis, also considering that the two isoforms are validated antitumor targets.     

Novel IL10 gene family associations with systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP) in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031) and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082 genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important role for these cytokines in sJIA pathogenesis.     

Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC) genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan) and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in disease pathogenesis in further detail.     

Identification of dendritic cells in the blood and synovial fluid of children with Juvenile Idiopathic Arthritis

Childhood chronic arthritis of unknown etiology is known collectively as juvenile idiopathic arthritis (JIA) and consists of heterogeneous subtypes with unique clinical patterns of disease. JIA is the commonest rheumatic disease in children and may still result in significant disability, with joint deformity, growth impairment, and persistence of active arthritis into adulthood. Basic research is rather focused on rheumatoid arthritis, and this lead to small number of publications considering JIA. In this study we examine, by flow cytometry, the expression of dendritic cells (DCs) in the peripheral blood and synovial fluid of children with active JIA in a group of 220 patients. We reveal a significant decrease in the percentage of immature DCs in the blood of patients compared to control children. Surprisingly, we found higher percentages of mature circulating dendritic cells. Both populations of DCs, immature and mature, were accumulated in patients' synovial fluid. We also confirmed the presence of CD206+/CD209+ in JIA samples, which can represent a population of macrophages with dendritic cells morphology. Our results support the thesis that dendritic cells are crucial in the induction and maintenance of autoimmune response and local inflammation during juvenile idiopathic arthritis.     

Comparing the feasibility, acceptability, clinical-, and cost-effectiveness of mental health e-screening to paper-based screening on the detection of depression, anxiety, and psychosocial risk in pregnant women: a study protocol of a randomized, parallel-group, superiority trial

Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.

Methods/design

This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients <30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.

Discussion

This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.

Trial registration

ISRCTN10065623     

Treatment of growth failure in juvenile chronic arthritis

We retrospectively assessed linear growth and final height in a group of 24 patients suffering from juvenile idiopathic arthritis (JIA) during childhood, receiving steroid therapy. In these patients, a significant loss of height (-2.7 +/- 1.5 SDS) occurred in the first years of the disease which was positively correlated with prednisone therapy duration. After remission of the disease and prednisone discontinuation, most of the patients (70%) had catch-up growth but 30% had a persistent loss of height. Their mean final height was strongly correlated with their mean height at the end of steroid therapy and was significantly different between the group of patients with catch-up growth (-1.5 +/- 1.6 SDS) and the group without catch-up growth (-3.6 +/- 1.2 SDS). This pattern of growth observed in JIA patients should help us to define strategies of GH treatment in these patients in order to improve their final height. We have previously reported the beneficial effects on growth and body composition of a 1-year GH treatment in a group of 14 growth-retarded patients suffering from juvenile idiopathic arthritis, receiving glucocorticoid therapy. These patients (n = 13) were treated again with GH at the same dosage (0.46 mg/kg/week) for another 3-year period. GH treatment markedly increased growth velocity in these patients, but had a minor effect on SDS height suggesting that these children will remain short at adult age. Using GH earlier in these patients during the course of their disease may prevent growth deterioration and metabolic complications induced by chronic inflammation and long-term steroid therapy.     

Lymphocyte transformation to connective tissue antigens in adult and juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and a nonarthritic control population

Transformation of peripheral blood lymphocytes after exposure to connective tissue antigens was measured in patients with adult (n = 35) and juvenile rheumatoid arthritis (n = 34), osteoarthritis (n = 21), ankylosing spondylitis (n = 15), and systemic lupus erythematosus (n = 26) and in control subjects (n = 36). The connective tissue antigens included homologous cartilage-type proteoglycan, cyanogen bromide-derived peptides of type I, II, and III collagens, and type I and II helical collagens. Lymphocyte transformation was not detected in the osteoarthritic and control groups, with one exception. Sensitization to at least one connective tissue antigen was detected in approximately one-third of the rheumatoid arthritic and lupus patients and in one-quarter of the juvenile rheumatoid patients. In ankylosing spondylitis, positive responses occurred to proteoglycan in 20% of patients tested but never to collagens or peptides. Sensitivity to proteoglycan was detected only in ankylosing spondylitis except for one patient with juvenile rheumatoid arthritis. In patients with systemic lupus erythematosus and both forms of rheumatoid arthritis, lymphocyte transformation was usually more frequently detected to peptides than to the helical collagens. In adult rheumatoid arthritis, type II peptides elicited an elevated number of responses (14%) as did type I (9%) and III (8%) peptides to lesser degrees. Responses to type I (4%) and II (4%) helical collagens were infrequent. Rheumatoid arthritic patients usually exhibited sensitivity to only one antigen and lymphocyte transformation was often detected when the arthritis was improving. In juvenile rheumatoid arthritis, lymphocyte transformation was detected to peptides of type I (16%), II (9%), and III (29%) collagens and to helical type I (12%) and II (8%) collagens. In systemic lupus erythematosus, sensitization was detected to peptides of type I (13%), II (20%), and III (14%) collagens and to helical type I collagen (18%) but not type II collagen. Simultaneous sensitivity to several antigens often occurred in both systemic lupus erythematosus and juvenile rheumatoid arthritis. Examination of individual patients in all three rheumatic disease groups revealed that immune sensitivity developed to collagen peptides rather than to the helical molecules, particularly in the case of type II collagen. Thus, some patients with inflammatory arthritis exhibit immune responses to connective tissue components which are, as a group, characteristic for each type of arthritis. These responses, which were not obviously associated with disease activity, may develop as a result of inflammation or trauma which destroys connective tissue and exposes molecules, in either a native or degraded state, to cells of the immune system. Expression of sensitivity to these tissue antigens may contribute to the chronicity of the inflammatory arthritides.     

Early onset pauciarticular arthritis is the major risk factor for naproxen-induced pseudoporphyria in juvenile idiopathic arthritis

Pseudoporphyria (PP) is characterized by skin fragility, blistering and scarring in sun-exposed skin areas without abnormalities in porphyrin metabolism. The phenylpropionic acid derivative group of nonsteroidal anti-inflammatory drugs, especially naproxen, is known to cause PP. Naproxen is currently one of the most prescribed drugs in the therapy of juvenile idiopathic arthritis (JIA). The prevalence of PP was determined in a 9-year retrospective study of children with JIA and associated diseases. In addition, we prospectively studied the incidence of PP in 196 patients (127 girls and 69 boys) with JIA and associated diseases treated with naproxen from July 2001 to March 2002. We compared these data with those from a matched control group with JIA and associated diseases not treated with naproxen in order to identify risk factors for development of PP. The incidence of PP in the group of children taking naproxen was 11.4%. PP was particularly frequent in children with the early-onset pauciarticular subtype of JIA (mean age 4.5 years). PP was associated with signs of disease activity, such as reduced haemoglobin (<11.75 g/dl), and increased leucocyte counts (>10,400/μl) and erythocyte sedimentation rate (>26 mm/hour). Comedications, especially chloroquine intake, appeared to be additional risk factors. The mean duration of naproxen therapy before the onset of PP was 18.1 months, and most children with PP developed their lesions within the first 2 years of naproxen treatment. JIA disease activity seems to be a confounding factor for PP. In particular, patients with early-onset pauciarticular JIA patients who have significant inflammation appear to be prone to developing PP upon treatment with naproxen.     

Lack of association between mannose-binding lectin gene polymorphisms and juvenile idiopathic arthritis in a Han population from the Hubei province of China

Many studies have reported that polymorphisms of the mannose-binding lectin (MBL) gene are associated with autoimmune disease. Here, we investigate the relationship between MBL gene polymorphisms and susceptibility to juvenile idiopathic arthritis (JIA) in a Han-nationality population from the Hubei province of China. PCR-restriction fragment length polymorphism was used to investigate polymorphisms of codons 54 and 57 in exon 1 of the MBL gene in 93 patients with JIA and 48 control children. Neither group showed codon 57 polymorphisms. There was no significant difference in the genotypic frequencies of codon 54 between patients with JIA and healthy controls (wild type, 71.0% versus 75.0%, respectively; heterozygous type, 25.8% versus 25.0%, respectively; and homozygous type, 3.2% versus 0.0%, respectively). In addition, no association was found between the subgroups of patients with JIA and control individuals. Our results provide no evidence for a relationship between MBL gene mutation and susceptibility to JIA.     

Restoration of the immune balance by autologous bone marrow transplantation in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is one of the most frequent autoimmune diseases in childhood and is characterized by chronic inflammation of the synovial fluid in joints. Several drugs are available for the treatment of JIA, including various biological agents that interfere with critical cytokine pathways. Though very effective in suppressing disease activity, none of these drugs can cure the disease and induce a lasting medication free remission. A small proportion of JIA patients will become or are unresponsive to any form of medical treatment. For these severely ill patients autologous bone marrow transplantation (aBMT) is a last resort treatment. aBMT is remarkably effective in suppressing disease activity, with beneficial outcome reported in around 70% of these previously refractory patients. Moreover aBMT is the only treatment that can induce a lasting medication-free-disease remission in these patients. In the very long term (after 7 years of remission) however, some disease relapses are observed, with the disease returning in a less severe form compared to prior aBMT. The exact mechanism of how aBMT is inducing this lasting disease remission is still largely unknown, but data from both animal models and humans suggest a prominent role for regulatory T cells. In this review we reviewed the current views of the cellular mechanisms that lay beneath disease induction of JIA and the disease remission caused by aBMT therapy.     

Subtype specific genetic associations for juvenile idiopathic arthritis: <Emphasis Type="Italic">ERAP1</Emphasis> with the enthesitis related arthritis subtype and <Emphasis Type="Italic">IL23R</Emphasis>with juvenile psoriatic arthritis

Introduction  

Juvenile idiopathic arthritis (JIA) is an umbrella term for all chronic childhood arthropathies and can be divided into seven subtypes. It includes the enthesitis related arthritis (ERA) subtype which displays symptoms similar to ankylosing spondylitis (AS) and juvenile-onset psoriatic arthritis which has similarities to psoriatic arthritis (PsA) and psoriasis (Ps). We, therefore, hypothesized that two well-established susceptibility loci for AS and Ps, ERAP1 and IL23R, could also confer susceptibility to these JIA subtypes.