Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab

SIR, Juvenile idiopathic arthritis (JIA), being the most commonchronic musculoskeletal disease of childhood, has a prevalenceestimated to be 1 in 1000 children [1]. Up to 10% of these remainseverely disabled in adulthood [2]. Numerous disease-modifyinganti-rheumatic drugs (DMARDs) have been trialled with varyingsuccess in JIA, and therefore additional therapeutic targetshave been investigated. Pro-inflammatory cytokines have beenimplicated in the pathogenesis of JIA especially tumour necrosisfactor- (TNF-), interleukin-1 (IL-1) and IL-6. Biological     

Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis

Objective

To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA).

Methods

Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin‐1α [IL‐1α], IL‐2, IL‐4, IL‐6, IL‐10, interferon‐α1 [IFNA1], interferon‐γ [IFNG], and interferon regulatory factor 1 [IRF‐1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom.

Results

A novel 3′–untranslated region (3′UTR) polymorphism in IRF‐1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL‐1α, IL‐2, IL‐4, IL‐6, IL‐10, IFNA1, or IFNG was observed.

Conclusion

An association between JIA and a previously unreported 3′UTR polymorphism of IRF‐1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF‐1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology.

     

Quantification of the familial contribution to juvenile idiopathic arthritis

Objective

We previously demonstrated that there is familial aggregation of juvenile idiopathic arthritis (JIA). Using a large JIA cohort, we sought to identify additional clusters of JIA cases and to calculate robust estimates of the relative risk (RR) of JIA in the siblings and cousins of JIA probands. We also estimated the population attributable risk (PAR) of familial factors in JIA.

Methods

A probabilistic record‐linking analysis was performed by matching the records of 862 patients with JIA with the records of ∼7 million individuals in the Utah Population Database (UPDB), a computerized genealogic database. For each patient, 5 control subjects matched for birth year and sex were selected from the UPDB. Specialized software was used to test for familial aggregation of disease, to estimate the magnitude of familial risks, and to identify families at high risk of disease.

Results

We identified 22 founders who had significantly more descendants with JIA than expected (5–13 descendants; P values ranged from <0.0001 to <0.008). The PAR of familial factors for JIA was ∼13%. The RR of JIA in the siblings of patients was significantly increased (11.6, 95% confidence interval [95% CI] 4.9–27.5, P < 2.59 × 10⁻⁸). The RR of JIA in first cousins was also increased (5.82, 95% CI 2.5–13.8, P < 6.07 × 10⁻⁵).

Conclusion

We have identified the largest sets of JIA pedigrees described to date. Approximately 13% of cases of JIA can be attributed to familial factors. Siblings and first cousins of probands with JIA have an increased risk of JIA. The observed decline in the magnitude of risk between siblings and cousins suggests that JIA is influenced by shared genetic factors.

     

Subtype‐specific peripheral blood gene expression profiles in recent‐onset juvenile idiopathic arthritis

Objective

To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent‐onset JIA prior to treatment with disease‐modifying antirheumatic drugs (DMARDs) or biologic agents.

Methods

Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis‐related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]–negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG‐U133 Plus 2.0).

Results

A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF‐negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF‐negative polyarthritis, and systemic JIA subtypes, up‐regulation of genes associated with interleukin‐10 (IL‐10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL‐2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up‐regulation of innate immune pathways, including IL‐6, Toll‐like receptor/IL‐1 receptor, and peroxisome proliferator–activated receptor signaling, were noted, along with down‐regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up‐regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well.

Conclusion

Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.

     

Disease control and health‐related quality of life in juvenile idiopathic arthritis

Objective

To examine variability in health‐related quality of life (HRQOL) in children with juvenile idiopathic arthritis (JIA) experiencing no or minimal clinical symptoms, and in a subgroup with polyarticular JIA treated with biologic agents for 12 months.

Methods

We defined 3 samples using a database of patients ages 2–18 years with JIA (n = 524; patient visits [PV] = 2,354): visits (PV = 2,155) with no or minimal clinical symptoms on at least 1 of 4 measures (active joint count, pain, physician global disease rating, Childhood Health Assessment Questionnaire); visits (PV = 941) with no or minimal symptoms on all 4 measures; and children (n = 31) with polyarticular JIA treated with biologic agents for 12 months. HRQOL was measured using the Pediatric Quality of Life Inventory (PedsQL) and the percentage of patients with suboptimal HRQOL was determined.

Results

In PV with a PedsQL score, suboptimal HRQOL by self‐report occurred in 362 (20.6%) PV with at least 1 indicator of minimal symptoms, and in 64 (7.9%) PV with all 4 measures indicating minimal symptoms (519 [25.7%] and 95 [10.7%], respectively, by parent report). For children with polyarticular JIA treated for 12 months with biologic agents, 7 (25.9%) patients by self‐report and 10 (35.7%) patients by parent report were in the suboptimal range of HRQOL.

Conclusion

A substantial percentage of patients with JIA who report no or mild clinical symptoms experience suboptimal HRQOL. This is also true for patients with polyarticular JIA treated with biologic agents for 12 months. Although disease activity and clinical symptoms are related to HRQOL, considerable unexplained variation in HRQOL exists. HRQOL needs to be assessed independently regardless of clinical status.

     

Delayed maculopapular, urticarial rash due to infliximab in two children with systemic onset juvenile idiopathic arthritis

Sir, The tumour necrosis factor- (TNF-) blockers (infliximaband etanercept) have been widely used for the treatment of uncontrolledrheumatoid arthritis in adults, but there is little experiencewith infliximab in children with juvenile idiopathic arthritis(JIA) [1, 2]. Here we describe adverse drug reactions in twochildren treated with infliximab for systemic onset JIA (s-JIA). Patient A (girl, 10 yr) and patient B (boy, 16 yr) were diagnosedas having s-JIA at the     

Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis

Objective

Uveitis is the most common extraarticular manifestation of juvenile idiopathic arthritis (JIA) and is associated with considerable morbidity. The aim of this study was to examine the risk factors associated with uveitis in JIA.

Methods

We conducted a chart review of 1,047 patients with JIA from a single tertiary care pediatric rheumatology center for factors associated with the development of uveitis. Special emphasis was put on the following known risk factors: oligoarthritis, antinuclear antibody (ANA) status, sex, and age at the time of onset of JIA.

Results

The risk of uveitis developing was age dependent in girls but not in boys. Among girls, the risk was maximal (47%) in those who were ANA positive and were ages 1–2 years at the time of the onset of JIA; this risk decreased to <10% in those in whom the age at onset was >7 years. Only girls had an age‐dependent and ANA‐associated increased risk of uveitis. The time interval from the diagnosis of JIA to the diagnosis of uveitis was statistically significantly longer in patients in whom the onset of JIA occurred at a younger age (P = 0.04). This effect was even more pronounced in ANA‐positive patients (P = 0.004). The JIA subtype did not influence a patient's risk of the development of uveitis.

Conclusion

An age‐associated risk of uveitis was observed only in girls who were younger than 7 years of age at the time of the onset of JIA. The duration of time between the diagnosis of JIA and the onset of uveitis was longer in patients in whom JIA was diagnosed at a younger age, especially in those who were ANA positive. We suggest that our findings have implications for uveitis screening in patients with JIA.

     

Wnt‐1–inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis

Objective

To determine whether Wnt‐1–inducible signaling pathway protein 3 (WISP3) polymorphisms are associated with susceptibility to juvenile idiopathic arthritis (JIA).

Methods

The exons and the intron/exon boundaries of the WISP3 gene were mutation‐screened by denaturing high‐performance liquid chromatography in 86 patients with polyarticular‐course JIA (≥5 joints affected) and 15 controls. Seven single‐nucleotide polymorphisms (SNPs) were genotyped, using allelic discrimination, in a case–control study. Initially, 159 patients with polyarticular‐course JIA and 263 controls were studied, followed by study of a replication cohort of 181 patients with polyarticular‐course JIA and 355 controls. Available parents of patients with polyarticular‐course JIA were also genotyped. Finally, other JIA subgroups were studied (initial cohort, n = 218; replication cohort, n = 213). Single‐point and haplotype analysis was carried out.

Results

Positive association with SNP WISP3*G84A was observed and replicated in 2 cohorts of patients with polyarticular‐course JIA. Specifically, homozygosity of the mutant allele (WISP3*84AA) conferred a 2‐fold increased risk of disease susceptibility (for the initial cohort, odds ratio [OR] 2.1, 95% confidence interval [95% CI] 1.1–4.2, P = 0.03; for the replication cohort, OR 2.0, 95% CI 1.0–4.3, P = 0.05). Strong linkage disequilibrium was observed between SNPs; however, no haplotypic effect of an order of magnitude greater than the single‐point WISP3*G84A association was observed. Using the transmission disequilibrium test, a trend toward overtransmission of the WISP3*84A allele was observed in patients with polyarticular‐course JIA. No association of any WISP3 polymorphism was observed in the other JIA subgroups.

Conclusion

Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular‐course JIA. The functional significance of the WISP3*G84A SNP is being determined.

     

Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis

Objective

Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA.

Methods

A case–control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped.

Results

In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55–0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61–1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62–0.93, P = 7.08 × 10⁻³). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor–negative polyarthritis [P = 0.038]).

Conclusion

Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

     

Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor–negative juvenile idiopathic arthritis in Finnish patients: Haplotype analysis in Finnish families

Objective

The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)–negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2.

Methods

A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single‐nucleotide polymorphisms: an intragenic insertion/deletion, a promoter microsatellite (NRAMP1), and a 3′ microsatellite (D2S1471).

Results

Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6‐marker, 4‐marker, and 2‐marker haplotypes. Most impressively, 1 of the 6‐marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6–6.2) in all JIA patients, 3.5 (95% CI 1.9–6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5–6.7) in those with polyarticular RF‐negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well‐characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9–9.2] versus P = 0.5, OR 1.6 [95% CI 0.4–6.0]).

Conclusion

Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.

     

Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis

Objective

IL2RA/CD25, the gene for interleukin‐2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single‐nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA).

Methods

Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66–0.88], P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63–1.0], P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65–0.99], P for trend = 0.05). Meta‐analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62–0.88], P = 4.9 × 10⁻⁵).

Conclusion

These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.

     

High-dose intravenous azathioprine pulse treatment in refractory Wegener's granulomatosis

SIR, in Wegener's granulomatosis (WG) standard therapy withcyclophosphamide (CYC) is limited by treatment-associated short-and long-term morbidity and mortality as well as insufficientresponse in about 10% of all cases [1]. Several therapeuticregimes have been used for refractory disease with varied results,including monoclonal antibodies to TNF- [2] and different surfacemarkers of T-cells (CD4, CD 52) [3] and B-cells (CD20) [4].We report two patients with WG responding     

Juvenile idiopathic arthritis and risk of cancer: A nationwide cohort study

Objective

Reports of therapy‐related adverse events suggest an elevated rate of malignancy in patients with juvenile idiopathic arthritis (JIA) treated with biologic therapies. However, the scarcity of data on the underlying risk of malignancy in JIA hampers interpretation of these signals. Therefore, the aim of this study was to determine the risk of cancer in patients with JIA as compared with that in the general population.

Methods

Through linkage with a national database, the Swedish Patient Register (comprising inpatient discharges in 1969–2007 and specialist outpatient visits in 2001–2007 in Sweden), a national JIA cohort (n = 9,027) was identified, and each JIA case was matched with 5 general population comparators. Using data from the Swedish Cancer, Census, Death, and Biologics Registers, the occurrence of cancer, vital status, and start of a biologic therapy were identified. The relative risk (RR) of first occurrence of a primary cancer in patients who had not been treated with biologics (biologics‐naive patients with JIA) was estimated using Poisson regression, stratified a priori by year of earliest identification of JIA (before 1987 versus 1987 and thereafter). In sensitivity analyses, the data were followed up to 1999, when biologics first became available.

Results

In this biologics‐naive JIA cohort, 60 malignancies were observed during 131,144 person‐years of followup, compared with 266 cancers observed during 661,758 person‐years in the general population comparator (0.46 cases/1,000 person‐years versus 0.40 cases/1,000 person‐years; RR 1.1, 95% confidence interval [95% CI] 0.9–1.5). Patients with JIA identified before 1987 were not at increased risk of cancer, whereas JIA identified in 1987 and thereafter was significantly associated with incident lymphoproliferative malignancies (RR 4.2, 95% CI 1.7–10.7) and cancers overall (RR 2.3, 95% CI 1.2–4.4). Sensitivity analyses did not reveal any ready explanation for this heterogeneity.

Conclusion

Although absolute risks were low, an elevated risk of malignancy was observed among biologics‐naive patients in whom the diagnosis of JIA was made in the past 20 years, which may have implications for the interpretation of cancer signals in patients with JIA treated with newer therapies.

     

Long‐term outcome in patients with juvenile idiopathic arthritis

Objective

To describe the long‐term outcome of juvenile idiopathic arthritis (JIA).

Methods

All patients with JIA referred to a pediatric rheumatology center between 1978 and 1988 were identified and invited to undergo an assessment. Patients with JIA from a population‐based cohort from East Berlin were included. The outcome assessment considered changes in body function and structure (e.g., mortality, joint abnormalities, disease activity), activities at the individual level (Health Assessment Questionnaire), and participation in society (e.g., mobility, educational and vocational background).

Results

Of 260 eligible patients, 215 (83%) were evaluated. Subtypes of JIA at disease onset included oligoarthritis (40%), polyarthritis (14%), systemic arthritis (14%), psoriatic arthritis (1%), enthesitis‐related arthritis (15%), and other arthritis (16%). Followup was conducted after a median of 16.5 years. No deaths occurred in this cohort. At followup, approximately half of the patients had active disease and/or changes in body structures to a variable extent. Approximately one‐third of patients rated themselves as being functionally limited. Patients demonstrated good social integration: few mobility problems were reported, and the educational achievements of patients were higher and their rate of unemployment was lower compared with the age‐matched population. No significant differences in outcome were found between the population‐based and the referral‐based cohorts.

Conclusion

Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped. Because JIA often persists into adulthood, long‐term followup and care are necessary.

     

A comparison of response criteria to evaluate therapeutic response in patients with juvenile idiopathic arthritis treated with methotrexate and/or anti–tumor necrosis factor α agents

Objective

There are no validated criteria to evaluate clinical response in juvenile idiopathic arthritis (JIA). The purpose of this study was to compare 4 sets of criteria (2 from the American College of Rheumatology [ACR] and 2 from the European League Against Rheumatism [EULAR]) for clinical response evaluation in JIA patients treated with methotrexate and/or anti–tumor necrosis factor α drugs.

Methods

Seventy‐five patients with JIA were evaluated at baseline and after 6 months of therapy with second‐line drugs. Mean age at study onset was 12.8 years (range 2–32.9 years). Diagnoses were systemic JIA (n = 16), rheumatoid factor–positive JIA (n = 5), rheumatoid factor–negative JIA (n = 9), persistent oligoarticular JIA (n = 10), extended oligoarticular JIA (n = 33), and psoriatic arthritis (n = 2). Clinical response was evaluated with the ACR Pediatric 30 criteria and the ACR 20% response criteria (ACR20), and with the EULAR Disease Activity Score (DAS) and 28‐joint DAS (DAS28). Patients with EULAR criteria responses of “good” or “moderate” were classified as responders. Responders and nonresponders according to the different criteria were then compared.

Results

For patients younger than 16 years, Cohen's kappa varied between 0.51 and 0.72, with a good‐to‐excellent reproducibility index for all comparisons, except for the DAS28/ACR20 comparison. The best agreement was obtained by comparing the DAS and the ACR Pediatric 30. For patients older than 16 years, the reproducibility index was good or excellent in only 2 cases, i.e., comparing the DAS and the ACR Pediatric 30 and comparing the DAS and the DAS28 (as expected).

Conclusion

Our study shows a good agreement overall for the different criteria tested. The highest concordance was observed between the DAS and the ACR Pediatric 30, the lowest between the DAS28 and the ACR20. Our data suggest that the ACR Pediatric 30 criteria can be used also in adult patients affected by JIA, and that the original DAS can be an alternative to the ACR Pediatric 30 in both children and young adults with JIA.

     

Chest wall stabilization and reconstruction: short and long-term results 5 years after the introduction of a new titanium plates system

Background

We report short and long-term results with the dedicated Synthes^® titanium plates system, introduced 5 years ago, for chest wall stabilization and reconstruction.

Methods

We retrospectively analyzed (January 2010 to December 2014) 27 consecutive patients (22 males, 5 females; range 16–83 years, median age 60 years), treated with this system: primary [3] and secondary [8] chest wall tumor; flail chest [5]; multiple ribs fractures [5]; sternal dehiscence-diastasis [3]; sternal fracture [1]; sternoclavicular joint dislocation [1]; Poland syndrome [1]. Short-term results were evaluated as: operating time, post-operative morbidity, mortality, hospital stay; long-term results as: survival, plates-related morbidity, spirometric values, chest pain [measured with Verbal Rating Scale (VRS) and SF12 standard V1 questionnaire].

Results

Each patient received from 1 to 10 (median 2) titanium plates/splints; median operating time was 150 min (range: 115–430 min). Post-operative course: 15 patients (55.6%) uneventful, 10 (37%) minor complications, 2 (7.4%) major complications; no post-operative mortality. Median post-operative hospital stay was 13 days (range: 5–129 days). At a median follow-up of 20 months (range: 1–59 months), 21 patients (78%) were alive, 6 (22%) died. Three patients presented long-term plates-related morbidity: plates rupture [2], pin plate dislodgment [1]; two required a second surgical look. One-year from surgery median spirometric values were: FVC 3.31 L (90%), FEV₁ 2.46 L (78%), DLCO 20.9 mL/mmHg/min (76%). On 21 alive patients, 7 (33.3%) reported no pain (VRS score 0), 10 (47.6%) mild (score 2), 4 (19.1%) moderate (score 4), no-one severe (score >4); 15 (71.5%) reported none or mild, 6 (28.5%) moderate pain influencing quality of life.

Conclusions

An optimal chest wall stabilization and reconstruction was achieved with the Synthes^® titanium plates system, with minimal morbidity, no post-operative mortality, acceptable operating time and post-operative hospital stay. Long-term restoration of a normal respiratory function was achieved, with minimal plates-related morbidity and chest pain.     

The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat‐shock protein 60 capable of producing the regulatory cytokine interleukin‐10

Objective

To test the hypothesis that T cell reactivity to self heat‐shock protein 60 (Hsp60) in patients with remitting juvenile idiopathic arthritis (JIA) is part of an antiinflammatory, regulatory mechanism.

Methods

Using peripheral blood–derived mononuclear cells (PBMCs) and synovial fluid–derived mononuclear cells (SFMCs) obtained from patients with JIA, we analyzed the expression of CD30 and the induction of regulatory cytokines in response to human and mycobacterial Hsp60.

Results

In oligoarticular JIA patients, in vitro activation of PBMCs and SFMCs with Hsp60 induced a high expression of CD30 on CD4+, activated (HLA–DR–positive), memory (CD45RO+) T cells. The expression of CD30 induced by human Hsp60 was much higher than that induced by mycobacterial Hsp60. In oligoarticular JIA patients with active disease, the expression of CD30 in response to human Hsp60 was paralleled by a high interleukin‐10 (IL‐10):interferon‐γ (IFNγ) ratio. In addition, restimulated human Hsp60–specific T cell lines from oligoarticular JIA patients showed a high production of IL‐10 and a low production of IFNγ. In contrast, PBMCs and SFMCs from polyarticular JIA patients responded to human Hsp60 with virtually no expression of CD30 and a low IL‐10:IFNγ ratio.

Conclusion

The results show that T cells responding to human Hsp60 in oligoarticular JIA patients express CD30, and during active phases of the disease, these T cells have a cytokine profile with a high IL‐10:IFNγ ratio. These findings suggest that in oligoarticular JIA patients, human Hsp60–specific CD4+ cells have a regulatory function and contribute to disease remission.

     

Clinical outcomes after withdrawal of anti–tumor necrosis factor α therapy in patients with juvenile idiopathic arthritis: A twelve‐year experience

Objective

To estimate the length of time to disease flare and the likelihood of achieving clinical remission after discontinuation of treatment with tumor necrosis factor α (TNFα) blockers in patients with juvenile idiopathic arthritis (JIA).

Methods

We conducted a retrospective chart review in a cohort of patients with JIA treated with TNFα inhibitors between January 1, 1998 and November 1, 2009. Demographic information, laboratory data, and medication exposure were extracted using a standardized tool. Outcomes of interest were based on preliminary criteria for remission in JIA.

Results

One hundred seventy‐one patients with 255 discrete episodes of anti‐TNFα treatment were reviewed. The median duration of patient observation was 59.7 months (range 5.8–211.2 months). Among patients in whom disease was inactive after discontinuation of anti‐TNFα therapy, 50% had persistently inactive disease at 6 months, and 33% had clinical remission at 12 months. The median duration of anti‐TNFα therapy after inactive disease was obtained was 6.1 months (range 0–67.9 months). No significant association was observed between the time to disease flare after cessation of treatment with TNFα antagonists and the length of time from the diagnosis of JIA to the initiation of anti‐TNFα therapy, the duration of therapy following the onset of inactive disease, or the total duration of treatment with TNFα antagonists prior to discontinuation. The category of JIA, sex, and age at diagnosis were not associated with the risk of relapse.

Conclusion

One‐third of patients with JIA can successfully undergo withdrawal of treatment with TNFα antagonists and be spared the cost and potential morbidity of treatment for at least 12 months. Further studies are needed to identify factors to accurately identify these patients.

     

Prevalence,risk factors,and outcome of uveitis in juvenile idiopathic arthritis: A long‐term followup study

Objective

To assess the prevalence, risk factors, and long‐term outcome of uveitis in patients with juvenile idiopathic arthritis (JIA).

Methods

An inception cohort of all 1,081 patients diagnosed as having JIA at a single tertiary care center was established. A questionnaire and followup telephone calls were used to confirm the diagnosis of uveitis. Ophthalmologists' records of patients with uveitis were collected. Kaplan‐Meier and Cox regression analyses were used to assess risk factors for developing uveitis and for complications of uveitis.

Results

After a mean followup time of 6.9 years, 142 of 1,081 patients (13.1%) had developed uveitis. Risk factors were young age at diagnosis, female sex, antinuclear antibody positivity, and the subtype of JIA. The relative contribution of these risk factors was different for the different subtypes of JIA. Until the end of the study, uveitis complications had developed in 53 of 142 patients with uveitis (37.3%; 4.9% of the total cohort). Only 16 of 175 involved eyes (9.1%) in 14 of 108 patients (13%; 1.3% of the total cohort) for whom ophthalmology reports were available had best corrected visual acuity less than 20/40 (mean followup time for uveitis of 6.3 years). Abnormal vision was associated with synechiae or cataract.

Conclusion

Risk factors for developing uveitis were different among subtypes of JIA. The long‐term outcome of JIA‐associated uveitis in our cohort was excellent despite the high rate of complications.

     

Impact of Uveitis on Quality of Life in Adult Patients With Juvenile Idiopathic Arthritis

Objective

To establish the impact of uveitis on the quality of life (QoL) in adult patients with juvenile idiopathic arthritis (JIA ).

Methods

Adult patients with a history of JIA , both with (n = 31) or without (n = 51) chronic anterior uveitis, were included. Their scores on 3 validated QoL questionnaires (National Eye Institute Visual Functioning Questionnaire [NEI VFQ ‐25], Medical Outcomes Study 36‐Item Short Form health survey [SF ‐36], and EuroQol 5‐domain questionnaire [EQ ‐5D]) were analyzed to find factors that could influence QoL.

Results

The median overall composite score (OCS ) of the NEI VFQ ‐25 was significantly worse in the uveitis group compared to the non‐uveitis group (respectively, 83.4 [range 15.2–94.7] and 94.9 [range 46.3–100]; P < 0.001). Nearly all subscale scores were lower in patients with uveitis than in patients without uveitis (P < 0.001 for all). After adjusting for duration of arthritis, JIA subtype, arthritis onset before or after 1990, and the use of systemic immunomodulatory medication, the QoL was still worse in patients with uveitis (NEI VFQ ‐25 OCS regression coefficient = ?11.7; P = 0.002). No significant differences were found between the groups for the SF ‐36 and the EQ ‐5D. In the total JIA group, the use of systemic medication appeared to negatively influence some general QoL scores.

Conclusion

Having a history of uveitis has a substantial negative effect on the vision‐related QoL in JIA in adulthood, despite good visual acuity. General QoL scores did not differ between uveitis and non‐uveitis patients, but the use of systemic immunomodulatory treatment, independent of uveitis, did negatively influence general QoL scores in adult JIA patients.