Search

Background:Juvenile Idiopathic Arthritis (JIA) is the most common auto-immune disease in children and pain is a common symptom. Despite treatment advances in recent years, pain often persists when the disease is inactive. Treating JIA to target has been widely recommended1, but effectiveness in pain reduction has not been proven yet2.Objectives:To compare pain scores over two years in three treatment arms in JIA patients that were treated to target and to identify baseline characteristics predicting unfavorable pain outcomes.Methods:DMARD naïve children who participated in the BeSt for kids study3 with oligoarticular JIA, RF negative polyarticular JIA and juvenile psoriatic arthritis were included. Patient were treated to target aimed at inactive disease according to 1 of 3 different treatment groups; 1) initial sequential DMARD monotherapy 2) initial methotrexate (MTX) with prednisolone bridging or 3) initial MTX with etanercept. Pain intensity was measured using a 100 mm Visual Analogue Scale during 24 months of follow up with 3-monthly intervals. Potential differences in VAS pain scores over time between treatment arms were compared using linear mixed models with random intercept and random slope for visits clustered within patients. A similar multivariable mixed model was used to assess the ability of several baseline characteristics to predict the chance of high pain levels during follow-up.Results:92 patients were randomized into the three treatment groups. Overall, pain scores over time reduced from mean 55.3 (SD 21.7) at baseline to 19.5 (SD 25.3) after 24 months. When comparing pain over time per arm, pain scores decreased significantly over time β -1.37 (95% CI -1.726; -1.022). No significant difference was found in pain over time between treatment groups (interaction term treatment arm*time (months) β (95% CI) arm 1 0.13 (-0.36; 0.62) and arm 2 0.37 (-0.12; 0.86) compared to arm 3), Figure 1. Correction for sex and symptom duration as possible confounders yielded similar results. Multiple baseline characteristics demonstrated a significant predictive value for pain over time: VAS pain (scale 0-100) with β 0.44 (95% CI 0.25; 0.65), VAS physician (scale 0-100) with β -0.34 (-0.55; -0.06), number of active joints with β 0.77 (0.19; 1.34), Child Health Questionnaire Physical summary Score with β -0.42 (-0.72; -0.11) and Psychosocial summary Score β -0.42 (-0.77; -0.06). Symptom duration, VAS patient/parent and NSAID use were no significant predictors, Table 1.Conclusion:Treatment to target seems effective in pain reduction in non-systemic JIA patients irrespective of initial treatment strategy. Several baseline predictors for pain over time were identified, which could serve as an initial indication for non-systemic JIA-patients with a high risk of pain despite a strict treat-to-target strategy.References:[1]Ravelli A, Consolaro A, Horneff G, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77(6):819–828.[2]Schoemaker, C.G., Swart, J.F. & Wulffraat, N.M. Treating juvenile idiopathic arthritis to target: what is the optimal target definition to reach all goals?. Pediatr Rheumatol. 18, 34 (2020)[3]Hissink Muller P, Brinkman DMC, Schonenberg-Meinema D, et al. Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. Ann Rheum Dis. 2019 Jan;78(1):51-59.Table 1.Baseline Characteristicsβp-value95% Confidence IntervalVAS Pain0.450.0000.25 to 0.65VAS Physician-0.310.014-0.55 to -0.06VAS Patient/parent-0.020.873-0.21 to 0.18No. of active joints0.770.0090.19 to 1.34PhS*-0.420.008-0.72 to -0.11PsS**-0.420.022-0.77 to -0.06Symptom duration (mo.)8.090.118-2.08 to 18.26NSAID use-1.300.791-10.91 to 8.31VAS Pain, VAS physician and VAS patient/parent was measures on a 100mm scale.*PhS= Physical Summary Score of the Child Health Questionnaire Parent form 50 (scale 0-100).**PsS= Psychosocial Summary Score of the CHQ-PF50 (scale 0-100).Disclosure of Interests:None declared

LMM for Poznanski, BA and BMD adjusted for age and/or symptom duration. (DOCX 14 kb)

A Sensitivity analysis of patients with wrist arthritis, without nâ =â 6 with never wrist arthritis. B Sensitivity analysis of patients with polyarticular JIA. C LMM for mean JADAS10 score in relation to Poznanski, BA and BMD. (DOCX 804 kb)

Bland-Altman plots with 95% limits of agreement. (DOCX 245 kb)

Flow chart of patient selection process for the Poznanski-score. (DOCX 23 kb)

Background In rheumatoid arthritis treatment, targeted treatment has shown to improve disease outcomes including the option of drug tapering and discontinuation. In non-systemic juvenile idiopathic arthritis (nsJIA) this has not been tried in a trial. Objectives To investigate which of three treatment strategies, targeting at drug-free inactive disease, is most effective and safe in recent onset DMARD-naive nsJIA. Methods We conducted a randomised, multicenter, treatment strategy study with 24 months of follow up. Patients, 2–16 years old with symptom duration Results 94 children (67% girls) with a median (InterQuartile Range) age of 9.1 (4.6–12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. Eleven had oligo-articular JIA, n=73 polyarticular JIA and n=8 juvenile psoriatic arthritis, 37% were ANA positive. At baseline VAS physician was median (IQR) 50 39–58 mm, VAS patient 54 37–70 mm, ESR 6 (2–14) mm/hr, active joints 8, 5–12 limited joints 2.5 (1–5), and CHAQ score 0.9 (0.6–1.5). After 24 months 61% (arm 1), 63% (arm 2) and 61% (arm 3) of patients had inactive disease and 45% (arm 1) 31% (arm 2) and 38% (arm 3) had stopped all DMARD(s). Time to inactive disease (median 9.0 (6.0–12.0) months) was not significantly different between arms, nor was time to flare (18.0 (15.0–21.0) months). Adapted ACRpedi-scores were comparably high between arms. Functional ability improved and remained almost normal. Toxicity reports showed mild events in similar rates across all arms. Results after 24 months by GEE. Conclusions Treatment to target drug free inactive disease is feasible in recent onset non-systemic JIA, resulting, regardless of initial treatment, in over 60% of patients in inactive disease and 38% drug free. Disclosure of Interest None declared

Background At present no clear evidence based guidelines exist to standardise the tapering and discontinuation of corticosteroids (CS) in juvenile dermatomyositis (JDM). Objectives To provide evidence-based recommendations for CS tapering/discontinuation through the analysis of the patients in the PRINTO new onset JDM trial. Secondary objective of the study was to identify predictors of clinical remission and CS discontinuation. Methods New onset JDM children were randomised to receive either prednisone (PDN) alone or in combination with MTX or CSA. All children were given initially intravenous methylprednisolone, and then PDN starting with 2 mg/kg/day. Gradual tapering according to a specific protocol could lead to the safe dose of 0.2 mg/kg/day by month 6, then discontinued at month 24. Major therapeutic changes (MTC) were defined as the addition or major increase in the dose of MTX/CSA/other drugs or any other reasons for which patients were dropped from the trial. Patients were divided according to clinical remission (CR) (CMAS=52 and MD global=0 for 6 continuous months) into two major groups. Group 1 included those on CR, who could discontinue PDN, with no MTC (reference group). Group 1 was compared with those who did not achieve CR, without or with MTC (group 2 and 3, respectively). JDM core set measures (CSM) were compared within the 3 groups. We also calculated the gold standard group 1 median change in the CSM in the first 6 and over 24 months and applied a logistic regression model to identify predictors of CR with PDN discontinuation. Results 139 children were enrolled in the trial: 47 on PDN, 46 on PDN +CSA and 46 on PDN +MTX. We identified 30 (21.6%) patients for group 1, 43 (30.9%) for group 2 and 66 (47.5%) for group 3. At baseline all 3 groups had no differences in the CSM. Already in the first 2 months a clear differential trend in disease activity measures, according to clinical remission status and PDN discontinuation, could be identified. From the observation of the median change in the CSM of group 1 in the first 6 months, the following recommendations could be extrapolated: decrease corticosteroids from 2 to 1 mg/kg/day in 2 months if the MD-global, parent-global, CHAQ, DAS, CMAS, MMT or Phs measures have changed of at least 50%; from 1 to 0.5 mg/kg/day in the following 2 months if the MD-global, CHAQ, DAS, CMAS show a change of at least 20%; in the following 2 months (month 4–6) corticosteroids can be tapered up to the safe dose of 0.2 mg/kg/day, if the disease activity measures remain at low/normal values. We finally ran a logistic regression model that showed that the achievement of PRINTO criteria 50–70–90 at 2 months from disease onset, an age at onset >9 years and the combination therapy PDN +MTX, increase the probability of clinical remission from 4 to 7 times (table 1). Conclusions We propose evidence based specific cut-offs for corticosteroid tapering/discontinuation based on the change in JDM CSM of disease activity, and to identify the best predictors for clinical remission and corticosteroid discontinuation. Disclosure of Interest None declared

Biological modelling of thermoradiotherapy may further improve patient selection and treatment plan optimisation, but requires a model that describes the biological effect as a function of variables that affect treatment outcome (e.g. temperature, radiation dose). This study aimed to establish such a model and its parameters. Additionally, a clinical example was presented to illustrate the application. Cell survival assays were performed at various combinations of radiation dose (0-8 Gy), temperature (37-42 °C), time interval (0-4 h) and treatment sequence (radiotherapy before/after hyperthermia) for two cervical cancer cell lines (SiHa and HeLa). An extended linear-quadratic model was fitted to the data using maximum likelihood estimation. As an example application, a thermoradiotherapy plan (23 × 2 Gy + weekly hyperthermia) was compared with a radiotherapy-only plan (23 × 2 Gy) for a cervical cancer patient. The equivalent uniform radiation dose (EUD) in the tumour, including confidence intervals, was estimated using the SiHa parameters. Additionally, the difference in tumour control probability (TCP) was estimated. Our model described the dependency of cell survival on dose, temperature and time interval well for both SiHa and HeLa data (R2=0.90 and R2=0.91, respectively), making it suitable for biological modelling. In the patient example, the thermoradiotherapy plan showed an increase in EUD of 9.8 Gy that was robust (95% CI: 7.7-14.3 Gy) against propagation of the uncertainty in radiobiological parameters. This corresponded to a 20% (95% CI: 15-29%) increase in TCP. This study presents a model that describes the cell survival as a function of radiation dose, temperature and time interval, which is essential for biological modelling of thermoradiotherapy treatments

Combination therapy with prednisone or etanercept may induce earlier and/or more improvement in disease activity in Disease Modifying Anti Rheumatic Drug (DMARD) naive non-systemic Juvenile Idiopathic Arthritis (JIA) patients. Here we present three months clinical outcome of initial treatments of the BeSt-for-Kids study. Included patients were randomized to either: 1. initial DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX)), 2. Initial MTX / prednisolone-bridging, 3. Initial combination MTX/etanercept. Percentage inactive disease, adjusted (a) ACR Pedi30, 50 and 70 and JADAS after 6 and 12 weeks of treatment (intention to treat analysis) and side effects are reported. 94 patients (67% girls, 32 (arm 1), 32 (arm 2) and 30 (arm 3) with median (InterQuartileRange) age of 9.1 (4.7-12.9) years were included. 38% were ANA positive, 10 had oligo-articular disease, 68 polyarticular JIA and 16 psoriatic arthritis. Baseline median (IQR) ACRpedi-scores: VAS physician 49 (40-58) mm, VAS patient 54 (37-70) mm, ESR 6.5 (2-14.8)mm/hr, active joint count 8 (5-12), limited joint count 3 (1-5), CHAQ score 0.88 (0.63-1.5). In arm 1, 17 started with MTX, 15 with SSZ. After 3 months, aACR Pedi 50 was reached by 10/32 (31%), 12/32(38%) and 16/30 (53%) (p = 0.19) and aACR Pedi 70 was reached by 8/32 (25%), 6/32(19%) and 14/30(47%) in arms 1-3 (p = 0.04). Toxicity was similar. Few serious adverse events were reported. After 3 months of treatment in a randomized trial, patients with recent-onset JIA achieved significantly more clinical improvement (aACRPedi70) on initial combination therapy with MTX / etanercept than on initial MTX or SSZ monotherapy. NTR1574 . Registered 3 December 2008.

This study aimed to determine disease activity patterns in juvenile systemic lupus erythematosus (jSLE) and its relation to early treatment. All jSLE patients who visited the outpatient departments of three Dutch university hospitals for at least 6 months were included. Data were retrospectively collected from each patient visit and hospitalization. Patient characteristics, clinical and laboratory findings categorized in organ systems, flare rate, medication use and disease course were analysed. Included were 35 patients (female 77%; White 47%) with a total follow-up of 142 years. Median age at diagnosis was 12.8 years. Flare rate was 0.45/patient-year. An organ system not earlier involved was affected in 34% of flares. Identifiable disease activity patterns were: chronic active (49%), relapse remitting (14%) and long quiescence (37%), with no significant difference in organ involvement at diagnosis. Positive anti-Sm and non-White ethnicity were significantly associated with a chronic active pattern. In 14 patients with severe symptoms at diagnosis, treatment with intravenous cyclophosphamide and/or biologics and/or intravenous methylprednisone in the first 6 months resulted in a long quiescence pattern in seven patients. In conclusion, distinct disease activity patterns are identifiable in children. Suppression of disease with early aggressive treatment may decrease the rate of progression. Lupus (2010) 19, 1550-1556.

Objective:To evaluate changes in health-related quality of life (HRQoL) in patients with refractory juvenile idiopathic arthritis (JIA) who are being treated with etanercept.Methods:53 patients with JIA from seven Dutch centres were included. HRQoL was measured by the Childhood Health Assessment Questionnaire (CHAQ), Child Health Questionnaire (CHQ) and Health Utilities Index mark 3 (HUI3) at the start and after 3, 15 and 27 months of treatment. At the same time points the following JIA disease activity variables were collected; physician’s global assessment through the visual analogue scale (VAS), number of active and limited joints and erythrocyte sedimentation rate. A statistical method linear mixed models was used to assess outcomes over time.Results:During etanercept treatment both disease-specific and generic HRQoL outcomes improved dramatically. Significant improvements were shown after 3 months and these improvements continued at least up to 27 months of treatment. The disease-specific CHAQ, including VAS pain and wellbeing, showed a significant improvement in all domains. The generic health-profile measure CHQ improved for all the health concepts except for “family cohesion”, which was normal. The generic preference-based HUI3 showed impairment and, subsequently, significant improvement in the more specific domains (“pain”, “ambulatory”, “dexterity”). In accordance disease activity variables also improved significantly over time.Conclusion:This study shows that the HRQoL of patients with refractory JIA can be substantially improved by the use of etanercept for all aspects impaired by JIA. Information on HRQoL is crucial to understand the complete impact of etanercept treatment on patients with JIA and their families.

Objective Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients. Methods A cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis. Results The time from diagnosis to start of MTX treatment, physician's global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physician's global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined. Conclusion In children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.

OBJECTIVES: Most clinical studies use paper case record forms (CRFs) to collect data. In the Dutch multi-centre observational study on biologicals we encountered several disadvantages of using the paper CRFs. These are delay in data collection, lack of overview in collected data and difficulties in obtaining up-to-date interim reports. Therefore, we wanted to create a more effective method of data collection compared with CRFs on paper in a multi-centre study.METHODS: We designed a web-based register with the intention to make it easy to use for participating physicians and at the same time accurate and up-to-date. Security demands were taken into account to secure the safety of the patient data.RESULTS: The web-based register was tested with data from 161 juvenile idiopathic arthritis patients from nine different centres. Internal validity was obtained and user-friendliness guaranteed. To secure the completeness of the data automatically generated e-mail alerts were implemented into the web-based register. More transparency of data was achieved by including the option to automatically generate interim reports of data in the web-based register. The safety was tested and approved.CONCLUSIONS: By digitalizing the CRF we achieved our aim to provide easy, rapid and safe access to the database and contributed to a new way of data collection. Although the web-based register was designed for the current multi-centre observational study, this type of instrument can also be applied to other types of studies. We expect that especially collaborative study groups will find it an efficient tool to collect data.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Diagnosis is made in a child with arthritis lasting longer than 6 weeks and by excluding other causes. In current classification seven categories are recognized. Increasing knowledge in various aspects (genetics, imaging, pathophysiology) of the disease has improved care for JIA patients. Improvement in treatment options expanded with the introduction of biologicals, which are available since the beginning of the 21st century. The goal of reaching inactive disease has come closer but is still not always feasible for nonsystemic JIA patients. This chapter summarizes aspects of pathophysiology, clinical manifestations, diagnostic investigations, differential diagnosis, treatment, and outcome measures of nonsystemic JIA.

Autologous stem cell transplantation (ASCT) to treat autoimmune diseases (AID) is thought to reset immunological memory directed against autoantigens. This hypothesis can only be studied indirectly because the exact nature of the pathogenetic autoantigens is unknown in most AID. Therefore, 19 children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematodes (SLE) and 10 adults with multiple sclerosis (MS) were vaccinated with the T-cell-dependent neoantigen rabies and the recall antigen tetanus toxoid after, respectively before, bone marrow harvest. Both vaccinations were repeated after ASCT. All except two of the responders mounted a primary antibody response to rabies after revaccination, and 44% of the responders mounted a primary antibody response to tetanus boost after ASCT. These data show that immunological memory to a neoantigen is lost in most patients with AID after immunoablative pretreatment; however, memory to a recall antigen boosted before bone marrow harvest is only lost in part of the patients. Disease progression was arrested in all patients with JIA/SLE except one, but only in a minority of MS patients. Clinical outcome on a per case basis was not associated with the profile of the immune response toward the vaccination antigens after ASCT.

ObjectivesJuvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA.MethodsA genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before.ResultsSNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (pCD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively).ConclusionsThe CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

Purpose Cisplatin was found to radiosensitize SW-1573 cells by inhibition of PLDR. Therefore, it was investigated whether cisplatin combined with γ-radiation leads to an increase in the number of chromosomal aberrations or apoptotic cells compared with radiation alone. Methods Confluent cultures of the human lung carcinoma cell line SW-1573 were treated with 1 μM cisplatin for 1 h, 4 Gy γ-radiation, or a combination of both. Cell survival was studied by the clonogenic assay. Aberrations were analysed by FISH in prematurely condensed chromosomes (PCC) and the induction of apoptosis by counting fragmented nuclei. Results A radiosensitizing effect of cisplatin on cell survival was observed if time for PLDR was allowed. An increased number of chromosomal fragments were observed immediately after irradiation compared with 24 h after irradiation whereas color junctions are only formed 24 h after irradiation. No increase in chromosomal aberrations was found after combined treatment, but a significantly enhanced number of fragmented nuclei were observed when confluent cultures were replated after allowing PLDR. Conclusion The inhibition of PLDR by cisplatin in delayed plated SW-1573 cells did not increase chromosomal aberrations, but increased the induction of apoptosis.

Background: In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group.Aims: To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account.Methods: Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m(2)/day (similar to 0.045 mg/kg/ day) during two years. The controls (n = 7) received no GH treatment.Results: During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score ( HSDS) in the hGH group (0.42 +/- 0.16 SDS) and a non-significant decrease in the controls (-0.18 +/- 0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64 +/- 0.19 SDS versus -0.20 +/- 0.17 SDS), while the decrease in percentage fat was not significant.Conclusions: There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.

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.

In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF. JIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft …

The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course.To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity.A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms.In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.

Item does not contain fulltext OBJECTIVE: The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. METHODS: Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. RESULTS: Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10(-5)) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10(-5)), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. CONCLUSIONS: This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.

Objective: Juvenile idiopathic arthritis (JIA) is a chronic disorder in which both genetic and environmental factors are involved. Recently, we identified the TRAF1/C5 region (located on chromosome 9q33–34) as a risk factor for rheumatoid arthritis (RA) (p combined = 1.4×10 −8 ). In the present study the association of the TRAF1/C5 region with the susceptibility to JIA was investigated. Methods: A case–control association study was performed in 338 Caucasian patients with JIA and 511 healthy individuals. We genotyped the single nucleotide polymorphism rs10818488 as a marker for the TRAF1/C5 region. Results: The A allele was associated with the susceptibility to rheumatoid factor-negative polyarthritis with an 11% increase in allele frequency (OR 1.54, 95% CI 1.09 to 2.18; p = 0.012). This association was stronger when combining subtypes with a polyarticular phenotype (OR 1.46, 95% CI 1.12 to 1.90; p = 0.004). In addition, we observed a trend towards an increase in A allele frequency in patients with extended oligoarthritis versus persistent oligoarthritis (49%, 38% respectively); p = 0.055. Conclusions: Apart from being a well replicated risk factor for RA, TRAF1/C5 also appears to be a risk factor for the rheumatoid factor-negative polyarthritis subtype of JIA and, more generally, seems to be associated with subtypes of JIA characterised by a polyarticular course.

Objective. To assess the efficacy, tolerability, and safety of sulfasalazine (SSZ) in the treatment of juvenile chronic arthritis (JCA). Methods. We conducted a 24-week randomized, placebo-controlled, double- blind, multicenter study of patients with active JCA of both oligoarticular and polyarticular onset. Patients were treated with a dosage of 50 mg/kg/day of SSZ (maximum 2,000 mg/day) or placebo. The efficacy variables were joint scores, physician's, parents', and patient's overall assessments, and laboratory parameters of inflammation. Results. Of the 69 patients enrolled, 52 (75%) completed the trial. Six patients (18%) withdrew from the placebo group, and 11 (31%) withdrew from the SSZ group (P = 0.18). In the intention- to-treat analysis of end point efficacy, between-group differences were significant for the overall articular severity score (P = 0.02), all global assessments (P = 0.01), and the laboratory parameters (P < 0.001). Adverse events occurred more frequently in the SSZ group and were the main reason for withdrawal (P < 0.001), but in all instances, these events were transient or reversible upon cessation of treatment. Conclusion. The results of this first placebo-controlled study show that SSZ is effective and safe in the treatment of children with oligoarticular- and polyarticular-onset JCA, although it was not well tolerated in one-third of the patients.

Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biologics in 1999. Because of more insight in the cytokines involved in JIA the number of available biologic agents increased. Together with the introduction of these new drugs, new insights in the optimal treatment of JIA indicate that earlier and more aggressive therapy is associated with better outcomes. Whether these developments with regard to biologic treatment have resulted in better patients' outcomes in daily practice is not yet reported.

DNA double-strand breaks (DSBs) can efficiently kill cancer cells, but they can also produce unwanted chromosome rearrangements when DNA ends from different DSBs are erroneously joined. Movement of DSB-containing chromatin domains might facilitate these DSB interactions and promote the formation of chromosome rearrangements. Therefore, we analyzed the mobility of chromatin domains containing DSBs, marked by the fluorescently tagged DSB marker 53BP1, in living mammalian cells and compared it with the mobility of undamaged chromatin on a time-scale relevant for DSB repair. We found that chromatin domains containing DSBs are substantially more mobile than intact chromatin, and are capable of roaming a more than twofold larger area of the cell nucleus. Moreover, this increased DSB mobility, but not the mobility of undamaged chromatin, can be reduced by agents that affect higher-order chromatin organization.

Background Recent genetic studies have reported an association of the Gly307Ser single nucleotide polymorphism (SNP) in the CD226 gene with susceptibility to multiple autoimmune diseases. CD226 or DNAM-1 is a type 1 membrane protein belonging to the Ig-superfamily and is involved in the adhesion and co-stimulation of T cells and NK cells. A trend towards association of this SNP with Juvenile Idiopathic Arthritis (JIA) was recently reported, but was not statistically significant (p=0.13) (Genes Immun. 2010 Mar;11(2):194-8).

Results 262 previously biologic-naive JIA-patients initiated etanercept; 71% female, 18% systemic-onset subtype. Median age at onset 6.9 (IQR 3.6-11.1) years, median followup 35.6 (IQR 17.4-53.6) months. In the long-term, the overall majority responded to etanercept and up to 40% reached inactive disease. Excellent response after 15 months (85 patients, 32%) was associated with low baseline disability (OR 0.49/point increase, 95%CI 0.33-0.74), fewer DMARDs used before etanercept (OR 0.64/ DMARD used, 95%CI 0.43-0.95) and younger age at onset (OR 0.92/year, 95%CI 0.84-0.99); poor response (88 patients, 34%) was associated with female gender (OR 2.12, 95%CI 1.11-4.08) and systemic-onset subtype (OR 3.24, 95%CI 1.39-7.56). However, 24% of systemiconset patients reached excellent response. Reasons for discontinuation: ineffectiveness in 78, adverse events (AEs) in 25, remission in 39 patients. Etanercept was well tolerated. Patients who developed AEs could not be identified at baseline.

Methods A questionnaire is taken at the start in all parents of the participants of the BeSt for Kids trial, treated with either initial sequential monotherapy (group 1) with either methotrexate or sulfasalazine, initial combination therapy with methotrexate and tapered prednisone (group 2), or initial combination therapy with methotrexate and etanercept (group 3). ACRp50 is the primary goal, treatment adjustments are made every 3 months to aim at clinical remission on medication from 6 months and onwards. The questionnaire explores parental preferences or dislikes for the initial therapy.

Background CCR5 is expressed on Th1 cells and may play a role in Rheumatoid Arthritis by recruiting these cells to the synovium, where they drive an inflammatory process. The CCR5Δ32 variant, a deletion variant which leads to a dysfunctional receptor, has been reported in several genetic association studies in Juvenile Idiopathic Arthritis (JIA), with conflicting results. CCL14 is one of the ligands of CCR5 and polymorphisms in the CCL14 gene have been reported to be associated with Systemic Lupus Erythematosus.

Objective. Juvenile idiopathic arthritis (JIA) is a heterogeneous disease involving chronic arthritis. The clinical course is characterized by a fluctuating pattern of active and inactive disease. We have described in detail the clinical course in different JIA subtypes during the first 2 years after diagnosis and studied its relationship to disease activity in the following years. Methods. Detailed clinical data on different parameters describing the disease activity in sequential time periods covering the first 2 years after diagnosis were retrieved from the charts of 311 patients with JIA and compared between subtypes. In a cohort of 146 patients, the relation of these different clinical variables to the course of disease in the following 3 years was evaluated. Results. The percentage of time with active disease in the first 2 years differed significantly between subtypes. In all subtypes, a broad spectrum of activity was observed. The time with active disease in the first 2 years was the most significant factor associated with the duration of active disease in the following years. Conclusion. Different percentages of time with active disease have been observed between JIA subtypes in the first 2 years. The cumulative duration of activity varied widely within each subtype. Regarding the prognosis of the individual patient, the clinical course in the first 2 years appears to be predictive of the clinical course in the following years. Patients that have less time with active disease in the first 2 years are not likely to develop an unremitting clinical course later on.

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 x 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.

The analysis of chromosomal aberrations by premature chromosome condensation (PCC) induced by Calyculin A (Cal) is feasible in tumor biopsies from patients and has the potential to predict sensitivity to radiotherapy. As hyperthermia (HT) improves radiotherapy outcome in certain tumor sites, it was investigated whether PCC induction is still possible after temperatures reached in the clinic. Human cervical carcinoma (CaSki) and lung carcinoma (SW-1573) cells were incubated with Cal to induce PCC immediately after 1 h treatment at temperatures ranging from 41 degrees C to 43 degrees C and after recovery for up to 24 h after treatment with 43 degrees C. Levels of phosphorylated Cdc2 (at the Tyr15 residue), histone H3 (at the Ser10 residue) and Cyclin B1 were investigated by immunoblotting. The amount of cells positive for phosphorylated histone H3 was determined by flow cytometry. Temperatures > or =42.5 degrees C inhibited the induction of PCC by Cal, while recovery of PCC-induction was observed at >20 h after treatment in both cell lines. The phosphorylation status of Cdc2 as well as of histone H3 in cells treated with Cal directly after HT at 43 degrees C was similar to that of cells treated with Cal alone or treated with Cal 24 h after HT at 43 degrees C. HT alone did not affect the levels of phosphorylated Cdc2, while phosphorylation levels of histone H3 were increased as compared with control status of these two proteins. Phosphorylated and total Cyclin B1 levels were not influenced by any of the treatments. Flow cytometric analysis confirmed that HT at 43 degrees C did not interfere with phosphorylation of histone H3. Our data indicate that HT transiently inhibits PCC induction by Cal in a temperature-dependent manner. Therefore, an interval of at least 24 h after HT should be applied before taking tumor biopsies for karyogram analysis of patients treated with temperatures above 42.5 degrees C

Objective:We undertook an observational study to obtain a complete overview of the long-term effectiveness and safety of etanercept in patients with different juvenile idiopathic arthritis (JIA) subtypes.Methods:At baseline we collected patient and disease characteristics of all Dutch patients with JIA who started treatment with etanercept. Disease activity was evaluated (at start of the study, after 3 months and then yearly) according to the JIA core set of the American College of Rheumatology paediatric definition for 30, 50 and 70% improvement (ACR Pedi 30, 50 and 70). Use of etanercept and concomitant drugs was monitored. Adverse events were recorded.Results:We included 146 patients with JIA with a median follow-up of 2.5 years per patient (range 0.3–7.3). JIA subtypes represented: 27% systemic, 8% polyarticular rheumatoid factor positive, 38% polyarticular rheumatoid factor negative, 19% oligoarticular extended, 3% enthesitis-related and 5% psoriatica. Most patients (77%) met the criteria of the ACR Pedi 30 in the first 3 months of treatment. For the majority of patients this improvement was sustained; 53 (36%) of all patients met the remission criteria. No other second-line agents were needed in 43 patients. Although patients with systemic JIA responded initially less to etanercept therapy than patients from other subtypes, those who did respond showed equal effectiveness in the long term. Serious adverse events rate was low (0.029 per patient year).Conclusions:Etanercept is effective and safe in JIA, even for a large proportion of the patients with systemic JIA. The greatest improvement occurred in the first 3 months of treatment, and was sustained for a long time in most patients (up to 75 months).

Dentine of 27 permanent human teeth was examined by scanning electron microscopy. The teeth were incisors, canines, premolars and molars, ranging in age from 18 to 54 yr. Intratubular collagen was found in 65% of the dental tubules in inner dentine (closest to the pulp) with 16% of the tubules containing large collagen bundles occupying more than one-fifth of the lumen. In middle dentine the corresponding figures were 42 and 7%, and for outer dentine, 12 and 0% This pattern of distribution was the same for all tooth families examined and appeared to be unrelated to age.

Open Access Poster presentation Does incorporation of aids/devices and help, make a difference in the childhood health assessment questionnaire disability index? Analysis from the printo juvenile idiopathic arthritis database C Saad-Magalhaes*, A Pistorio, A Ravelli, R Brik, D Mihaylova, R Ten Cate, B Andersson-Gare, V Ferriani, K Minden, P Hashkes, M Rygge, MJ Sauvain, H Venning, A Martini and Ruperto for the Paediatric Rheumatology International Trials Organisation (PRINTO) N

Purpose and background: Variation in radiosensitivity of normal tissues is related to genetic susceptibility (Svensson et al. 2006). Persistence of gamma-H2AX foci after ionizing radiation is higher in DNA-DSB repair deficient cells than in normal cells. We investigated whether differences in number of ?-H2AX foci may be useful as a predictor of radiosensitivity. Materials and methods: Induction of gamma-H2AX foci was measured in various cell types: freshly isolated lymphocytes, fibroblast cells (AT+/+, AT+/-, AT-/-), DNA-DSB repair deficient and normal hamster cells and human tumour cells (lung carcinoma, SW-1573 and prostate cancer cell lines with different TP53 status: LNCaP: TP53 wt, PC3: TP53 null and DU145: TP53 mutant). A radiation dose of 2.4 Gy was given as a single dose or as pulsed doses of 100 mGy in 24 h (PDR: 240 pulses of 100mGy, 1 pulse every 6 min). The number of gamma-H2AX foci was determined 30 min and 24 h after single dose and directly after PDR. Results: Maximal number of γ-H2AX foci occurred after single dose at 30 min after irradiation without significant differences in numbers of foci between different cell lines. The number of gamma-H2AX foci was radiation dose dependent and linearly correlated with clonogenic survival. Both 24 h after a single dose and after PDR more remaining foci are observed in repair deficient cells than in normal cells. In addition the TP53 null cells have more remaining foci than the mutant and wt TP53 cells. Conclusions: The detection gamma-H2AX after in vitro irradiation of lymphocytes and cell lines is simple, reproducible and sensitive. The number of residual gamma-H2AX foci after single dose as well as after PDR enables us to distinguish cells with differences in DNA-DSB repair capacities. However, it remains to be established whether gamma-H2AX assay applied in lymphocytes can be used to predict for late normal tissue toxicity after radiotherapy. Sponsored by the Dutch Cancer Foundation UVA2008-4019

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.

Objective: Temporomandibular joint (TMJ) involvement is a frequent feature in cross-sectional prevalence studies among juvenile idiopathic arthritis (JIA) patients. The cross-sectional design makes it almost impossible to study the incidence. Follow-up data on TMJ involvement are sparse. In this study patients were reviewed with an interval of a minimum of 1 year and a maximum of 2 years to study the yearly incidence of TMJ involvement and to obtain follow-up data on TMJ involvement and orthopantomogram (OPT) alterations. Methods: Children with JIA from a previous study on TMJ involvement were included. OPTs were scored according to Rohlin's grading system (grade 0-5). A paediatric rheumatologist measured the level of disease activity during the interval. Results: Eighty-nine of the 97 patients were included in this study with a mean follow-up of 14 months. The yearly incidence of TMJ involvement was 7.1% in patients with JIA. Improvement on the OPT was seen in 27 patients (66%), and 19 of these patients no longer showed any signs of TMJ involvement. Worsening on the OPT was seen in four patients (10%). Disease activity was significantly lower in the improved patients than in the patients with worsening. Conclusion: Condylar lesions due to arthritis can improve over time, indicating a regenerative capacity of the mandibular condyle. As condylar improvement seems to be associated with low disease activity, it is important to consider the TMJ when deciding on a therapeutic regimen.

Background In the BeSt for Kids (a three-armed treatment strategy study in juvenile idiopathic arthritis (JIA)) time to inactive disease, time to flare after Disease Modifying Anti Rheumatic Drug (DMARD) discontinuation, ACRpedi scores, functional ability, safety, and radiological damage are compared. Follow up will be 2 years. Here we present the 3 months clinical outcomes of initial treatments. Methods Recent onset, DMARD naive JIA patients (Rheumatoid Factor-negative polyarticular, oligoarticular or with psoriasis (ILAR-criteria), 2 /week, based on physician9s preference), 2. combination therapy: MTX 10mg/m 2 /week and 4 weeks prednisolone-bridging 0.5mg/kg/day, in 2 weeks tapered to nil, and 3. combination therapy with MTX 10mg/m 2 /week and etanercept 0.8mg/kg/wk. NSAIDs and intra-articular steroids are permitted in all patients. MTX was combined with folic acid 5mg/week. Treatment adjustments were made every 3 months after assessment by a trained, blinded examiner. Target was ACRpedi50 after 3 months and inactive disease from 6 months and onwards. Results From October 2009 to April 2014, 95 children, of which 33% boys, were enrolled: 32 in arm 1, 32 in arm 2 and 31 in arm 3. Baseline median (IQR) age was 8,6 (4,5-12,9) years. 38% were ANA positive, 12 patients had oligoarticular disease, 68 patients oligoextended/polyarticular JIA and 15 patients had JIA with psoriasis. Baseline median (IQR) ACRpedi scores: VAS physician 49 (40-58) mm, VAS patient 54 (37-70) mm, ESR 6,5 (2-14,8) mm/hr, number of active joints 8 (5-12), number of joints with limited range of motion 3 (1-5), CHAQ score 0,88 (0,63-1,5). In arm 1, 17/32 had started with MTX, the others with SSZ. One patient in arm 1 (lost to FU) and 1 in arm 3 (uveitis) dropped out before 3 months. By 3 months ACRpedi50 was reached by 10/32 (31%),12/32 (38%) and 16/30 (53%) (p=0,19) and ACRpedi70 was reached by 8/32 (25%), 6/32 (19%) and 14/30 (47%) in arms 1-3, respectively (p=0.04). Toxicity (mainly gastrointestinal complaints) was similar in the treatment arms. Three short hospital admissions (serious adverse events) were reported. In 2/32, 1/32 and 2/30 patients MTX dose was reduced or switched to subcutaneous and 3/15 patients stopped SSZ after 6 weeks because of nausea, malaise, headache. Conclusions After 3 months of initial treatment in a three-armed strategy trial, patients with recent onset JIA achieve more clinical improvement (significantly more ACRpedi70) on initial combination therapy with MTX and etanercept than on initial MTX or SSZ monotherapy. Numerically, response to initial treatment with MTX and prednisolone bridging seems more effective than monotherapy and less effective than combination with etanercept, but these differences were not statistically significant. Disclosure of Interest P. Hissink Muller Grant/research support from: Pfizer, D. Brinkman: None declared, D. Schonenberg: None declared, Y. Koopman-Keemink: None declared, J. van den Berg: None declared, P. Bekkering: None declared, M. van Rossum: None declared, L. van Suijlekom-Smit: None declared, C. Allaart: None declared, R. ten Cate: None declared

Female sex hormones affect susceptibility to systemic lupus erythematosus (SLE). To determine the effect of female sex hormones at onset of SLE on the survival of these patients, a retrospective survey was performed. The charts of 168 female SLE patients were evaluated to study the disease course, in particular the presence and kind of SLE criteria. Patients were classified as either belonging to the 'high female sex hormone at onset (HH)' or 'low female sex hormone at onset (LH)' group according to age at diagnosis. The statistics of the Dutch population, matched for age, were used to control for differences in life expectancy in these groups. A Cox regression model revealed that the relative mortality risk of HH patients vs HH controls was 4.2 times higher than the relative mortality risk of LH patients compared to LH controls. No differences in the frequency of SLE criteria between HH and LH patients were found that could explain the observed difference in mortality risk.

The time dependence of the kink power in weakly index guided high power stripe lasers in the AlGaAs system are investigated. A periodic dependence of the kink power on the length of the laser is observed in continuous and pulsed modes, but the pulsed mode kink curve is shifted with respect to the continuous one. This is observed to be proportional to 1/τ, where τ is the pulse width. The kink is due to phase locking of the modes of the waveguide resulting from a shift of the effective indexes, which is driven by self-heating due to free-carrier absorption of the laser mode.

The aetiology of several autoimmune diseases has not yet been elucidated. Microchimerism, the persistence of small numbers ofallogeneic cells in an individual, has been mentioned recently in connection with the occurrence of autoimmune diseases such as systemic sclerosis and juvenile inflammatory idiopathic myopathy. These allogeneic cells can originate from mutual foeto-maternal exchange of blood cells during pregnancy or from a donor after blood transfusion or (organ) transplantation. In some cases, a syndrome then develops that resembles the chronic graft-versus-host reaction after stem-cell transplantation, in which allogeneic cells react with autologous cells. Studies on microchimerism in patients with systemic sclerosis and juvenile inflammatory idiopathic myopathy, compared to controls, sometimes reveal a clearly increased prevalence of microchimerism in patients. However, microchimerism can also be found in healthy individuals. Direct proof of a causal relation between microchimerism and autoimmune diseases does not exist. Additional genetic or environmental factors may be partly responsible for a disturbed balance between tolerance and aggression.