Familial autoimmunity: maternal parent-of-origin effect in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is an autoimmune (AI) disease characterized by chronic arthritis in children. Children with JIA have increased prevalence of other AI diseases. Furthermore, relatives of children with JIA have been shown to have an increased prevalence of AI diseases. Our objective was to determine if there were differences in the prevalence of AI diseases among maternal and paternal relatives of children with JIA. Information about AI diseases among all living first- and second-degree relatives was collected by structured interviews with families of 121 simplex JIA families, 23 multiplex JIA families, and 45 control families. Overall, the prevalence of AI diseases was significantly increased among maternal second-degree relatives of cases compared to that of maternal second-degree relatives of controls [14% vs. 4.3%; p < 0.001]. The prevalence of AI diseases among mothers of JIA cases was three times that of fathers [32.3% vs. 11.4%; p < 0.0001]. The prevalence of AI diseases among all maternal second-degree relatives of children with JIA was significantly higher than that of all paternal second-degree relatives [14% vs. 7.9%; p < 0.004]. Although additional paternal effects cannot be excluded, together these results demonstrate that maternal relatives of children with JIA have an increased prevalence of autoimmunity compared to paternal relatives, suggesting that there might be a maternal parent-of-origin effect in JIA. This work is supported in part by The National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR50177, AR42218, AR47363, and AR42272), The Arthritis Foundation, The Val A. Browning Charitable Foundation, The Clinical Genetics Research Program, The Primary Children's Medical Center Foundation, and the Children's Health Research Center, Salt Lake City, UT, USA.     

Low cortisol levels in active juvenile idiopathic arthritis

The aim of our study was to evaluate the neuroendocrine system in patients with juvenile idiopathic arthritis (JIA) regarding the activity of disease. Twenty-one JIA patients (mean age ± standard deviation 10.5 ± 4.1 years) were included. None of the patients was taking steroids or antitumor necrosis factor-α therapy during this study. Ten healthy volunteers and ten volunteers with upper respiratory tract infection composed the control groups. Furthermore, ten of the 21 JIA patients were also evaluated during the remission period. Erythrocyte sedimentation rate, C-reactive protein, adrenocorticotropic hormone (ACTH), cortisol, prolactin, insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein 3, free T3, free T4, thyroid-stimulating hormone, interleukin-6 (IL-6) levels, and 24-h urinary cortisol were evaluated both during the active period and remission. The median levels of ACTH and cortisol at 08:00 a.m. were significantly lower in patients with active JIA than patients in remission period and the control groups (p < 0.05). Furthermore, the median level of urine cortisol in active JIA patients was significantly lower than remission period and control groups (p < 0.05). The median level of IGF-1 was significantly lower in active patients than that of remission (p < 0.05). The median level of IL-6 in active JIA patients was significantly higher than those in remission and control groups (p < 0.05). Our preliminary study suggested that impaired secretion of adenohypophyseal hormones and distorted bilateral interactions between the immune and endocrine systems in JIA. Further studies are needed to clarify the consequences of the impaired hormone secretion in JIA.     

Power Doppler sonography in the evaluation and follow-up of knee involvement in patients with juvenile idiopathic arthritis

Introduction This study was undertaken to evaluate the role of ultrasound (US), conventional color (CD) and power Doppler (PD) in the detection and quantification of inflammatory signs of the knee in children with juvenile idiopathic arthritis (JIA) and to correlate these findings with patient history, clinical, laboratory and radiological findings. Patients and methods Thirty patients with JIA who had clinical signs of knee involvement as well as 15 healthy children as a control group where subjected to full clinical examination and laboratory investigations on the same day of US examination. The knee joints were evaluated with plain radiography, US, and color Doppler in 13 patients, while the remaining 17 were assessed with power Doppler. Fourteen patients were subjected to follow-up assessment. Results A highly significant difference in synovial thickening and cartilage thickness detected by US between JIA affected knees and those of controls (p<0.0001). Knee effusion was demonstrated in 93% of patients. Synovial vessles were detected by Doppler in 76.7% of patients. A significant correlation was detected between the degree of vascularity detected by PD and knee score (p<0.05), and JAFAR score (P<0.05). On comparing the findings of the follow-up with those of the initial examination, a significant positive correlation was detected between the differences in the knee score and those in synovial thickness (p<0.05), and with the vascularity scale detected by PD (p<0.05). Conclusion This study suggests the Doppler sonography as a non-invasive, low-cost, and readily available tool for the evaluation and follow-up of articular involvement in knees of JIA patients.     

Elevated serum receptor activator of NFκB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and ProMMP1 in patients with juvenile idiopathic arthritis

We studied the serum levels of receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), pro-matrix metalloproteinase (MMP) 1, MMP3, and tissue inhibitor of metalloproteinase (TIMP) 1 in patients with juvenile idiopathic arthritis (JIA) and correlated these with different disease variables. Sera of 70 patients with JIA (ILAR 2001 criteria) and 33 age- and sex-matched controls were assayed by enzyme-linked immunosorbent assay. Nonparametric tests were used for analysis of data. The subtype distribution of the JIA patients was: enthesitis-related arthritis (ERA) 24, polyarticular 22, systemic onset 13, oligoarticular 8, and others 3. The median level of RANKL, OPG, pro-MMP1, MMP3, and TIMP-1 were elevated in JIA patients as compared to controls (p < 0.001). There was no difference in levels among different types of JIA. RANKL/OPG ratio was elevated in all subtypes of JIA. MMP3/TIMP-1 ratio correlated with measures of disease activity including swollen and tender joint count, erythrocyte sedimentation rate, and disease activity score (rS 0.28, p < 0.05). Ours is the first study to show elevated RANKL in serum of patients with JIA. Further, our data suggest that patients with ERA have similar levels to other forms of JIA. Association of the MMP3/TIMP-1 ratio with disease activity suggests that it may be a useful biomarker for follow-up.     

Rheumatoid arthritis in the United Arab Emirates

Studies have shown that patients with rheumatoid arthritis (RA) in the Middle East have delayed diagnosis and low disease-modifying anti-rheumatic drug (DMARD) utilization. We describe the characteristics and treatments of consecutive RA patients presenting to a new musculoskeletal clinic in Dubai, United Arab Emirates (UAE). Demographic and clinical data were collected over a 10-month period at the first visit to our clinic for patients meeting the American College of Rheumatology (ACR) criteria for RA. A total of 100 patients were seen: (average ± SD) age 42.2 ± 12.3 years; female 87%; Arabs 38%, Indian 36%, Caucasian and others 26%; 73% rheumatoid-factor positive; years since diagnosis: 3.9 ± 5.7; lag time between symptom onset to diagnosis 1.2 ± 1.3 years and lag time to first DMARD was 1.6 ± 2.0 years. Mean tender joint count was 8.9 ± 7.9, mean swollen joint count 9.0 ± 7.6, mean patient’s global assessment of disease activity 57.4 ± 25.0 mm, mean ESR 33 ± 25 mm/h, mean DAS28 5.2 ± 1.6, physician global assessment 55.0 ± 23.8. Only 43% were on DMARDs (25% MTX, 5% TNF blockers). Among the patients who were not on DMARD, only 28.1% had disease duration less than 1 year (p = <0.01). Erosions were present in 55.2% of patients with available X-rays, and deformities in 26% of patients. There were no racial differences in disease characteristics. The UAE has a unique population with many races residing in the country. Among the first 100 consecutive patients seen at our clinic, there were no significant differences in disease characteristics with the majority of the patients having very active disease, delayed diagnosis, and not being treated with DMARDs. Footline: RA in the United Arab Emirates     

Arthritic presentation of acute leukemia in children: experience from a tertiary care centre in North India

The objectives of this study are to highlight the arthritic presentation of acute lymphoblastic leukemia (ALL) in children and to delineate features that could help differentiate it from juvenile idiopathic arthritis (JIA). We present a retrospective case control study based on records of the Pediatric Rheumatology Clinic, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India for the period January 2005–October 2008. We compared the clinical profile of 11 children referred to us with musculoskeletal complaints who were ultimately diagnosed to have ALL, with the clinical profile of an equal number of age and sex matched children with JIA. Important features that predicted a diagnosis of ALL and differentiated it from JIA were history of night pain (P = 0.001), non-articular bony pain (P = 0.001), presence of joint pain out of proportion to physical findings (P = 0.0001), anemia (P = 0.004), leucopenia (P = 0.045), lymphocytic predominance (P = 0.002) and thrombocytopenia (P = 0.012). In conclusion, children with musculoskeletal complaints are often referred to the rheumatologist for evaluation. The treating physician should always exclude the possibility of an underlying ALL especially if there are atypical clinical features or subtle hematological abnormalities.     

The relationship between physical activity level,anxiety, depression,and functional ability in children and adolescents with juvenile idiopathic arthritis

The aim of this study was to assess the relationships between physical activity level and anxiety, depression, and functional ability in children and adolescents with juvenile idiopathic arthritis (JIA). Cross-sectional study design including patients with JIA aged between 8 and 17 years and healthy controls was used. Sociodemographic data and clinical features were assessed. Physical activity level and energy expenditure were assessed with a 1-day activity diary. Anxiety was screened by The Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire. Depressive symptoms were assessed by the Children’s Depression Inventory (CDI). Functional ability was assessed with the Childhood Health Assessment Questionnaire (CHAQ). Pain and overall well-being were measured using a visual analog scale (VAS). Fifty-two patients and 48 controls were included with a mean age of 12.13 ± 2.92 and 11.27 ± 1.59 years, respectively. The mean disease duration was 64 months. The JIA group had significantly less time in physical activity (p = 0.000), decrease in energy expenditure (p = 0.04), and higher CHAQ scores (p = 0.000) compared with the control group. In the JIA group, significant relationships were found between the number of active joint and disease duration (r = 0.44, p = 0.000) and VAS pain (r = 0.30, p = 0.02), between SCARED and CDI (r = 0.54, p = 0.000). Significant relationships were found between VAS overall well-being and CDI (r = 0.29, p = 0.03), CHAQ (r = 0.37, p = 0.000), and VAS pain (r = 0.41, p = 0.000). Correlation between CHAQ and CDI (r = 0.34, p = 0.01) was significant. The result of our study suggested that only depression was related to anxiety, functional ability, and well-being in children and adolescents with JIA.     

Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation

This study evaluated the prognostic value of minimal residual disease (MRD) monitoring by four-color flow cytometry (FCM) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). MRD was examined with four-color FCM at different time points in 139 patients (including pediatric and adult patients) with ALL after allo-HSCT. Real-time quantitative polymerase chain reaction (RQ-PCR) was applied to evaluate the MRD of Philadelphia chromosome-positive ALL (Ph+ ALL) patients. Patients who were FCM-positive (FCM+) after transplantation had a lower event-free survival (EFS) of 0.54 and a higher cumulative incidence of relapse (CIR) of 0.54 compared to an EFS of 0.80 and a CIR of 0.08 in FCM-negative (FCM−) patients (EFS, p < 0.001; CIR, p < 0.001). Similar results were obtained in high-risk patients and Ph+ ALL patients. Moreover, a FCM+ status after the second month post-HSCT (defined as MRD positive) proved to be a predictor of leukemia relapse. Multivariate analysis for EFS, OS and CIR showed that MRD status after transplantation was an independent prognostic factor (p < 0.001, p = 0.013, and p < 0.001, respectively). A good correlation was found between the MRD results of FCM and RQ-PCR (n = 126 pairs, Spearman r = 0.8139, p < 0.001). MRD monitoring by four-color FCM post-transplantation is an important tool for relapse prediction in ALL patients. Prompt and appropriate pre-emptive anti-leukemia treatment could be considered based on the status of MRD after HSCT.     

Serum heat shock protein 60 can predict remission of flare-up in juvenile idiopathic arthritis

Heat shock protein (Hsp) 60 has been implicated in the pathogenesis of various inflammatory and autoimmune diseases. This study aimed to investigate synovial fluid and serum concentrations of Hsp60 and anti-Hsp60 and their relationship with juvenile idiopathic arthritis (JIA). Forty-eight patients with JIA, including 22 oligo-articular, 19 poly-articular, and 7 systemic diseases, and 33 normal controls were enrolled in this study. Synovial fluid and serum Hsp60 and anti-Hsp60 concentrations were measured via ELISA. Serum concentrations of Hsp60 of active and inactive oligo- and poly-articular JIA were significantly higher than those of normal controls. Serum concentration of anti-Hsp60 in active oligo-articular JIA was higher than that of normal controls (49.25 vs. 35.76 ng/mL, p = 0.059). Similarly, serum concentration of anti-Hsp60 in active poly-articular JIA was significantly higher than that of inactive samples (65.05 vs. 26.54 ng/mL, p = 0.008). In addition, serum concentration of Hsp60 correlated with the time required for remission from flare-ups in patients with JIA. Serum concentration of Hsp60 correlated well with time required for remission from flare-ups in patients with JIA, representing a potential disease marker to monitor disease activity.     

Performance of tuberculin skin test and interferon gamma assay for the diagnosis of latent tuberculosis infection in juvenile idiopathic arthritis

The objective of this prospective cross-sectional study was to compare a Mycobacterium tuberculosis-specific interferon gamma (IFN-γ) enzyme linked immunosorbent assay [QuantiFERON-TB Gold In-Tube (QFT-GIT)] test with tuberculin skin test (TST) for detection of latent tuberculosis infection (LTBI) in patients with juvenile idiopathic arthritis (JIA). To our knowledge, this is the first study evaluating the performance of QFT-GIT in comparison with TST in JIA. A cross-sectional study of 39 children with JIA and 40 healthy controls was conducted in İzmir, Turkey. Blood was for drawn for the QFT-GIT assay prior to administration of the TST using 5 tubercullin units (TU) of purified protein derivative (PPD-S). A positive TST was defined as ≥10 mm for JIA and ≥15 mm for controls. Statistical analysis was performed using SPSS version 16.0 for Windows. There were no significant differences between JIA patients and controls for age, sex, and Bacillus Calmette–Guérin (BCG) vaccination. Of patients, 70% had active JIA disease. The median TST induration was 5.8 mm (±5.7 mm) for JIA and 10.7 mm (±4.5 mm) for the control group, which was statistically significant (p = 0.000). The rate of patients who showed no reaction to TST was 38%, of which 93% had active disease. There were two patients who had positive IFN-γ results but negative TST, who had systemic and polyarticular type JIA, respectively. Overall agreement between TST and QFT-GIT was low both in JIA and control group (κ value =0.06 and 0.10, respectively). TST may be inadequate to diagnose LTBI in JIA patients. The IFN-γ assay may be useful to identify false negative TST response in cases with latent M. tuberculosis infection. The combination of IF QFT-GIT method with TST would provide successful diagnostic screening for LTBI in JIA, particularly prior to anti-tumor necrosis factor treatment. Long-term prospective studies are still necessary to appreciate the advantages and the applicability of these tests in pediatrics.     

Computed direct magnification radiography of bone tumors

The purpose of this study was to assess the diagnostic performance of computed direct magnification radiography in diagnosing bone tumors as compared with conventional radiography. Ninety-one patients with primary bone tumors and tumor-like lesions were radiographed with conventional and magnification techniques. All radiographs were analyzed by one orthopedic surgeon and two radiologists and the findings were correlated with histopathology. Two microfocal X-ray units were used for computed direct magnification radiography with a focal spot size of 20–130 μm. Using magnification versus conventional radiography, the diagnosis of benign and malignant lesions as well as the individual tumor diagnosis was obtained with higher accuracy (85% versus 71% and 69% versus 51%, respectively, P < 0.01). Margins of destruction, periosteal reactions, and matrix patterns were evaluated with higher accuracy by all observers (P < 0.01). We conclude that computed direct magnification radiography may improve evaluation and diagnosis of bone tumors. Received: 28 September 1999 / Accepted: 30 June 2000     

Correlation of telomerase activity to apoptosis and survival in adult acute lymphoblastic leukemia: an Egyptian single-center study

Telomerase is activated in most tumors, but suppressed in normal human somatic cells. Current evidence indicates that telomerase reactivation is a critical step in carcinogenesis, with a close relationship to apoptosis. The goal of this study was to investigate the levels and relationship of telomerase activity to apoptosis and its impact on the survival of Egyptian adult acute lymphoblastic leukemia patients. Telomerase activity was quantified by polymerase chain reaction (PCR) and detected by enzyme-linked immunosorbent assay (ELISA), while apoptosis was measured at the single-cell level by fluorescence in situ detection using flow cytometry in 15 control subjects and 40 acute lymphoblastic leukemia (ALL) patients at presentation. Telomerase activity in ALL patients was negatively correlated to apoptosis [percent and mean fluorescence intensity (MFI)] (p < 0.001 for percent and p < 0.001 for MFI) and to the 4-year survival rate (p < 0.05), to which apoptosis (percent and MFI) was consequently positively correlated (p < 0.001 for percent and p < 0.05 for MFI). For telomerase, the highest positive predictive value (PPV) for mortality (93.3%) was at a cut-off value of 13 amol/ml, while those for apoptosis (85% for percent of apoptotic cells and 90.9% for MFI) were at a cut-off of 8% and 0.19 MFI. This makes the measurement of telomerase activity in ALL patients a potential tool to predict disease with unfavorable outcome and a candidate tumor marker.     

Mechanisms of resistance to methotrexate in childhood acute lymphoblastic leukemia: circumvention of thymidylate synthase inhibition

Purpose: In about 25% of patients suffering from acute lymphoblastic leukemia (ALL) treatment failures occur that are most likely due to development of resistance to methotrexate (MTX). Blasts from patients with ALL were evaluated for MTX uptake, formation of long-chain MTX polyglutamates (MTX-Glu₅₊₆), cytotoxicity and thymidylate synthase inhibition by MTX and compared to blasts from patients with acute myelogenous leukemia (AML). Methods: Radioactively labeled MTX-Glu _n were analyzed by means of HPLC. Thymidylate synthase activity was measured by a tritium-release assay. Cytotoxicity was determined by trypan blue exclusion. Results: In most ALL blasts (n = 9) large amounts of MTX-Glu₅₊₆ (1.06–7.03 pmol/10⁷cells) and high cytotoxicity (43.5%–92.7%) were found, while in others small amounts of MTX-Glu₅₊₆ (0.0–0.39 pmol/10⁷cells) caused only weak cytotoxicity (6.0%–27.9%) (n = 5, 2 relapsed patients). Resistance to MTX in blasts from AML patients (n = 5) was also caused by reduced synthesis of MTX-Glu₅₊₆ (0.0–0.42 pmol/10⁷cells). In contrast, some ALL blasts (n = 7, 4 relapsed patients) were able to survive MTX treatment despite large amounts of MTX-Glu₅₊₆ (1.5–5.05 pmol/10⁷cells) and extensive thymidylate synthase inhibition. Conclusions: Since the majority of ALL patients were examined at first diagnosis, an inherent mechanism of resistance seems most likely. We propose a mechanism based on the switch of thymidylate synthesis to the salvage pathway. Received: 30 October 1998 / Accepted: 6 April 1999     

Primary Care Visit Length,Quality, and Satisfaction for Standardized Patients with Depression

BACKGROUND The contribution of physician and organizational factors to visit length, quality, and satisfaction remains uncertain, in part, because of confounding by patient presentation. OBJECTIVE To determine associations among visit length, quality, and satisfaction when patient presentation is controlled. DESIGN A factorial experiment using standardized patients to make primary care visits presenting with either major depression or adjustment disorder, and a musculoskeletal complaint. PARTICIPANTS One hundred fifty-two primary care physicians, each seeing 2 standardized patients. MEASUREMENTS Visit length was determined from surreptitiously obtained audiorecordings. Other key measures were derived from physician and standardized patient report. RESULTS Mean visit length for 294 completed encounters was 22.3 minutes (range = 5.8–72.2, SD = 9.4). Key factors associated with visit length were: physician style (ρ = 0.68 and 0.54 after multivariate adjustment), nonprofessional experience with depression (11% longer, 95% CI = 0–23%), practicing within an HMO (26% shorter, 95% CI = 61–90%), and greater practice volume (those working >9 half-day clinic sessions/week had 15% shorter visits than those working fewer than 6, 95% CI = 0–27%, and those seeing >12 patients/half-day had 27% shorter visits than those seeing <10 patients/half-day, 95% CI = 13–39%). Suicidal inquiry (a process-based quality-of-care measure for depression) was not associated with adjusted visit length. Satisfaction was linearly associated with visit length but not with suicide inquiry or follow-up interval. CONCLUSIONS Despite experimental control for clinical presentation, wide variation in visit length persists, largely reflecting individual physician styles. Visit length is a significant determinant of standardized patient satisfaction.     

Iron status during anti-TNF therapy in children with juvenile idiopathic arthritis

Patients with active juvenile idiopathic arthritis (JIA) have frequently low haemoglobin (Hgb) due to inflammation and/or iron deficiency. The aim of the study was to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on their iron status. Twenty children with JIA were treated with either etanercept (n = 8) or infliximab (n = 12) for 12 months. Iron status was assessed during anti-TNF treatment by Hgb, mean corpuscular volume of red blood cells (MCV), serum iron (sFe), ferritin, percent transferrin saturation (sTrfesat) and serum transferrin receptor concentration (sTfR). The sTfR/log ferritin index (TfR/logF) was also used. Prior to the therapy, Hgb and MCV were 118 ± 15.5 g/L and 79 ± 7.7 fl in the infliximab group, and 113 ± 12.5 g/L and 78 ± 5.8 fl in the etanercept group, respectively. In the whole group of patients, sFe was 6.3 ± 4.1 μmol/L and sTrfesat was 9% ± 6%. During anti-TNF therapy, Hgb and MCV improved significantly without use of iron supplementation, and sFe and sTrfesat increased from low to normal levels while inflammation markers decreased, except in one patient, in whom sTfR stayed elevated and the TfR/logF index value was high. In patients with active JIA associated with anaemia, low levels of sFe and sTrfesat cannot be used as markers for iron deficiency. In such patients, sTfR together with TfR/logF seem to be useful in assessing iron deficiency.     

Autologous hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: still not out of fashion

The role of autologous hematopoietic stem cell transplantation (autoHSCT) in adult acute lymphoblastic leukemia (ALL) is still unclear. We retrospectively analyzed the results of the autoHSCT and maintenance therapy, with oral 6-mercaptopurine and methotrexate, in comparison to conventional-dose chemotherapy in the consolidation treatment of adult ALL and lymphoblastic lymphoma (LBL). The patients, with HLA identical sibling donor, underwent allogeneic transplantation, while the others were treated with autoHSCT and maintenance therapy with oral 6-mercaptopurine and methotrexate, or by conventional-dose chemotherapy (patient’s decision, no autologous hematopoietic stem cells harvest). Sixty consecutive adult patients (median age 35.2 years; range 17.3 to 70.7) with ALL (n = 52), LBL (n = 7), and acute biphenotypic leukemia (n = 1) were treated in our center from 1997 to 2007. Patients treated with chemotherapy alone (n = 35) had a shorter median progression-free survival (PFS) compared to patients who underwent autoHSCT plus maintenance therapy (n = 18), 8.4 and 46.8 months, respectively (p = 0.017). Patients treated with chemotherapy alone had also a shorter median overall survival (OS) compared to patients treated with autoHSCT: 13.0 vs. 46.8 months (p = 0.046). The differences remained statistically significant even after excluding patients with Ph positivity. We can conclude that, in our case, autoHSCT followed by maintenance chemotherapy is a good option for adult patients with ALL and, in standard-risk and high-risk patients, provides more favorable OS and PFS rates compared to patients treated by chemotherapy alone. However, we are aware of the fact that our analysis may have been distorted by the fact that the analysis is retrospective, that treatment with autoHSCT was based on patient’s decision, and that chemotherapy may have been administered to negatively selected patients.     

Serious musculoskeletal infections in children receiving anti-tumor necrosis factor-α therapy: a case series

Anti-tumor necrosis factor-α (anti-TNF-α) agents are widely used to treat children with juvenile idiopathic arthritis (JIA) whose disease is resistant to conventional therapy. Although generally well tolerated, use of these agents has been associated with an increased risk of infection. In particular, in patients treated with anti-TNF-α agents, there is an increased susceptibility to infection by intracellular organisms such as tuberculosis, and common infections may present atypically or be more severe. We report four cases of serious musculoskeletal infections among 31 children with JIA being treated with anti-TNF-α agents, two of which were secondary to group A β-hemolytic Streptococcus.     

Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis

Treatment of severe juvenile idiopathic arthritis (JIA) represents a serious challenge. This study investigates the efficacy and safety of repeat courses of rituximab in patients with different forms of JIA refractory to infliximab and standard immunosuppressive therapy. Patients (n = 55; age 2.3–17.0 years) with severe polyarticular and systemic JIA (International League of Association for Rheumatology diagnostic criteria) received rituximab (one intravenous infusion/week for 4 weeks, 375 mg/m² per dose). Efficacy was assessed using the American College of Rheumatology Pediatric (ACR Pedi) criteria. The primary endpoint was an ACR Pedi 30 response at week 24. At week 24, ACR Pedi 30, 50, and 70 responses were achieved by 98%, 50%, and 40% of patients, respectively. By week 96, ACR Pedi 30, 50, and 70 responses were achieved by 98%, 93%, and 93% of 25 patients, respectively. Remission was recorded in 25%, 52%, 75%, and 98% of patients following the first (24 weeks), second (48 weeks), third (72 weeks), and fourth (96 weeks) courses of rituximab, respectively. Rituximab treatment significantly reduced the number of systemic manifestations at week 12 and also enabled 52% of patients to achieve remission of arthritis by week 48. This study supports the efficacy of rituximab in patients with severe forms of JIA, refractory to several prior agents.     

A modified juvenile arthritis damage index to improve articular damage assessment in juvenile idiopathic arthritis—enthesitis-related arthritis (JIA-ERA)

Juvenile arthritis damage index (JADI) consists of two parts which measure articular (JADI-A) and extra-articular (JADI-E) damage in patients with juvenile idiopathic arthritis (JIA). It does not include assessment of cardiac dysfunction and joint areas commonly affected in enthesitis-related arthritis (ERA) category of JIA. We have tried to study if modification of JADI will improve its performance in JIA-ERA. We studied 101 consecutive patients of JIA-ERA. JADI-A was modified (JADI-AM) to include damage assessment of tarsal joints and lumbar spine. JADI-E was modified (JADI-EM) to include assessment of symptomatic cardiac dysfunction. The performances of the modified and standard JADI were compared. Ninety-seven patients were male. The median age was 18 years (9–36). At a median disease duration of 6 years (1–24), joint damage was observed in 47 as assessed by JADI-A. JADI-AM could identify 11 more patients (N = 58) with articular damage. JADI-AM had good correlation with number of joints with limitation of movement (Spearman’s [rS] = 0.9) and low to moderate correlation (rS < 0.7) with measures of disease activity and functional status. JADI-AM discriminated well among patients with different disability levels. Extra-articular damage was observed in 35, and modification of JADI-E with inclusion of cardiac dysfunction did not identify any additional patient. Thus, we propose a modification of the JADI-A (JADI-AM). In JIA-ERA, modification of JADI-A improves its ability to identify articular damage. Modification of the JADI-E may not be needed as symptomatic cardiac involvement is rare.