Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept.

BACKGROUND: Alterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota. The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA. METHODS: In this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment. The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons. RESULTS: We did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept. Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes. There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept. CONCLUSIONS: Treatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.

Identification of Prevotella Oralis as a possible target antigen in children with Enthesitis related arthritis.

OBJECTIVES: Patients with Crohn's disease often produce antibodies against flagellated intestinal bacteria. There are mixed data as to whether such antibodies are present in patients with spondyloarthritis. Our objectives were to evaluate for the presence of antibodies against intestinal organisms in children with enthesitis related arthritis (ERA). METHODS: Children with ERA and healthy controls were recruited at three sites. Sera were plated on a nitrocellulose array and incubated with labelled antibodies to human IgA and IgG. RESULTS: At UAB, patients and controls had similar antibody levels against the majority of the bacteria selected, with the exception of increased IgA antibodies among ERA patients against Prevotella oralis (1231 [IQR 750, 2566] versus 706 [IQR 428, 1106], p = .007.) These findings were partially validated at a second but not at a third site. CONCLUSIONS: ERA patients may produce increased IgA antibodies against P. oralis. The possible significance of this finding bears further exploration.

Arthritis in children: comparison of clinical and biological characteristics of septic arthritis and juvenile idiopathic arthritis.

AIM: Childhood arthritis arises from several causes. The aim of this observational study is to compare the clinical and biological features and short-term outcome of different types of arthritis because they have different treatment and prognoses. METHODS: Children <16 years of age hospitalised in a French tertiary care centre for a first episode of arthritis lasting for less than 6 weeks who underwent joint aspiration were retrospectively included. We performed non-parametrical tests to compare groups (septic arthritis (SA), juvenile idiopathic arthritis (JIA) and arthritis with no definitive diagnosis). The time before apyrexia or C reactive protein (CRP) <10 mg/L was analysed using the Kaplan-Meier method. RESULTS: We studied 125 children with a sex ratio (M/F) of 1.1 and a median age of 2.2 years (range 0.3 to 14.6). SA was associated with a lower age at onset (1.5 years, IQR 1.2-3.0 vs 3.6 years, IQR 2.2-5.6), shorter duration of symptoms before diagnosis (2 days, IQR 1-4 vs 7 days, IQR 1-19) and higher synovial white blood cell count (147 cells ×103/mm3, IQR 71-227, vs 51 cells ×103/mm3, IQR 12-113), than JIA. Apyrexia occurred later in children with JIA (40% after 2 days, 95% CI 17% to 75%) than children with SA (82%, 95% CI 68% to 92%), as did CRP<10 mg/L (18% at 7 days, 95% CI 6.3% to 29.6% vs 82.1%, 95% CI 76.1% to 89.7%, p=0.01). CONCLUSIONS: There were no sufficiently reliable predictors for differentiating between SA and JIA at onset. The outcomes were different; JIA should be considered in cases of poor disease evolution after antibiotic treatment and joint aspiration.

Effect of probiotics on clinical and immune parameters in enthesitis-related arthritis category of juvenile idiopathic arthritis.

Gut microflora and dysbiosis as an environmental factor has been linked to the pathogenesis of enthesitis-related arthritis (JIA-ERA); thus, we performed a proof-of-concept study of probiotics to modulate the gut-flora and study the effects on immune and clinical parameters of children having JIA-ERA. Forty-six children with active JIA-ERA were randomized to placebo or probiotic therapy along with non-steroidal anti-inflammatory drugs (NSAIDs) for 12 weeks. Patients were assessed using a six-point composite disease activity index (mJSpADA) based on morning stiffness, joint count, enthesitis count, sacroiliitis/inflammatory back pain, uveitis and erythrocyte sedimentation rate/C-reactive protein (ESR/CRP). Frequencies of T helper type 1 (Th1), Th2, Th17 and regulatory T cells in blood were measured using flow cytometry. Serum cytokines interferon (IFN)-γ, interleukin (IL)-4, IL-17, IL-10, tumour necrosis factor (TNF)-α and IL-6 were measured by cytokine bead array using flow cytometer. The average age of 46 children (44 boys) was 15 ± 2.5 years and duration of disease was 3.5 ± 3 years. There was no significant difference in improvement in mJSpADA between the two groups (P = 0·16). Serum IL-6 levels showed a decrease (P < 0·05) in the probiotic-group. Th2 cell frequency (P < 0·05) and serum IL-10 levels (P < 0·01) showed an increase in the placebo group, but again the probiotic use did not show a significant change in immune parameters when compared to the placebo. Adverse effects among the probiotic and placebo groups were diarrhea (36 versus 45%), abdominal pain (9 versus 20%), minor infections (4·5 versus 20%) and flatulence (23 versus 15%), respectively. Thus, we can conclude that probiotic therapy in JIA-ERA children is well tolerated, but failed to show any significant immune or clinical effects over NSAID therapy.

Juvenile idiopathic arthritis and rheumatoid arthritis: bacterial diversity in temporomandibular joint synovial fluid in comparison with immunological and clinical findings.

Temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA) occurs in up to 80% of affected children. The purpose of this study was to investigate the presence of bacterial DNA in synovial fluid, and to compare this with clinical and immunological findings in children with JIA, adults with persistent JIA, and adults with rheumatoid arthritis, in order to detect whether bacteria contribute to inflammation in TMJ arthritis. Synovial fluid and skin swab samples were collected from 30 patients (54 TMJs). Bacterial detection was performed using 16S rRNA pyrosequencing. Bacterial DNA was detected in 31 TMJs (57%) in 19 patients (63%). A positive statistically significant correlation was registered between bacterial DNA detected in TMJ synovial fluid and the following factors: total protein concentration in synovial fluid, interleukin 1ß, tumour necrosis factor alpha, adrenocorticotropic hormone, and adiponectin, as well as the duration of the general medical disease. Fourteen different bacterial species were detected in synovial fluid. Bacterial DNA in TMJ synovial fluid without contamination was detected in more than 50% of the patients. Studies are needed to evaluate the consequences of this bacterial DNA in synovial fluid with regard to TMJ arthritis.

High prevalence of streptococcal or Epstein-Barr virus infections in children with acute non-septic monoarthritis.

To investigate associations between infections and acute monoarthritis, we performed a prospective study on 32 children consecutively hospitalized and 32 age-matched controls. Among 26 (81%) children having infections, the most frequent agents were Group A ?-hemolytic Streptococcus (GAS: 53%) and Epstein-Barr virus (EBV: 37.5%). Among controls, only 5 (16%) were infected with GAS and 2 (6%) with EBV (P<0.005). The most frequently involved joints were hip in 15 children and ankle in 10 children. Our study showed that acute monoarthritis in children may be frequently associated with streptococcal or EBV infections.

Rheumatologic conditions in children who may present to the orthopaedic surgeon.

Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of diseases characterized by onset of chronic arthritis in childhood. Diagnosis requires onset of disease by age 16 years, persistent arthritis in any joint for ≥ 6 weeks, and exclusion of other conditions that cause arthritis (eg, infection, malignancy, acute rheumatic fever, inflammatory bowel disease). Most patients with juvenile idiopathic arthritis present with subacute arthritis with minimal pain and few constitutional symptoms. Laboratory evaluation and imaging are useful to exclude other diagnoses and establish the presence of systemic inflammation. However, these modalities are of limited value in screening for rheumatic diseases, and they may be misleading because of the high rate of false-positive results. Most rheumatologic conditions are diagnosed based on pattern recognition, which is established with a thorough history and physical examination.

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 Izmir, 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.

A case of bovine valve endocarditis caused by Engyodontium album.

We report the first case of Engyodontium album bioprosthetic valve endocarditis in a 44-year-old male with a history of juvenile rheumatoid arthritis. There is only one other report of Engyodontium album as a human pathogen. The present case supports the increased incidence of fungal endocarditis especially in patients receiving immunotherapy.

Exposure to animals and risk of oligoarticular juvenile idiopathic arthritis: a multicenter case-control study.

BACKGROUND: An inverse association between early contact with microbial compounds and respiratory allergies is well established. The protective effect of infant contact with animals was also shown for inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). We aimed to test the association between animal contact in infancy and oligoarticular juvenile idiopathic arthritis (OA JIA). METHODS: Parents of children with OA JIA registered at the Hospital for Pediatric Rheumatology in Garmisch-Partenkirchen were asked to complete a questionnaire. Children who underwent strabismus surgery at six referral centers for ophthalmology served as controls. Children age 6 to 18 years born in Germany without malformations were included (238 cases; response 89% and 832 controls; response 86%). Data were analyzed using logistic regression models after adjusting for potential confounders. RESULTS: Neither place of living (urban vs. rural area), living on a farm, nor regular farm animal (adjusted odds ratio 0.79; 95% confidence interval 0.42-1.47) or pet contact (0.79; 0.55-1.14) during infancy were clearly related to case status. Allergic rhinitis was inversely related to OA JIA (0.57; 0.34-0.95).Neither place of living (urban vs. rural area), living on a farm, nor regular farm animal (adjusted odds ratio 0.79; 95% confidence interval 0.42-1.47) or pet contact (0.79; 0.55-1.14) during infancy were related to case status. Allergic rhinitis was inversely related to OA JIA (0.57; 0.34-0.95). CONCLUSIONS: Contact with farm environments in infancy might not be associated with OA JIA. This finding is consistent with previous findings for diabetes mellitus type 1 but contradicts results for IBD and SLE.

Safety of etanercept in patients at high risk for mycobacterial tuberculosis infections.

OBJECTIVE: The magnitude of the risk of reactivation of tuberculosis (TB) on use of etanercept, especially in patients with positive purified protein derivative (PPD) test, has not been assessed. We evaluated the risk of developing active TB among PPD-positive patients treated with etanercept. METHODS: All patients with a positive PPD test, as defined by American Thoracic Society guidelines, who received etanercept at Cook County Hospital from 2001 to 2008 were retrospectively reviewed. The primary endpoint was the development of active TB either while receiving or after completing etanercept therapy. RESULTS: Four hundred eighty-seven patients received etanercept, of whom 84 were PPD-positive and constituted the primary cohort. The cohort was composed largely of patients who were at high risk for development of active TB: born in endemic area (80%), ethnic/racial minorities (51 Hispanic, 16 African American, and 8 Asian), and low socioeconomic status (66, 78.57%). Overall etanercept exposure was a mean of 24.6 months (range 3 to 60 mo), with 196 patient-years of etanercept exposure in PPD-positive individuals. Indications for etanercept use included rheumatoid arthritis 58 (69%), ankylosing spondylitis 11 (13%), psoriatic arthritis 13 (15.5%), juvenile inflammatory arthritis 1 (1.2%), and vasculitis 1 (1.2%). Of the 80 subjects, 74 received treatment for latent TB infection (LTBI) prior to initiating etanercept. A comprehensive review of these patients' medical records failed to reveal any active TB infection. CONCLUSION: This systematic analysis suggests that the risk of reactivation of LTBI during etanercept therapy is low in appropriately treated individuals.

Is the enthesitis-related arthritis subtype of juvenile idiopathic arthritis a form of chronic reactive arthritis?

OBJECTIVE: Enteric organisms are known to trigger reactive arthritis. The enthesitis-related arthritis (ERA) form of juvenile idiopathic arthritis (JIA) clinically resembles reactive arthritis. Therefore, we looked for a role of enteric bacteria in ERA. METHODS: Synovial fluid (SF) was obtained from 26 patients with ERA and 10 patients with rheumatoid arthritis (RA). Blood specimens were also obtained from patients with ERA and from 10 normal individuals. Lymphocyte proliferation assays were done on whole blood and SF mononuclear cells using as antigens crude lysates of the enteric bacteria Salmonella typhimurium, Yersinia enterocolitica, Shigella flexneri and Campylobacter jejuni. Crude lysate of Escherichia coli was used as a control antigen. HLA-B27 typing was done using the polymerase chain reaction. Homing of gut-specific T cells (CD103+) to the synovial compartment was studied using tri-colour flow cytometry. The antigen-specific cytokine profile was determined by flow cytometry. RESULTS: Antigen-specific lymphoproliferative responses were observed in 14 of 26 patients. Among these patients, 12 showed a response in SF (four each to S. typhimurium and C. jejuni, and in two each to S. flexneri and Y. enterocolitica), and two patients in blood (S. typhimurium in both). None of the healthy controls showed a response in the blood. Lymphoproliferative responses in SF were more frequent in patients with JIA (12/26) than in controls with RA (1/10, P < 0.05). Patients with an antigen-specific response had a higher ratio of SF/blood CD103+ T cells compared with those with no antigen-specific response (P < 0.01). Antigen-specific as well as mitogen-stimulated cytokine production showed a Th1 bias. CONCLUSION: Enteric bacteria may have a role in exacerbation of disease in patients with ERA. The immune response in patients with ERA is Th1-dominant.

Rheumatoid arthritis, juvenile arthritis, iridocyclitis and the Epstein-Barr virus.

In order to examine the relation of Epstein-Barry virus (EBV) infection to chronic arthritis in children antibodies to EB virus capsid antigen (EBVCA) and rheumatoid arthritis nuclear antigen (RANA) were analysed in sera from 133 patients classified as juvenile rheumatoid arthritis (JRA) or pauciarticular, polyarticular, or systemic juvenile chronic arthritis. Except for an increased frequency in the systemic subgroup, the prevalence of antibodies to EBVCA and titres of anti-RANA antibodies was similar in patients and controls. These data do not support an aetiological role for EBV in chronic arthritis in children, including JRA, and suggest that the mechanisms which may account for the higher titres of anti-RANA antibodies in adult RA do not occur in children.

[Viremia in children with rheumatoid arthritis]. / Virusemiia u detei, bol'nykh revmatoidnym artritom.

The blood specimens from 22 children with rheumatoid arthritis, 57 children with other chronic diseases and 30 apparently normal children were tested for the presence of Coxsackie A and B, adeno, and rubella viruses by the method of co-cultivation of patient's lymphocytes with continuous HEp-2 cell culture. Children with chronic diseases were found to have viremia much more frequently than normal children. The frequency of finding of different viruses in patients with rheumatoid arthritis (86.4%) significantly exceeded that in healthy children (20%). These patients had rubella and adeno 5 viruses in their blood more frequently than children in the other groups under study. Repeated examinations of 14 patients with rheumatoid arthritis at intervals of 1 year or longer revealed in 11 of them the same viruses as those identified in initial examinations. Persistence of some viruses in patients with rheumatoid arthritis is discussed.

Failure to show mycoplasmas and cytopathogenic virus in rheumatoid arthritis.

Synovial needle biopsies, joint aspirates, and joint tissue obtained at open operation from 41 cases of rheumatoid arthritis were inoculated onto PPLO media, L-form medium, and cell cultures for the isolation of mycoplasmas, L-form bacteria, and viruses. Medium suitable for the isolation of 'T' strain mycoplasmas was not employed. No mycoplasmas, L-form bacteria, or cytopathogenic viruses were shown. Similar specimens from nine patients diagnosed as having Reiter's disease were examined in a like manner and yielded only one Mycoplasma hominis type 1 isolate from a knee joint biopsy. It is concluded that known strains of mycoplasma and bacterial L-forms do not play a direct role in early and established cases of rheumatoid arthritis. Some of the cell cultures used in this study contained mycoplasma contaminants. Bacterial contaminants were also encountered in occasional batches of L-form medium.