Higher concentrations of vitamin D in Canadian children with juvenile idiopathic arthritis compared to healthy controls are associated with more frequent use of vitamin D supplements and season of birth.

A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA).  The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents. Data from a Canadian cohort of children with new-onset JIA (n= 164, data collection 2007-2012) were compared to Canadian Health Measures Survey (CHMS) data (n=4027, data collection 2007-2011). We compared 25-hydroxy vitamin D (25(OH)D) concentrations with measures of inflammation, vitamin D supplement use, milk intake, and season of birth. Mean 25(OH)D level was significantly higher in patients with JIA (79 ± 3.1 nmol/L) than in healthy controls (68 ± 1.8 nmol/L P <.05). Patients with JIA more often used vitamin D containing supplements (50% vs. 7%; P <.05). The prevalence of 25(OH)D deficiency (<30 nmol/L) was 6% for both groups. Children with JIA with 25(OH)D deficiency or insufficiency (<50 nmol/L) had higher C-reactive protein levels. Children with JIA were more often born in the fall and winter compared to healthy children. In contrast to earlier studies, we found vitamin D levels in Canadian children with JIA were higher compared to healthy children and associated with more frequent use of vitamin D supplements. Among children with JIA, low vitamin D levels were associated with indicators of greater inflammation.

Cardiovascular Disease in Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA), is a term used to describe a group of inflammatory disorders beginning before the age of 16 years. Although for the majority of children remission is achieved early, those with systemic or polyarticular form of the disease may present persistent symptoms in adulthood. Considering that there is overlap in the pathogenesis of JIA with adult rheumatic diseases, concerns have been raised as to whether JIA patients could be at increased cardiovascular (CV) risk in the long-term. In this review, we summarize evidence for CV involvement in JIA and present data on CV risk factors and surrogate markers of arterial disease. We also provide information on beneficial and harmful CV effects of anti-inflammatory medications in the context of JIA and suggest strategies for CV screening. Overall, patients with systemic forms of JIA demonstrate an adverse lipid profile and early arterial changes relevant to accelerated arterial disease progression. Although there is paucity of data on CV outcomes, we recommend a holistic approach in the management of JIA patients, which includes CV risk factor monitoring and lifestyle modification as well as use, when necessary, of antiinflammatory therapies with documented CV safety.

Immunogenicity and safety of influenza vaccination in patients with juvenile idiopathic arthritis on biological therapy using the microneutralization assay.

BACKGROUND: Seasonal influenza virus vaccination should be considered in all pediatric patients with rheumatic diseases. Few studies have addressed influenza vaccination safety and efficacy in this group. We aim to prospectively evaluate immunogenicity and safety of the trivalent inactivated influenza vaccine including A/H1N1, A/H3N2 and B strains in children with juvenile idiopathic arthritis (JIA) receiving biological therapy. METHODS: Thirty-five children diagnosed with JIA and 6 healthy siblings were included. Serum samples were collected prior to, 4-8 weeks and one year after vaccination. Microneutralization assays were used to determine neutralizing antibody titers. The type and duration of therapy were analyzed to determine its effect on vaccine response. Clinical data of the participants were collected throughout the study including severe adverse events (SAE) and adverse events following immunization (AEFI). RESULTS: Twenty-five patients (74.3%) received biological treatment for JIA; anti TNF-α was prescribed in 15, anti IL-1 receptor in 4 and anti IL-6 receptor therapy in 6 children. The seroprotection rate 4-8 weeks after vaccination in the JIA group was 96% for influenza A/(H1N1)pdm and influenza A/H3N2, and 88% for influenza B. No differences were found in GMT, seroprotection and seroconversion rates for the three influenza strains between the control group and patients receiving biological therapy. Furthermore, long-term seroprotection at 12 months after vaccination was similar in patients receiving either biological or non-biological treatments. No SAEs were observed. CONCLUSIONS: In this study, influenza vaccination was safe and immunogenic in children with JIA receiving biological therapy.

Evolución de pacientes con artritis idiopática juvenil en terapia biológica que cursan infección por virus varicela zoster: a propósito de 4 casos / Outcomes of patients with juvenile idiopathic arthritis on biological therapy and have a varicella-zoster virus infection

En niños inmunocomprometidos, la infección por virus varicela puede producir una enfermedad grave. Existen pocos casos publicados de varicela en pacientes con artritis idiopática juvenil (AIJ) y terapia biológica. OBJETIVO: Describir la evolución de pacientes con AIJ con terapia biológica que adquirieron el virus varicela. CASOS CLÍNICOS: Se describe la historia clínica de 4 pacientes con AIJ, de entre 3 y 12 años de edad, que presentaron infección por virus varicela zoster estando con distintas terapias biológicas: 2 con anti TNF, uno con anti IL-6 y uno con bloqueador de la coestimulación del linfocito T. Dos de ellos habían recibido la vacuna contra la varicela. Todos recibieron diferentes terapias y evolucionaron sin complicaciones, no encontrando diferencias importantes en relación con el tipo de terapia biológica ni con el antecedente de haber sido vacunados. En todos los pacientes se suspendió el tratamiento biológico por al menos 2 semanas y se reinició sin reactivación de la artritis. CONCLUSIONES: En esta serie de pacientes con AIJ tratados con terapia biológica que cursaron con infección por VVZ no se observaron complicaciones graves.

Varicella virus infection may develop into severe disease in immunocompromised children. There are few studies that describe the clinical presentation of varicella infection in patients with Juvenile Idiopathic Arthritis when on biological therapy. OBJECTIVE: Describe the outcomes of patients with a diagnosis of Juvenile Idiopathic Arthritis, who acquired a varicella virus infection during treatment with biological therapy. CLINICAL CASES: A description is presented on 4 cases of Juvenile Idiopathic Arthritis in children between 3 and 12 years old, who developed a varicella-zoster infection during treatment with different biological therapies. Two patients were taking anti-TNF agents, one an Anti IL-6 agent, and one patient a T cell costimulatory blockade agent. Two of them received varicella vaccination prior to the start of biological therapy. All of them received different therapies and had favourable outcome without developing complications. No significant differences were found as regards the type of biological therapy or history of previous vaccination. Biological therapy was suspended for at least 2 weeks in all patients, and was restarted without reactivation of arthritis. CONCLUSIONS: No serious complications were observed in this patient series of children with JIA treated with biological therapy associated with VZV infection.

The profile of polyunsaturated fatty acids in juvenile idiopathic arthritis and association with disease activity.

We investigated the association between dietary intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs), serum profiles, and immune and inflammatory markers in juvenile idiopathic arthritis (JIA) in relation to onset, activity, and duration. A total of 66 JIA patients and 42 controls were included. Serum PUFA levels were assessed by gas-liquid chromatography-mass spectrometry, a dietary intake by 7-day dietary record method, and IL-6, IL-10, and IL-17A levels using ELISA. Dietary PUFA intake did not differ between the JIA group and controls. Intakes of n-6 and n-3 PUFA and serum levels were not associated. Levels of total n-6 PUFA and linoleic acid (LA) were higher in inactive JIA than in active JIA. Patients with active and short-lasting disease (less than 3 months from diagnosis) had significantly lower levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) than the control. Serum α-linolenic acid (ALA) levels were significantly higher in poly-JIA than in oligo-JIA and in controls. We found significantly higher serum IL-10 levels in JIA than in controls. Serum n-6 and n-3 levels were significantly negatively correlated with active joint count, erythrocyte sedimentation rate, and C-reactive protein and positively with platelet count. Our study presents the low levels of AA and DHA in the active phase of short-lasting JIA, particularly poly-JIA, and the relationship between n-6 and n-3 PUFA and classic markers of inflammation. PUFAs may contribute to the pathogenesis of JIA and support a necessity to identify new targets suitable for successful interventional studies in JIA patients.

[Outcomes of patients with juvenile idiopathic arthritis on biological therapy and have a varicella-zoster virus infection]. / Evolución de pacientes con artritis idiopática juvenil en terapia biológica que cursan infección por virus varicela zoster. A propósito de 4 casos.

Varicella virus infection may develop into severe disease in immunocompromised children. There are few studies that describe the clinical presentation of varicella infection in patients with Juvenile Idiopathic Arthritis when on biological therapy. OBJECTIVE: Describe the outcomes of patients with a diagnosis of Juvenile Idiopathic Arthritis, who acquired a varicella virus infection during treatment with biological therapy. CLINICAL CASES: A description is presented on 4 cases of Juvenile Idiopathic Arthritis in children between 3 and 12 years old, who developed a varicella-zoster infection during treatment with different biological therapies. Two patients were taking anti-TNF agents, one an Anti IL-6 agent, and one patient a T cell costimulatory blockade agent. Two of them received varicella vaccination prior to the start of biological therapy. All of them received different therapies and had favourable outcome without developing complications. No significant differences were found as regards the type of biological therapy or history of previous vaccination. Biological therapy was suspended for at least 2 weeks in all patients, and was restarted without reactivation of arthritis. CONCLUSIONS: No serious complications were observed in this patient series of children with JIA treated with biological therapy associated with VZV infection.

T cell subpopulations in juvenile idiopathic arthritis and their modifications after biotherapies.

Inflammatory T cells are thought to be central to the pathogenesis of juvenile idiopathic arthritis. In particular, recent evidence has underlined the importance of a balance between Th17 and Treg cells. Several mechanisms have come to light that control this reciprocal relationship. Moreover, it has been shown that in certain conditions, Th17 cells can shift toward a nonclassic Th1 phenotype. Anti-rheumatic biologic therapies may interfere with these mechanisms and re-establish immune tolerance.

Juvenile idiopathic arthritis-associated uveitis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.

Management of Children with Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous disorders of chronic arthritis in childhood and remains the commonest pediatric rheumatic disease associated with significant long-term morbidity. Advances in understanding of the pathogenesis, better definition of disease control/remission measures, and the arrival of biological agents have improved the outcomes remarkably. Methotrexate (Mtx) remains the first-line disease modifying (DMARD) therapy for most children with JIA due to its proven efficacy and safety. Sulphosalazine (SSz) (especially for enthesitis) and leflunomide may also have a secondary role. Tumor necrosis factor inhibitors (TNF-I), alone or in combination with Mtx have shown tremendous benefit in children with polyarticular JIA, enthesitis related arthritis (ERA) and psoriatic arthritis. Tocilizumab appears very efficacious in systemic arthritis and abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear, though clearly beneficial in adult RA. TNF-I with Mtx is also effective in uveitis associated with JIA. Biologicals have demonstrated an impressive safety record in children with JIA, although close monitoring for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of cancers is warranted.

Long-term safety and efficacy of varicella vaccination in children with juvenile idiopathic arthritis treated with biologic therapy.

OBJECTIVE: To evaluate the long-term safety and efficacy of varicella vaccination in children with juvenile idiopathic arthritis (JIA) treated with biologics. METHODS: We performed a prospective study with long term follow up. Six patients with JIA treated with biologics, received 2 doses of varicella vaccine. Before vaccination, JIA was stable on therapy and peripheral blood lymphocyte populations were within normal limits. After vaccination, children were followed for disease activity, infections and production of protective antibodies. RESULTS: There were no serious side effects after vaccination and no varicella infection. Disease activity remained stable. Five patients (83%) produced protective antibodies against varicella virus 6 weeks after the second vaccination. One patient with low level of protective antibodies got mild varicella infection 4 months after the second vaccination. CONCLUSION: Varicella vaccination appears to be safe in our group of six JIA patients treated with biologics. Vaccination does not always protect against varicella infection.

Association between condylar morphology and changes in bony microstructure and sub-synovial inflammation in experimental temporomandibular joint arthritis.

BACKGROUND: In juvenile idiopathic arthritis involvement of the temporomandibular joints (TMJs) is often associated with mandibular growth deviations. The relation between the growth deviations and severity of the inflammation, condylar shape, the micro-architecture, and the quality of the bone has not previously been investigated. This paper studies the effect on the bony structures in mandibular condylar development in rabbits with antigen-induced arthritis. METHODS: Included were 42 juvenile rabbits with ovalbumin-induced arthritis of the TMJs treated with intraarticular saline, intraarticular etanercept or subcutaneous etanercept. A TMJ from each animal was scanned using micro-computed tomography and structural parameters were calculated. Three-dimensional reconstructions of the mandibular condyle were scored blindly as normal or abnormal. TMJs were stratified for condylar morphology and were evaluated against data on trabecular structural parameters, inflammation, degree of mineralization, overall mandibular growth, and mineral apposition rate. RESULTS: Abnormal morphology were seen in 15/32 animals available for data analysis. Erosions were an uncommon finding. Abnormal morphology was strongly related to the degree of inflammation. The trabecular separation was larger in group with abnormal morphology than in the group with normal morphology. Abnormal condylar morphology was not associated with overall mandibular growth. No differences were observed in mineral apposition rate. No differences in structural parameters were seen according to treatment modality. CONCLUSION: We showed that severe inflammation in the TMJs during mandibular development was associated with morphological changes in the mandibular condyle. These changes were predominantly seen at the macro-morphological level and only very few differences were structural.

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.

[Stress and rheumatoid arthritis]. / Stress und Rheuma.

Rheumatoid arthritis (RA) is a chronic rheumatic disease of unknown aetiology and variable severity. It is now well known that several risk factors are involved in its pathogenesis, including genetic factors and sex hormones as well as environmental factors, i.e. infections and stress. In particular stress is now recognised as an important risk factor for the onset and even more for the modulation of disease activity in RA. Many studies have clearly shown that chronic mild stress (family or professional stress) may lead to proinflammatory effects, increasing disease activity. Furthermore, a positive correlation between the stress level at the onset of RA and radiological progression could be demonstrated. The onset of RA was associated with moderate stress at work, underlining the possible interactions between the various stress systems and the immune system. In this respect it could be demonstrated that coping strategies reduce stress episodes and change stress management with a positive impact on disease activity in RA. However, more studies are warranted to further explore the pathophysiological implications of stress on onset and activity of chronic autoimmune diseases.

Damage-associated molecular patterns--emerging targets for biologic therapy of childhood arthritides.

Juvenile idiopathic arthritis (JIA) is a group of chronic childhood arthritides of unknown origin. Although the use of glucocorticoids and immunosuppressants brought a substantial improvement in treatment, the present therapeutic regime could not be considered satisfactory. As inflammation seems to be an essential part of pathogenesis of JIA, efforts have been made to develop pharmaceutical means to mitigate the innate immune system. Emerging targets for treatment are alarmins, a family of multifunctional intracellular proteins with strong pro-inflammatory activity. In the context of JIA, particularly interesting are high mobility group box 1 (HMGB-1) and three members of the S100 family: S100A8, S100A9, and S100A12. No definite conclusion can be made at the time, but both animal models and clinical studies support the concept of alarmins as possible key mediators of JIA. Therefore, pharmacological interference with alarmin pathways could turn out to be an excellent strategy for long-term management of JIA. Several options have been tested and they either inhibit the release of alarmins or sequester the already secreted ones. Although still very few in number, therapeutic experiments on mice are quite optimistic. Thus, it was the purpose of the present review to give an overview of the present knowledge on the topic and to bring this exciting new therapeutic possibility to the focus of rheumatologists.

[Stress, hormones, and neuronal signals in the pathophysiology of rheumatoid arthritis. The negative impact on chronic inflammation]. / Stress, Hormone und neuronale Signale bei rheumatoider Arthritis Der negative Einfluss auf das chronische Entzündungsgeschehen.

This review demonstrates that hormonal and neuronal factors, which are released during stressful situations, can unfavorably influence the two chronic diseases of rheumatoid arthritis and juvenile idiopathic arthritis. Noradrenaline and cortisol are in the focus of this review. In the said two chronic inflammatory diseases, it is obvious that apart from the immune system also the endocrine and nervous system play an essential role in the stress-induced initiation and aggravation of these diseases.

Biologic therapies for juvenile arthritis.

A group of therapies with exciting potential has emerged for children and young people with severe juvenile idiopathic arthritis (JIA) uncontrolled by conventional disease modifying drugs. Theoretical understanding from molecular biologic research has identified specific targets within pathophysiological pathways that control rheumatoid arthritis (RA) and JIA. This review identifies the pathways of autoimmunity to begin to show how biologic agents have been produced to replicate, mimic, or block culpable molecules and so promote or inhibit cellular activity or proliferation. Of these agents, cytokine antagonists have shown greatest promise, and early clinical studies of tumour necrosis factor (TNF) blockade have identified dramatic clinical benefit in many children with JIA. However, as will also be discussed, overlap of pathways within a complex immune system makes clinical response unpredictable and raises additional ethical and administrative concerns.

Developing a service for biologic therapies: a personal experience.

Tumour necrosis factor alpha (TNFalpha) has been identified in the pathogenesis of synovitis and joint destruction in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Therefore selected targeting of pathogenic elements of disease is possible (Chu et al., 1991). TNFalpha is a pro-inflammatory cytokine (mediator) and the over-expression of mediators is considered to be responsible for the damage to articular cartilage in bones. Elevated levels of TNFalpha, correlating with disease activity, have been measured in the serum and synovial fluid of patients with rheumatic diseases and are therefore an ideal target for therapy (Mangge et al., 1995; Cope et al., 1992). The National Institute for Clinical Excellence (NICE) approved the use of two therapies; entanercept (Enbrel) and infliximab (Remicade) for use in patients with active RA in 2002 (NICE, 2002). Other biologic treatments including adalimumab (D2E7) and anakinra (Kineret) will also be available for use in the future. This paper explores the development of a service to provide these therapies to patients.

[A clinical and experimental analysis of the effects of laser therapy]. / Kliniko-éksperimental'nyi analiz éffektov lazerterapii.

Thymus area was exposed to laser radiation in 180 Wistar male rats. Intact animals experienced a stress response to a single laser procedure (a rise in the levels of hydrocortisone, a fall in those of insulin, triiodothyronine and thyroxine). Longer exposure to laser radiation caused a break of the hydrocortisone mechanism. Similar effects were seen in the course exposure. The immune system was unchanged. In adjuvant arthritis laser radiation induced similar hormonal shifts and additional suppression of immunity. In 82 children with active juvenile rheumatoid arthritis laser therapy produced an insignificant effect, while in adults with moderate rheumatoid arthritis the response was good.

Juvenile rheumatoid arthritis and spondyloarthropathies.

Further insight into the etiology and pathogenesis of juvenile rheumatoid arthritis (JRA) is presented in recent immunogenetic studies, particularly the allele associations of the pauciarticular pattern of disease. Evidence suggests that bacterial heat-shock proteins may be significant in the chronic inflammatory response in children with arthritis. Data on the role of complement activation and cytokines and their receptors also are presented. Coagulopathy in JRA may have more than one etiologic factor, including a viral agent, as may the disease itself. In the treatment of growth abnormalities in JRA, the neuroendocrine system, recombinant growth hormone, intravenous iron therapy, and nutritional supplementation are all areas of recent investigation. In outcome studies, ocular involvement and the presence of circulating IgM rheumatoid factor appear to be risk factors for disability. However, disease of less than 2 years' duration and absence of radiographic lesions likely predict good response to methotrexate therapy.

Seroprevalence of Helicobacter pylori infection is not increased in pediatric inflammatory arthritides.

OBJECTIVE: To determine the seroprevalence of H. pylori infection among children with inflammatory arthritides receiving antiinflammatory drug therapy. METHODS: An enzyme linked immunosorbent assay (ELISA) was used to detect H. pylori specific immunoglobulin G antibody in 95 children with inflammatory arthritides, 53 children with chronic inflammatory bowel diseases and 47 parents of children with inflammatory arthritis. RESULTS: The frequency of seropositivity in children with arthritis (9/95, 9.5%) was not significantly higher than in children with chronic inflammatory bowel diseases (1/53, 1.9%; p = 0.16). Serum samples from parents were positive in 16 of 47 (34%), including 4 parents with children who also demonstrated a positive immune response. CONCLUSION: These data do not provide evidence for an increased frequency of H. pylori infection among children with inflammatory arthritides. The therapeutic use of ulcerogenic medications is likely to be an independent risk factor predisposing to dyspeptic symptoms and gastritis in this patient population.