Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some auto- inflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established

T-Cell Memory Responses Elicited by Yellow Fever Vaccine are Targeted to Overlapping Epitopes Containing Multiple HLA-I and -II Binding Motifs

The yellow fever vaccines (YF-17D-204 and 17DD) are considered to be among the safest vaccines and the presence of neutralizing antibodies is correlated with protection, although other immune effector mechanisms are known to be involved. T-cell responses are known to play an important role modulating antibody production and the killing of infected cells. However, little is known about the repertoire of T-cell responses elicited by the YF-17DD vaccine in humans. In this report, a library of 653 partially overlapping 15-mer peptides covering the envelope (Env) and nonstructural (NS) proteins 1 to 5 of the vaccine was utilized to perform a comprehensive analysis of the virus-specific CD4+ and CD8+ T-cell responses. The T-cell responses were screened ex-vivo by IFN-γ ELISPOT assays using blood samples from 220 YF-17DD vaccinees collected two months to four years after immunization. Each peptide was tested in 75 to 208 separate individuals of the cohort. The screening identified sixteen immunodominant antigens that elicited activation of circulating memory T-cells in 10% to 33% of the individuals. Biochemical in-vitro binding assays and immunogenetic and immunogenicity studies indicated that each of the sixteen immunogenic 15-mer peptides contained two or more partially overlapping epitopes that could bind with high affinity to molecules of different HLAs. The prevalence of the immunogenicity of a peptide in the cohort was correlated with the diversity of HLA-II alleles that they could bind. These findings suggest that overlapping of HLA binding motifs within a peptide enhances its T-cell immunogenicity and the prevalence of the response in the population. In summary, the results suggests that in addition to factors of the innate immunity, "promiscuous" T-cell antigens might contribute to the high efficacy of the yellow fever vaccines. © 2013 de Melo et al

Long-term evaluation of infliximab in the treatment of persistently active juvenile idiopathic arthritis refractory to conventional therapy

Objectives: To evaluate, in long-term open label prospective study, infliximab as therapeutic choice for Juvenile Idiopathic Arthritis (JIA) non responsive to conventional therapy. Methods: We enrolled to treat with infliximab 78 JIA patients (66 females, 12 males): the mean age was 20.7±7.1 years (median 20.9, range 5.4-34.9); mean JIA duration was 13.6±7.6 years (median 13.5, range 0.4-31.4). Infliximab, at dose of 3-10 mg/kg/infusion added to weekly subcutaneous Methotrexate or other previous DMARDs, was administered by intravenous infusions at weeks 0, 2, 6 and every 8 weeks thereafter. Chest X-ray, Mantoux's test, electrocardiogram were performed at baseline; laboratory tests and clinical evaluation were performed at each infusion. Response was evaluated according to ACR improvement criteria. Results: Mean treatment period was 21.6 months±18.8 (median 14.7, range 1.4-72.4). Just after first infusion most of patients reported significant improvement in pain, fatigue, morning stiffness. Infliximab is still successfully administered to 23 patients (29.5%); 55 (70.5%) patients suspended because of: inefficacy (7), infusion reactions (17), adverse events (9), disease flare-up after a period of effectiveness on synovitis, pain, and morning stiffness (19), remission (2), lack of compliance to treatment (1). Infusion reactions, like dyspnea, flushing, chills, headache, hypotension, anxiety, throat oedema, were observed in 29 patients (34.5%). Anti-DNA antibodies were present in 7 patients (none developed Systemic Lupus Eritematous). Conclusions: Infliximab showed impressive effectiveness treating refractory JIA, although most of patients had to discontinue treatment because of disease flare-up or adverse events. Infliximab may represent a good therapeutic choice in patients non-responders to Methotrexate

Disease activity states, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept

The advent of biologic medications has increased considerably the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients. However, there is a need of data from the real world of clinical practice to evaluate thoroughly the efficacy and safety profile of the biologic agents currently approved

Anti-CD 20 monoclonal antibody (rituximab) treatment for inflammatory ocular diseases

Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B cells and widely used in the treatment of non-Hodgkin's lymphoma and rheumatoid arthritis. There is a growing amount of literature which suggests that rituximab may be useful for inflammatory ocular diseases and intraocular lymphoma. Few cases have been reported on treatment of refractory scleritis, peripherative ulcerative keratitis, uveitis and ocular surface inflammatory disorders. Rituximab may be effective in the treatment of ocular inflammatory diseases in particular the most aggressive, recalcitrant and sight-threatening forms of inflammation such as uveitis associated to juvenile idiopathic arthritis. We review the literature covering the use of Rituximab in these conditions and report our results on the efficacy of Rituximab in the treatment of 8 children with very severe and long-standing uveitis who failed to respond to one or more TNF blockers. Our patients showed improvement in activity of uveitis, reduction of concomitant corticosteroids and immunosuppressants after a mean follow-up time of 14.87 months on rituximab. No serious adverse events were encountered in our treated patients. Although further studies are needed for assessing the efficacy of rituximab and the exact dosing regimen, rituximab may be considered as a treatment alternative in patients with the most aggressive forms of inflammatory ocular diseases who fail to respond to conventional and anti-TNF immunosuppressive agent