Administration Of TNF-α Inhibitors Research Articles

Active flare of IgA nephropathy during long-term therapy with anti-tumor necrosis factor-α antibody drugs for Crohn's disease: three case reports and literature review.

In recent years, increasing numbers of reports have described new onset or active disease flare of IgA nephropathy (IgAN) during administration of TNF-α inhibitor (TNFi) therapy for chronic inflammatory diseases. Crohn's disease (CD) is the most common indication for TNFi therapy in this clinical setting, but the underlying etiology of IgAN in such patients remains unclear. We report our experience with three patients who developed acute worsening of preexisting urinalysis abnormalities and kidney dysfunction approximately 2 to 6years after TNFi administration for CD. Kidney biopsies at the time of kidney disease flare revealed IgAN in two patients and IgAN complicated by acute tubulointerstitial nephritis in one patient. The CD and IgAN in all three patients were successfully managed with additional corticosteroid therapy and tonsillectomy without discontinuing TNFi therapy. The clinical course of our patients and similar patients described in the literature suggests that TNFi therapy for CD is associated with a relatively high risk for new onset or disease flare of IgAN. This report discusses the possible involvement of Th1/Th2 imbalance on the immunological background of CD or IgAN.

Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.

Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-κB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development. These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR-146a-5p expression in patients’ sera in relation to clinical outcome of the treatment as well as predisposition to RA. Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-α inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level. Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023). In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 ± 0.171) as compared to those detected after three months of treatment (1.809 ± 0.658, p = 0.033) and observed for healthy controls (5.302 ± 2.112, p = 0.048). Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032). These results support the hypothesis that miR-146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF-α treatment.

Serum Neuroinflammatory Markers’ Levels and Evaluation of Peripheral Large Nerve Fibre Function in Patients with Psoriasis

Objective: Currently, tumor necrosis factoralpha (TNF-α) inhibitors are widely used all over the world, especially in the treatment of severe psoriasis. However, multiple sclerosis (MS) and peripheral neuropathy occurrence associated with TNF-α inhibitors have been reported in the treatment of patients with psoriasis. It is not known whether TNF-α inhibitors reveal underlying neurological disorders in patients with psoriasis. The aim of this study was to investigate whether there is an association between psoriasis and MS or peripheral neuropathy. Methods: In this study, 50 psoriasis patients and 25 healthy controls were enrolled. Neurological examination and needle electromyography test were performed. Serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), S-100 calcium-binding protein (S100B) and neuron specific enolase (NSE), which are involved in neuroinflammatory process, were measured. Results: Serum MMP-9 levels were higher in psoriasis patients compared to healthy controls. Serum MMP-2 and NSE levels were decreased in psoriasis patients compared to healthy controls. There was no significant difference in S100B levels between two groups. All neurophysiological parameters in each individual patient and control were found to be within normal limits and there was no difference between groups. Conclusion: NSE and MMP-9 might play role in the occurrence of MS in psoriasis patients. Especially, we are in the opinion that it might be useful to measure the serum levels of these markers before the administration of TNF-α inhibitors in psoriasis patients with family history of MS.

Intradiscal Administration of Tumor Necrosis Factor-α Inhibitor, Etanercept, Clinically Improves Intractable Discogenic Low Back Pain

Introduction Discogenic low back pain (LBP) has been clinically considered to be one of the sources of intractable LBP. Tumor necrosis factor-α (TNF-α) is one of the well-known pain-related proinflammatory mediators in the degenerative intervertebral disc. However, it is unclear whether its inhibition leads to any analgesic outcomes. In this study, we aimed to examine the effect of intradiscal TNF-α inhibitor administration in discogenic LBP patients. Materials and Methods Discogenic LBP patients were diagnosed on the basis of physical and radiographic (X-ray and magnetic resonance imaging) findings. Sixty patients were divided randomly into two groups: etanercept group ( n = 30; bupivacaine 2 mL with etanercept 10 mg) and control group ( n = 30; bupivacaine 2 mL). Numerical rating scale score for LBP before and 1 day, 1, 2, and 4 weeks after the injection and Oswestry disability index (ODI) score before and 4 weeks after the injection were evaluated. In addition, complications after the injection were evaluated. Results While both groups experienced considerable pain relief, the visual analog scale score significantly decreased in the etanercept group at every time point after the injection ( p &lt; 0.05). The ODI score decreased 4 weeks after the injection only in the etanercept group ( p &lt; 0.05). There were no complications in either group. Conclusion Single intradiscal administration of TNF-α inhibitor showed a greater analgesic effect without any complications lasting for 4 weeks, thereby implying that TNF-α may be profoundly involved in the pathogenesis of chronic discogenic LBP. The present study indicates that intradiscal administration of TNF-α inhibitor can be useful for intractable discogenic LBP treatment in humans. Disclosure of Interest None declared

Psoriasis occurring during anti-TNF-α therapy: causal effect or unrelated?

The introduction of biologic agents, such as tumor necrosis factor (TNF) inhibitors, has transformed our therapeutic approach to rheumatic diseases in recent years. Anti-TNF-α therapy has shown a significant reduction in disease activity in a variety of inflammatory joint conditions, such as rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and psoriatic arthritis [1–3]. In addition, TNF-α antagonists have been effectively used for the treatment of other inflammatory conditions, such as Crohn’s disease, Adamantiades-Behcet’s syndrome and refractory plaque-type psoriasis [4–6]. At present, there are three TNF-blocking agents that are used in rheumatology: two monoclonal anti-TNF-α antibodies (infliximab and adalimumab) and one soluble TNF-α receptor (etanercept). With the expanded use of these agents in clinical practice, outside the setting of randomized clinical trials, an increasing number of cutaneous adverse reactions have been observed [7,8]. Severe cutaneous reactions, such as urticaria, erythema multiforme, cutaneous lupus erythematosus, necrotizing vasculitis, dermatomyositis and lymphomatoid papulosis-like and bullous skin lesions have been described, either in anecdotal case reports or in larger prospective studies [7–10]. One of the most striking reactions has been the development of psoriatic or psoriasiform eruptions in patients without a previous history of psoriasis following the administration of TNF-α inhibitors [11–19]. This contradicts the documented efficacy of these agents in plaque-type psoriasis by virtue of their role in decreasing the activity of proinflammatory mediators in psoriatic inflammation [101]. Although there is an open debate as to whether the development of these psoriasiform lesions is triggered by anti-TNF-α treatment or whether it is a coincidental manifestation of a previously ‘latent’ psoriasis, the accumulating evidence in the literature suggests that psoriasis can occur with TNF-α inhibition and that its early recognition and treatment can spare the patient from substantial morbidity, without necessarily discontinuing a beneficial treatment for the underlying inflammatory condition.