TNF-α Blockers Research Articles

Obesity reduces the drug survival of second line biological drugs following a first TNF-α inhibitor in rheumatoid arthritis patients

ObjectivesThe aim of this study was to assess whether body mass index (BMI) affects clinical outcomes in rheumatoid arthritis (RA) patients starting a second line biological drug after failure of a first TNF-α blocker. MethodsFrom a longitudinal cohort, we analyzed 292 RA patients (66 obese, 109 overweight, and 117 normal-weight) treated with a first ever anti-TNF-α drug. Patients discontinuing the therapy were followed-up if began a second biological drug. Drug survival, by Kaplan-Meier life analysis, and 12 months disease remission based on the 28-joint Disease Activity Score (DAS28) were assessed for either course of biologics. The baseline predictors of clinical outcomes were assessed by Cox regression analysis. ResultsSurvival of the first anti-TNF-α drug was lower in obese (39.4%) than in normal-weight (49.1%) patients, but the difference was not statistically significant. Obese patients had the highest hazard to discontinue the first anti-TNF-α drug (HR 1.64, 1.02–2.62 95% IC, P=0.04), and the lowest percentage of DAS28-based disease remission at 12 months (P=0.04). In 97 (37 normal-weight, 36 overweight, 24 obese) patients who started a second non-anti-TNF-α biological drug, persistence on therapy was significantly lower in obese (43.5%) than in normal-weight (80%, P=0.04) group, and again obesity significantly predicted drug discontinuation (HR 2.9, 1.08–8.45 95% IC, P=0.04). Significantly, less obese patients attained a disease remission (12%, P=0.004) at 12 months. ConclusionOur study provides evidence that obese RA patients poorly respond to second line non-anti-TNF-α drugs after failure of a first TNF-α inhibitor.

Pro-inflammatory cytokines and leukocyte oxidative burst in chronic kidney disease: culprits or innocent bystanders?

Pro-inflammatory cytokines are elevated in chronic kidney disease (CKD), a condition characterized by microinflammation with oxidative stress as key feature. However, their role in the inflammatory response at uraemic concentrations has not yet been defined. In this study, the contribution of cytokines on induction of leukocyte oxidative stress was investigated. Whole blood from healthy donors was incubated with 20-1400 pg/mL TNFα, 5-102.8 pg/mL IL-6, 20-400 pg/mL IL-1β and 75-1200 pg/mL IL-18 separately or in combination. Oxidative burst was measured, at baseline and after stimulation with fMLP (Phagoburst™). The effect of the TNFα blocker, adalimumab (Ada), was evaluated on TNFα-induced ROS production. Finally, the association between TNFα and the composite end point all-cause mortality or first cardiovascular event was analysed in a CKD population stage 4-5 (n = 121). While interleukin (IL)-6, IL-1β and IL-18 alone induced no ROS activation of normal leukocytes, irrespective of concentrations, TNFα induced ROS activation at baseline (P < 0.01) and after fMLP stimulation (P < 0.05), but only at uraemic concentrations in the high range (400 and 1400 pg/mL). A similar pattern was observed with all cytokines in combination, but already at intermediate uraemic concentrations (all P < 0.05, except for monocytes after fMLP stimulation: n.s.), suggesting synergism between cytokines. ROS production induced by TNFα (400 pg/mL) and the cytokine combination was blocked with Ada. Uraemia-related oxidative stress in leukocytes of haemodialysis patients was however not blocked by Ada. In patients, TNFα was not associated to adverse events (HR: 1.52, 95% CI 0.81-2.85, P = 0.13). Among several pro-inflammatory cytokines, TNFα alone was pro-oxidative but only at high-range uraemic concentrations. Adding a TNFα blocker, Ada, blocked this ROS production, but not the oxidative stress in blood samples from haemodialysis patients, suggesting that other uraemic toxins than TNFα are more crucial in this process. However, the lack of association between TNFα and mortality suggests that the role of TNFα-linked oxidative stress is limited.

The risk of tuberculosis in Korean patients with inflammatory bowel disease receiving tumor necrosis factor-α blockers.

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-α blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-α blocker naïve and 160 TNF-α blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-α blockers compared to TNF-α-blocker-naïve patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-α blocker users, and 0.45 for TNF-α-blocker-naïve patients. The adjusted risk ratio of TB in IBD patients receiving TNF-α blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-α blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-α blockers. Treatment with TNF-α blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-α blocker therapy.

Old age at diagnosis is associated with favorable outcomes in korean patients with inflammatory bowel disease.

Background/AimsDespite the rising incidence and prevalence of inflammatory bowel disease (IBD) in Asian populations, data regarding clinical characteristics of patients in Asia based on age at diagnosis are relatively sparse. The aim of this study was to compare clinical characteristics based on the age at diagnosis according to the Montreal Classification in Korean IBD patients.MethodsWe recruited consecutive patients with IBD at two tertiary hospitals and retrospectively reviewed their medical information. Patients were divided into three groups according to their age at diagnosis: youth (<17 years), young adult (17-40 years), and middle-old (>40 years). The main clinical characteristics for comparison were the achievement of a remission state at the last follow-up visit, cumulative rate of surgery, and cumulative use of immunomodulators and tumor necrosis factor-α (TNFα) blockers during the follow-up period.ResultsIn total, 346 IBD patients were included (Crohn's disease [CD] 146 and ulcerative colitis 200; 36 youth, 202 young adult, and 113 middle-old). The middle-old group with CD was characterized by a predominance of uncomplicated behavior (P=0.013) and a lower frequency of perianal disease (P=0.009). The middle-old group was associated more with a less aggressive disease course than the younger group, as shown by more frequent remission (P=0.004), being less likely to undergo surgery (P<0.001), and lower cumulative use of immunomodulators and TNFα blockers (P<0.001).ConclusionsAge at diagnosis according to the Montreal Classification is an important prognostic factor for Korean IBD patients.

The story of CD4+ CD28- T cells revisited: solved or still ongoing?

CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

Application of Minicircle Technology of Self-Reproducing Synthetic Protein Drugs in Preventing Skin Allograft Rejection.

Recently, it has been reported that minicircle vectors could allow the expression of transgenes using the protein synthesis system of the host. Here, we tested a novel strategy to permit the production of synthetic biologics using minicircle technology and evaluated their feasibility as a therapeutic tool in a skin allograft model. We engineered vectors to carry cassette sequences for tocilizumab [anti-soluble interleukin-6 receptor (sIL-6R) antibody] and/or etanercept [tumor necrosis factor receptor 2 (TNFR2)-Fc fusion protein], and then isolated minicircle vectors from the parent vectors. We verified the production of proteins from minicircles and their duration in HEK293T cells and mice. We also evaluated whether these proteins were expressed at levels sufficient to ameliorate skin allograft rejection in mice. Each minicircle transfected into cells was detectable for at least 30 days. In mice, the drugs were mainly expressed in the liver and were detectable for at least 10 days after a single injection. These drugs were also detected in the blood. Treatment of mice with minicircles prolonged skin allograft survival, which was accompanied by a reduction of the number of interferon-γ+ or interleukin-17+ lymphocytes and an induction of forkhead box P3 expression. These findings suggest that blocking of sIL-6R and/or TNF-α using minicircles encoding tocilizumab and/or etanercept was functionally active and relevant for preventing acute allograft rejection. Self-reproducing synthetic protein drugs produced using minicircle technology are potentially powerful tools for preventing acute rejection in transplantation.

Assessment of tuberculosis infection during treatment with biologic agents in a BCG-vaccinated pediatric population.

Biologic therapies, such as tumor necrosis factor-alpha (TNF-α) blockers, are commonly used to treat rheumatological diseases in childhood. Screening patients for tuberculosis (TB) is highly recommended before starting therapy with TNF-α blockers. Despite appropriate screening, TB still remains a problem in patients receiving anti-TNF therapy in countries where TB is not endemic. TB in anti-TNF-treated patients is often diagnosed late due to altered presentation, and this delay results in high morbidity and mortality with a high proportion of extrapulmonary and disseminated disease. The aim of this study is to show the course of TB disease in children who are on biologic therapy, in an era where many of the children are BCG-vaccinated and TB is intermediately endemic. We recruited 71 patients with several types of inflammatory diseases. Six of them had a positive test result during TB screening and began taking isoniazid (INH) prophylactically. During the 3 years of follow-up, none of these patients developed TB disease. Biologic agents can be safely used in a BCG-vaccinated pediatric population, as long as patients are closely monitored to ensure that any cases of TB will be detected early.

Ankara Numune Eğitim Araştırma Hastanesi Göğüs Hastalıkları Kliniğinde son 8 yılda (2006-2013) Tnf-alfa blokeri kullanan hastalara verilen latent tüberküloz tedavisi sonuçları

Tuberculosis occurrence was evaluated in patients that applied tuberculosis chemoprophylaxis and currently receiving tumor necrosis factor-alpha (TNF-α) blocker. Incidence of tuberculosis were retrospectively evaluated in patients that currently receiving TNF-α-blocking therapy and received tuberculosis chemoprophylaxis at Ankara Numune Education and Research Hospital, Lung Disease Department, between 2006-2013 years. 134 patients that were diagnosed with rheumatologic and dermatologic diseases, were evaluated. Patients were in the age range 18-80 years. Age, gender, smoking status, BCG vaccination, chest radiography, diagnose of disease, presence of concomitant disease, tuberculosis story, PPD value, chemoprophylaxis acquisition, which anti-tuberculosis agents received, duration of chemoprophylaxis, duration of TNF-α blocker, other immunosuppressive using were measured. Rheumatologic diseases were often. Prophylaxis has given at 73.9% of patients. Patients with received anti-TNF-α therapy (n= 134) have not developed pulmonary or extra-pulmonary tuberculosis disease. Patients with received anti-TNF-α therapy, are scanned with TST or Quantiferon. If latent tuberculosis infection are diagnosed, tuberculosis prophylaxis should be started pre-anti-TNF-α therapy at least one month and INH chemoprophylaxis should be completed on 9 months or RIF should be completed on 4 months. Serum liver enzymes and bilirubin measurements monthly; follow-up physical examination and chest radiography should be performed for 3 months.

Effect of a TNFα Blocker and Peginfa on Polycythemia Vera Clonal Hematopoiesis and Suppressed Normal Dormant Hematopoiesis

Polycythemia vera (PV) is a clonal disorder arising from a single stem cell while normal stem cells are present in the marrow but are suppressed by the PV clone by an unknown mechanism. Pegylated interferon alfa-2a (PegInfa), a better-tolerated form of Infa induces clinical remission, reduces JAK2V617F allelic burden, and may convert clonal to polyclonal hematopoiesis (EL Liu, Blood 2003). Tumor necrosis factor-α (TNFa) levels are increased in patients with myeloproliferative neoplasms, including PV (Fleischman, Blood 2011). We previously reported that transcripts of TNFα mRNA are higher in CD34+ cells compared to more differentiated cells. TNFa is markedly reduced in those PegInfa-treated patients with decreased JAK2V617F allelic burden and/or return of polyclonal hematopoiesis (detected in females by X-chromosome allelic usage ratio), while no such decrease was seen in PV with hydroxyurea-induced normalization of elevated hematocrit/platelets/leukocytes (Swierczek, ASH 2012). To directly interrogate the role of TNFα in inducing suppression of normal hematopoiesis, we used a TNFα blocking antibody (adalimumab) and examined its role on PV erythropoiesis using a 3-week liquid culture system characterized by synchronized differentiation of expanding erythroid progenitors (Bruchova, Exp Hemat, 2007).In vitro expanded PV erythroid progenitors were grown with or without adalimumab or PegInfa. We evaluated apoptosis, proliferation and differentiation at different stages of erythroid maturation and correlated these parameters with TNFα transcripts, JAK2V617F allelic burden and, in females, clonality. Although the initial mononuclear cells represented a heterogeneous population, the expansion process favors erythroid progenitors and results in their synchronized differentiation. The JAK2V617F allelic burden increased concomitant with erythroid expansion and reached its peak at day 11 (when the majority of cells are proerythroblasts and basophilic erythroblasts), indicating a preferential expansion of erythroid progenitors, and then declined progressively. The addition of adalimumab markedly reduced TNFα mRNA and JAK2V617F allelic burden compared to controls. We previously reported that in this in vitro liquid expansion system, PV erythroid progenitors exhibit accelerated differentiation at days 7-14 and increased proliferation at days 9-14, with a larger S-phase population (40%) than controls (20%) at day 11 (Bruchova Exp Hemat, 2007). Compared to controls, adalimumab increased proliferation and delayed differentiation at early stages of PV erythropoiesis, with the proportion of apoptotic cells consistently decreased compared to erythroid cells expanded without adalimumab. Furthermore, X-chromosome-based clonality assays revealed preferential expansion of normal progenitors in 1 informative female patient. We also measured the impact of TNFα inhibition with adalimumab on burst-forming units-erythroid (BFU-E) colonies from PV patients cultured ex vivo. As expected, JAK2WT, JAK2WT/V617F and JAK2V617F BFU-E colonies were detected in cultures performed in the absence of adalimumab, while the addition of adalimumab preferentially abrogated JAK2V617F homozygous BFU-Es.In analogous experiments, PegInfa markedly decreased TNFα mRNA and JAK2V617F allelic burden, and decreased differentiation, but unlike adalimumab, it decreased proliferation and had no demonstrable effect on apoptosis. Ongoing studies are being performed to correlate the TNFα mRNA expression changes seen with adalimumab treatment in erythroid progenitors with differences in TNFα protein levels using intracellular cytokine staining and flow cytometry.These data suggest that blocking TNFα can suppress the JAK2V617F clone, rescue normal dormant hematopoiesis, and provide a foundation for a combined PV therapy using TNFα blockers with either PegInfa or JAK2 inhibitors. DisclosuresDeininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.

Clinical Disease Pattern and Drug Evaluation of Patients with Seronegative Spondyloarthritis at the Outpatient Department

Objective: There are a number of diseases in the spondyloarthritis (SpA) family. In this study, we evaluated the clinical disease pattern and drug use of outpatient department (OPD) patients with SpA. Methods: During a one-month period, we consecutively enrolled 100 patients with SpA. The diagnosis of ankylosing spondylitis (AS) was based on the modified New York criteria and that of psoriatic arthritis (PsA) followed The ClASsification of Psoriatic ARthritis (CASPAR) criteria. The new Assessment of SpondyloArthritis international Society (ASAS) classification criteria were used for the diagnosis of axial or peripheral SpA. Patients’ demographic characteristics, disease activity and laboratory tests were fully assessed. Medications currently used with the SpA family include non-steroidal anti-inflammatory drugs (NSAIDs) and TNF-α blockers. Results: A total of 100 SpA patients were consecutively enrolled in this short-term OPD survey. The male-to-female ratio of the enrolled patients was about 2:1 (66 males, 34 females). The clinical disease patterns of the 100 patients included 69 AS, 15 PsA, 12 non-radiographic axial SpA and 4 peripheral SpA. Uveitis was the most common extraarticular feature. Patients with positive HLA-B27 had higher Bath Ankylosing Spondylitis Functional Index (BASFI) scores, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores and CRP. Male AS patients seemed to have a higher CRP level and more severe sacroiliitis. AS patients receiving anti-TNFa therapy had significantly higher BASFI and BASDAI scores. AS patients had higher BASFI scores, and erythrocyte sedimentation rate (ESR) and CRP levels but no difference in BASDAI scores when compared to non-radiographic axial SpA patients. In terms of NSAIDs use, 45% of patients took cyclooxygenase-2 (COX-2) inhibitors (celecoxib, etoricoxib), 18% preferential COX-2 inhibitors (meloxicam), 30% nonselective NSAIDs (diclofenac, etodolac, naproxen), and 5% of patients used no NSAIDs. Besides, a higher percentage (33%) of our patients with SpA received regular anti-TNFα therapy (etanercept 17, adalimumab 15, golimumab 1). Conclusion: This OPD survey of Taiwan SpA patients disclosed not a small percentage (16%) of Taiwan SpA patients had either axial or peripheral SpA. The lack of significant difference in the BASDAI between AS and axial SpA suggests anti-TNFα therapy is indicated when traditional NSAIDs fail in axial SpA patients.

Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary

Chronic low-grade inflammation and oxidative stress (OS) appear to be two main pathways involved in the pathogenesis of polycystic ovary (PCO) syndrome. Therefore, targeting these pathways by means of anticytokine and antioxidant agents might be a therapeutic alternative approach to the current treatments of PCO syndrome. In this study, we investigated the protective effects of pentoxifylline (PTX), a drug with antioxidant and anti–tumor necrosis factor alpha (TNF-α) properties, in hyperandrogenism-induced PCO rats. The inflammatory and OS responses and their connections with ovarian functionality in induced PCO rats were investigated through ovarian histopathologic examination and a series of biochemical measurements including serum estradiol, progesterone, testosterone, insulin, and TNF-α, ovarian and serum lipid peroxidation, total antioxidant power, and reactive oxygen species. Experimental PCO was induced in rats by oral administration of letrozole (1 mg/kg body weight) for 21 consecutive days. In a different group, PTX was administrated orally (50 mg/kg/d) for 21 days simultaneous with letrozole to assess its potential protective effects. The letrozole-induced PCOs were characterized by irregular cycles, high incidence of subcapsular ovarian cysts with diminished or scant granulosa cell layers, increased number of atretic preantral and antral follicles, and absence of CL. In addition, the letrozole-induced PCO rats exhibited notable increase in lipid peroxidation and reactive oxygen species of serum and ovary, serum testosterone, insulin, and TNF-α and significant decline in total antioxidant power, serum estradiol, and serum progesterone. Our results indicated that all the identified pathologic parameters and biochemical characteristics in letrozole-induced PCO rats in this study were preserved close to normal levels by simultaneous PTX treatments. Present results demonstrate that there is a direct connection between ovarian dysfunction and increased OS and inflammation in PCO. For the first time, the beneficial effects of PTX as a powerful antioxidant and TNF-α blocker in hyperandrogenism-induced PCO are reported.

Prevalence of TNF-α blocker immunogenicity in psoriatic arthritis.

The longterm use of tumor necrosis factor (TNF)-α blockers is limited by the formation of neutralizing antibodies. To the best of our knowledge, immunogenicity in psoriatic arthritis (PsA) has not been investigated in depth. Our objective was to evaluate the prevalence and significance of TNF-α blocker immunogenicity in PsA. Consecutive patients with PsA treated with either infliximab (IFX), adalimumab (ADA), or etanercept (ETN) > 3 months participated in our cross-sectional study. Their demographic and clinical characteristics, skin and joint disease activity, and records of use of methotrexate (MTX) and other medications were collected. Drug levels (ELISA) and antidrug antibodies (ADAb; Bridging ELISA) were evaluated before the next injection or infusion. A total of 93 patients with PsA were recruited (48 receiving ADA, 24 IFX, and 21 ETN), with a mean age of 53 years (range 21-83 yrs), composed of 53% women. One-fourth of the patients were concomitantly treated with MTX. Altogether, 77% of the patients demonstrated therapeutic drug levels. High levels of ADAb were found in 29% of patients taking ADA, 21% taking IFX, and 0% taking ETN. ADAb significantly correlated with lower drug levels, higher 28-joint Disease Activity Scores, and higher global assessments. MTX use correlated significantly with a lower prevalence of ADAb. Significant levels of ADAb were present in up to 29% of patients with PsA treated with ADA or IFX. ADAb clearly correlated with low therapeutic drug levels and higher disease activity variables. The use of MTX significantly decreased ADAb prevalence, and its use should be strongly considered in combination with TNF-α blocker antibodies in patients with PsA.

Clinical markers predictive of primary inefficacy: a "real life" retrospective study in psoriatic patients treated with etanercept.

Overexpression of tumor necrosis factor alpha (TNF-α) has been demonstrated to play a pivotal role in the pathogenesis of both plaque-type psoriasis and psoriatic arthritis. TNF-α blockers, including etanercept, a human protein that acts as a TNF-α soluble receptor, are effective in the treatment of psoriasis. This retrospective study investigated the impact of psoriasis patients' demographic and clinical characteristics on primary inefficacy to etanercept. Our findings suggest that the presence of psoriatic arthritis is a risk factor for primary inefficacy to etanercept in the treatment of psoriasis. However, etanercept efficacy appears to be independent of patient age, gender, or previous biologic treatments.

Thalassemic trait prevalence in patients affected by psoriatic arthritis in anti-TNF treatment.

Thalassemic trait (Thal) is associated with rheumatic disease, particularly a mild form of seronegative polyarthritis resembling rheumatoid arthritis (RA), but not with other rheumatic diseases. The aim of this study was to estimate the frequency of Thal in patients with psoriatic arthritis (PsA) and to evaluate the efficacy of anti-tumor necrosis factor alpha (TNF-α) therapy in patients with PsA and Thal. We performed a retrospective study in 321 patients with PsA who started therapy with TNF-α blockers. For all patients included in the study, at baseline and every 3 months for the 1 year of follow up, data concerning PsA activity and ferritin levels were registered. In our group of PsA patients, a total of 27 (8%) with concomitant Thal were identified and included in the study. In patients without Thal, all variables improved significantly after 6 months of therapy, while in patients with Thal, the same variables showed a significant decrease after 12 months.: Our study shows that PsA is significantly associated with Thal, but further studies are needed to address this issue. The presence of Thal could be a negative predictor of achieving remission during treatment with TNF-α-blockers.

Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-α reagents.

A third of the world’s population is exposed to Mycobacterium tuberculosis in their lifetime. Over eight million people develop a tuberculosis (TB) illness and 1.3 million people die from the disease every year. Acquired immunity (cytotoxic CD8+ T cells (CBT), Th1 CD4+ helper T cells) macrophages, and dendritic cells all play important roles in TB infection. Recently, it is well established that innate immunity as well plays a definitive role in the development of TB immunity under the effects of several cytokines, microbicidal proteins and Toll-like receptors. Meanwhile, the introduction and widespread use of biological disease-modifying anti-rheumatic reagents over the last 15 years worldwide has dramatically advanced and improved the standard care and prognosis of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA).However, as clinical experience with these drugs has grown, the risk of granulomatous infections, especially disseminated TB and fungal infections, has become apparent, especially because having RA or JIA may innately increase the risk of infection (bacterial, viral and fungal). The knowledge of basic immunology has also advanced over the past 10 years and adult and pediatric rheumatologists should increase their understanding of this dynamic between arthritis diseases, anti-TNF- α medications, and TB. This review will provide an up-to-date discussion of both the immunology of the TB organism in the human host and the pathophysiologic mechanisms of the TNF-α blockers in the development of secondary (disseminated) tuberculosis.

Hidradenitis suppurativa in children and adolescents: a review of treatment options.

Hidradenitis suppurativa (HS) is a burdensome disease and has the potential to affect the life course of patients. It is a rare disease in children, and the recorded literature is correspondingly scarce. This article reviews the therapeutic options for HS in children and adolescents, and highlights particular differences or challenges with treating patients in this age group compared with adults. The work-up of paediatric patients with HS should include considerations of possible endocrine co-morbidities and obesity. Medical therapy of lesions may include topical clindamycin. Systemic therapy may include analgesics, clindamycin and rifampicin, finasteride, corticosteroids or tumour necrosis factor alpha (TNFα) blockers. Superinfections should be appropriately treated. Scarring lesions generally require surgery.

Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy.

Interleukine-6 and TNFα blockers provide only partial and short-term temporal improvement in cryopyrin-associated periodic syndrome

Cryopyrin-associated periodic syndrome (CAPS) is an inherited disease which is caused by gain-of function mutations in CIAS1 gene function resulting in increased secretion of active IL-1β. IL-1β also can stimulate the production of other proinflammatory cytokines, such as IL-6, TNFα and so on (downstream cascade). The use of IL-1 blockers dramatically controls inflammation in CAPS patients and provide a persistent amelioration of the inflammatory manifestations. The data about using of IL-6 or TNFα blockers in CAPS are very limited.

Non-anti TNF biologic modifier drugs in non-infectious refractory chronic uveitis: the current evidence from a systematic review

Non-infectious chronic uveitis is a serious and disabling sight-threatening disease accounting for up to 10% of pathologies leading to blindness. Currently, a step-by step escalating immunosuppressive therapy is generally used, in children as well as in adults, and anti-TNFa biologic therapies have markedly increased the treatment options for sight-threatening uveitis refractory to conventional immune-modulatory therapy (DMARD) in addition to topical and/or systemic corticosteroids. However, a subset of patients fails to respond to TNFa blockers or is unable to tolerate these therapies and may therefore benefit from switching to another drug. In this clinical setting, the large availability of several different molecules, mostly off-label, poses the clinical question if it can be useful and safe to administer another class of biologic drugs, such as Abatacept or Rituximab, for patients with refractory auto-immune uveitis.

TNF-α blocker effect of naringenin-loaded sericin microparticles that are potentially useful in the treatment of psoriasis.

This study aims to evaluate the effect of combined use of the racemic flavanone Naringenin (NRG) and the protein sericin as TNF-α blockers. Sericin (SMs) and (R/S) NRG-loaded Sericin (SNRGMs) microparticles were prepared by spray-drying, characterized in terms of morphology and particle size distribution, and encapsulation efficiency was determined. Concerning morphology and particle size distribution of microparticles, results indicated that they were not affected by the presence of NRG. The encapsulation efficiency was almost quantitative (93%), thus proving that sericin can be advantageously loaded with (R/S) NRG. Biological evaluation of (R/S) NRG, SMs and SNRGMs was then performed in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (hPBMC). SNRGMs resulted cytotoxic at the higher dose used (200 μg/mL) and the effect was greater than (R/S) NRG alone. Moreover, even if sericin alone was not effective in suppressing LPS-induced serum TNF-α levels, SNRGMs loaded with 9.3% of (R/S) NRG were significantly more potent than (R/S) NRG alone. In summary, this study provides the proof of concept that sericin-based microspheres loaded with TNF-α-blockers could contribute to the down regulation of the cytokine and represents the starting point for the development of new topical formulations for the treatment of middle-stage psoriasis.