TNF-α Blockers Research Articles

Elderly psoriatic arthritis patients on TNF-α blockers: results of an Italian multicenter study on minimal disease activity and drug discontinuation rate.

Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis. Real world data on efficacy and safety of TNF-α blockers in the elderly with PsA are lacking. The aim of this study was to evaluate the effectiveness, through the achievement of minimal disease activity (MDA), drug discontinuation rate, and safety in elderly patients with PsA on TNF-α blockers. A multicenter, observational study was carried out in four Italian centers. The assessment of disease activity and safety were performed at the start of anti-TNF-α (T0), at 6months (T6) and at 12months (T12). A total of 145 PsA patients were included in the study. At baseline 68 (46.9%) patients were on etanercept, 60 (41.3%) on adalimumab, 11 (7.6%) on golimumab, and 6 (4.1%) on infliximab. All the variables concerning PsA activity showed a statistically significant improvement when comparing T6 and T12 with T0. After 6 and 12months of therapy, respectively, 31 (22.6%) and 71 (51.8%) patients achieved MDA (p<0.001). The drug discontinuation rate was 5.5% with a mean of 6.8months (range 2-10months), and it was due to lack of efficacy, adverse events, and lost to follow-up. Nine patients (6.2%) reported the onset of mild infections resolved with antimicrobial specific oral regimen without therapy interruption. TNF-α blockers are effective in the achievement of a low disease status and safe in elderly patients with PsA. Therefore, age should not be considered a limitation to their use.

Understanding how immune checkpoint modulators alter pre-existing rheumatologic disorders in cancer patients

Abstract The aim of cancer immunotherapy is to reinvigorate an exhausted immune system. Checkpoint modulators PD1/PDL1 and CTLA4 antagonists “release the breaks” on ineffective T cells and subsequently bolster tumor-targeted T cells. These checkpoint modulators are increasingly available for numerous cancers and therefore the number of patients on immunotherapy are ever increasing. In contrast, patients with autoimmune diseases are prescribed immune therapies that dampen the immune system. Of note, immune suppressive therapies increase the incidence of various cancers. The interesting question that has not been fully addressed- what is happening immunologically in patients who have pre-existing autoimmune diseases and are treated with checkpoint modulators for cancer? We have been evaluating the immune correlates in patients with pre-existing rheumatoid arthritis (RA; often being treated with TNF-α blocker) who later receive checkpoint therapy when diagnosed with cancer. Following checkpoint therapy, we saw an increase in central memory T cells, a decrease in PD1 and CTLA4 expression, and a decrease in Th1 and Th17 cells in the peripheral blood. Additionally, we have been working on a dual disease animal model- collagen-induced arthritis (CIA) and lung cancer models. This will has allowed us to study the direct immunological consequences of giving treatments that either dampen or boost the immune system on both cancer and CIA disease states. Outcomes from this work will continue to expand our understanding of the immune system in patients with dual diseases and thus be better equipped to evaluate immunological correlates for exacerbated autoimmune disease and to productively treat patients with both autoimmune and cancer diagnoses.

Metabolic syndrome in patients with ankylosing spondylitis receiving anti-TNFα therapy: association with predictors of cardiovascular risk.

The purposes of this study were to determine the prevalence of metabolic syndrome (MetS) in patients with ankylosing spondylitis (AS) receiving anti-TNFα therapy and evaluate the association of the two conditions with clinical and laboratory findings and predictors of cardiovascular risk. In this cross-sectional study, 63 patients diagnosed with AS according to the modified New York criteria and treated with TNFα blockers and 33 healthy controls were submitted to clinical examination and anthropometric measurements. Glucose levels, lipid profile, and inflammatory markers were registered. The Framingham score (FS), atherogenic index of plasma (AIP), and waist-to-height ratio (WHtR) were calculated. MetS was diagnosed according to the revised National Cholesterol Education Program - Adult Treatment Panel III guidelines. The prevalence of MetS was higher among AS patients than controls (27 vs. 9.1%, p=0.04). AS patients also had greater body mass index (27.6kg/m2±4.5 vs. 24.5kg/m2±2.7; p=0.001) and WHtR (0.59±0.08 vs. 0.49±0.05; p<0.01). Patients with MetS had higher FS (9.66 (4.08-20.5) vs. 2.54 (1.56-6.75); p<0.001), WHtR (0.6444±0.0706 vs. 0.5729±0.0759; p=0.001), and AIP (0.68±0.46 vs. 0.34±0.24; p=0.02) than patients without MetS. When stratifying patients with and without MetS according to disease activity, the former had stronger predictors of cardiovascular risk than the latter, regardless of disease activity. MetS was more prevalent in AS patients than in controls. Predictors of cardiovascular risk were stronger in MetS patients than in non-MetS patients.

The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management.

The purpose of the study is to briefly review the molecular mechanisms that leads to structural damage in ankylosing spondylitis (AS), defined as new bone formation resulting in complete or incomplete ankylosis of the spine, and the impact of treatment with biologics to retard this process. The understanding of molecular mechanisms leading to new bone formation in AS has significantly improved but is still incomplete. Availability of biologics has greatly enhanced the treatment of patients with AS, but its impact on slowing the structural damage is still a matter of debate, although a few observational studies have shown that long term use of TNF-α blockers may slow radiographic progression. The availability of newer biologics targeting IL-17/1L23 has shown some promising results in slowing radiographic progression in AS. Although the availability of TNF-inhibitors has greatly enhanced the treatment options for patients with AS, their impact on slowing the structural damage is still not clearly established. However, preliminary results using newer biologics targeting IL-17/1L23 axis are more encouraging but longer follow-up is needed.

Ultrasound Evaluation of the Entheses in Daily Clinical Practice during Tumor Necrosis Factor-α Blocking Therapy in Patients with Ankylosing Spondylitis.

To assess structural and inflammatory ultrasound (US) lesions of entheses in ankylosing spondylitis (AS) patients with active disease and to evaluate inflammatory lesions after 6 months of tumor necrosis factor (TNF-α) blocking therapy, in daily clinical practice. Consecutive patients with AS were clinically evaluated and underwent US examination of 9 bilateral entheses before and after 6 months of TNF-α blocking therapy. US examination included the following as inflammatory lesions: bone erosions/cortical irregularities, enthesophytes, calcifications as structural lesions; adjacent bursitis, effusion, increased tendon hypoechogenicity or thickness; and positive power Doppler (PD) signal. At baseline, 105 (95%) of 111 included patients showed US abnormalities. Structural lesions were seen in 74 patients (67%) and inflammatory lesions in 88 (79%). Enthesophytes and positive PD signal were the most prevalent structural and inflammatory lesions, respectively. Most lesions were found at the lower extremities. Additionally, inflammatory lesions occurred at the lateral epicondyle of the elbow. Patients with structural lesions at baseline were significantly older, had longer disease duration, higher modified Stoke AS Spine score, and higher C-reactive protein. Individually, there was a great diversity in changes of inflammatory entheseal lesions during treatment, but on the group level no significant decrease was found. This prospective observational cohort study in daily clinical practice shows a high prevalence of structural and inflammatory US lesions in AS patients with longstanding and active disease. Positive PD signal was the most common inflammatory feature. No significant change in inflammatory US lesions was found after 6 months of TNF-α blocking therapy.

Correction: Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression.

[This corrects the article DOI: 10.1371/journal.pone.0171347.].

M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases.

The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D4 (LTD4 ). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD4 ) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD4 induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD4 . The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD4 promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.

Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R expression.

Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.

IL-6: the next key target for rheumatoid arthritis after TNF-α

IL-6 is an important cytokine that plays an important role in the pathogenesis of rheumatoid arthritis. We summarized the clinical efficacy and safety of tocilizumab, the IL-6 receptor monoclonal antibody in rheumatoid arthritis, and compared tocilizumab with TNF-α blocking mAbs. The efficiency of tocilizuamb is equivalent to that of TNF-α blockers, and each of the drugs has its advantages and disadvantages. We also summarized the clinical trials of the mAbs blocking IL-6 pathway in development. According to the results of recent studies by several research teams including our research group, IL-6 is another key target for the treatment of rheumatoid arthritis after TNF-α. The listing of the IL-6 blockers provides more choices for personalized treatment of rheumatoid arthritis in the future.

Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases.

Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.

Inter- and intra-cellular mechanism of NF-kB-dependent survival advantage and clonal expansion of radio-resistant cancer cells

Understanding the underlying mechanism by which cancer cells acquire resistance to radiation and favorably selected for its clonal expansion will provide molecular insight into tumor recurrence at the treatment site. In the present study, we investigated the molecular mechanisms prompted in MCF-7 breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radio-resistance and tumor relapse/recurrence. Our findings showed that 2 or 10Gy of 137Cs γ-rays at a dose rate of 1.03Gy/min trigger the activation of nuclear factor kappa B (NF-κB), its DNA-binding activity and recycles its own transcription. NF-κB DNA-binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Gene manipulation approach revealed that radiation triggered NF-κB-mediated TNF-α transcriptional activity. TNF-α blocking approach confirmed that the de novo synthesis and secretion of TNF-α serves as a pre-requisite for the second phase of NF-κB activation and sustained maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells, in parallel, activates NF-κB in the non-targeted un-irradiated bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through inter-cellular paracrine mechanism) after radiation exposure. Further, the data suggest that this self-sustained NF-κB in the irradiated cells determines radio-resistance, survival advantage and clonal expansion of the tumor cells at the treatment site. Parallel maintenance of NF-ΚB-TNF-α-NF-κB feedback-cycle in the un-irradiated non-targeted bystander cells initiates supportive mechanism for the promotion and progression of surviving tumor cells. Intervening this molecular pathway would help us to achieve disease-free cancer survivors.

Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review.

Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic interventions in this setting should be discouraged. Finally, adverse effects on sperm quality, or causing embryo-fetal anomalies, in men treated with TNF inhibitors have not been described.

Crohn's disease and smoldering multiple myeloma: a case report and literature review.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) that presents with abdominal pain, weight loss, and diarrhea. Although the etiology has not been fully elucidated, both environmental and genetic causes are known to be involved. In chronic inflammatory conditions such as IBD, B lymphocytes are chronically stimulated, and they induce monoclonal expansion of plasma cells, sometimes resulting in monoclonal gammopathy of undetermined significance. Immunomodulators that are commonly used to control inflammation, such as tumor necrosis factor-α (TNF-α) blockers could increase the possibility of hematologic malignancy. The pathogenesis of multiple myeloma in association with TNF-α inhibitor therapy is attributed to decreased apoptosis of plasma cell populations. Here, we describe a case of a 36-year-old male patient who was diagnosed with immunoglobulin A subtype smoldering multiple myeloma during the treatment for CD with infliximab and adalimumab. We report this case along with a review of the literature on cases of multiple myeloma that occurred in conjunction with CD.

Glycan and Peptide IgE Epitopes of the TNF-alpha Blockers Infliximab and Adalimumab - Precision Diagnostics by Cross-Reactivity Immune Profiling of Patient Sera.

Biological drugs like therapeutic antibodies are widely used for the treatment of various diseases like inflammatory disorders and cancer. A drawback of these novel treatments is the substantial proportion of patients experiencing adverse reactions such as loss-of-drug effect or hypersensitivity reactions. These reactions are associated with pre-existing and/or developing anti-drug antibodies. Especially IgE development is a risk factor for life-threatening systemic anaphylaxis.Methods: In order to characterize the individual drug-specific serum IgE, an IgE cross-reactivity immune profiling (ICRIP) assay was developed. Individual IgG epitopes of anti-drug antibodies against adalimumab were identified by epitope mapping via peptide microarray.Results: ICRIP analyses of sera from patients treated with the therapeutic antibodies adalimumab (ADL) and infliximab (IFX) reveal individual, distinct IgE binding patterns. IgG epitopes were identified mostly located in the variable region of ADL.Conclusions: Using ICRIP and peptide microarrays for pharmacovigilance of the TNF-α blockers IFX and ADL, risk factors and biomarkers before and during therapy shall be identified. These diagnostic systems provide the basis for a safe and efficacious therapy decision for each patient in cases of adverse drug reactions mediated by different types of anti-drug antibodies.

抗TNF-α製剤使用下における関節リウマチ大関節破壊予測 : FDG-PET/CTとARASHIスコアによる検討

抗TNF-α製剤使用下における関節リウマチ大関節破壊予測 : FDG-PET/CTとARASHIスコアによる検討

The effectiveness of UVB (311 nm emission) therapy and cyclosporine treatment in the patients with poor responsiveness to TNF-a blockers

The authors present data concerning the effectiveness of the application of UVB (311 nm emission) therapy and the treatment using low doses of cyclosporine in the patients receiving therapy with TNF-alpha blockers that resulted in the 50% reduction of the Psoriasis Area and Severity Index (PASI 50). The study has demonstrated that the introduction of narrow-band phototherapy into the combined treatment can make it possible to reach the PASI values of 75 and even 100%. Monitoring of the safety of the application of the combined approach has revealed the absence of early adverse reactions within 1 year after the treatment.

Penile constitutive nitric oxide synthase expression in rats exposed to unpredictable chronic mild stress: role of inflammation

Chronic psychological stress cause erectile dysfunction (ED). Considering recent evidence that tumor necrosis factor-α (TNF-α) levels are increased in serum of patients with ED, the present study investigated the effects of infliximab (a TNF-α blocker) on endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) immunoreactivity of rat penile corpus cavernosum in unpredictable chronic mild stress (UCMS). Male adult rats were randomly divided into three groups (n=8 per group): Control, UCMS and UCMS+infliximab. Control and UCMS groups received physiological saline, UCMS+infliximab group received infliximab (5 mg kg-1 per week, intraperitoneally) during 8 weeks of UCMS. UCMS and UCMS+infliximab groups were subjected to different types of stressors, which were randomly applied four to five times during this time period. After 8 weeks, penile eNOS and nNOS expressions were determined immunohistochemically. In UCMS group, nNOS and eNOS immunoreactivity was found to be decreased in penile corpus cavernosum compared with the control group. Whereas in infliximab treatment group eNOS and nNOS immunoreactivity increased compared with the UCMS group. These findings support that UCMS decreases penile constitutive NOS expression via TNF-α, which may contribute to the development of ED. Blockage of TNF-α actions may represent an alternative therapeutic approach for ED in chronic psychological stress.

Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity

Leucine-rich repeat kinase (LRRK2), a major causal gene of Parkinson's disease (PD), functions as a kinase. The most prevalent mutation of LRRK2 is G2019S. It exhibits increased kinase activity compared to the wildtype LRRK2. Previous studies have shown that LRRK2 can phosphorylate p53 at T304 and T377 of threonine-X-arginine (TXR) motif in neurons. Reduction of LRRK2 expression or inhibition of LRRK2 kinase activity has been shown to be able to alleviate LPS-induced neuroinflammation in microglia cells. In this study, we found that LRRK2 could also phosphorylate p53 in microglia model BV2 cells. Transfection of BV2 with phosphomimetic p53 T304/377D significantly increased the secretion of pro-inflammatory cytokine TNFα compared to BV2 transfected with p53 wild type after LPS treatment. In addition, conditioned media from these transfected cells increased the death of dopaminergic neuronal SN4741 cells. Moreover, such neurotoxic effect was rescued by co-treatment with the conditioned media and etanercept, a TNFα blocking antibody. Furthermore, TNFα secretion was significantly increased in primary microglia derived from G2019S transgenic mice treated with LPS compared to that in cells derived from their littermates. These results suggest that LRRK2 kinase activity in microglia can contribute to neuroinflammation in PD via phosphorylating p53 at T304 and T377 site.

TNF-α blockers for the treatment of Kawasaki disease in children

TNF-α blockers for the treatment of Kawasaki disease in children

Radiographic damage and progression of the cervical spine in ankylosing spondylitis patients treated with TNF-α inhibitors: Facet joints vs. vertebral bodies.

To investigate radiographic damage and 4-year progression of the cervical facet joints in a prospective observational cohort of AS patients treated with TNF-α inhibitors, to compare this with damage and progression of the cervical vertebral bodies, and to study the relation with patient characteristics and clinical outcome. Patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-α inhibitors with baseline and 4-year radiographs were included. Cervical facet joints and vertebral bodies were scored by two independent readers according to the method of de Vlam and mSASSS, respectively. At baseline, 25 of 99 (25%) AS patients had partial or complete ankylosis of the cervical facet joints, whereas 51 (52%) patients had non-bridging or bridging syndesmophytes of cervical vertebral bodies. During 4 years, 13 (13%) patients developed new (partial) ankylosis of the facet joints, whereas 26 (26%) developed new (bridging) syndesmophytes. Facet joint damage and progression without involvement of the vertebral bodies were seen in 5 (5%) and 8 (8%) patients, respectively. Damage of facet joints was associated with longer disease duration, history of IBD/uveitis/psoriasis, higher disease activity, larger occiput-to-wall distance, higher mSASSS, and presence of syndesmophytes. Progression of the facet joints was associated with larger occiput-to-wall distance and more facet joint damage at baseline. Cervical facet joints were frequently involved in AS. During 4 years of TNF-α blocking therapy, 13% of the patients showed radiographic progression of cervical facet joints of which the majority did not show progression of vertebral bodies.