TNF-α Blockers Research Articles

Prediction of Response to Tumor Necrosis Value-α Blocker Is Suggested by 18F-NaF SUVmax But Not by Quantitative Pharmacokinetic Analysis in Patients With Ankylosing Spondylitis.

OBJECTIVE. We aimed to evaluate the pharmacokinetics and maximum standardized uptake value (SUVmax) of 18F-NaF PET/CT for assessment of disease activity and prediction of response in patients with ankylosing spondylitis (AS). MATERIALS AND METHODS. Twenty-seven patients (age, interquartile range, 30.25-49.75 years) with AS who were receiving a tumor necrosis factor-α (TNF-α) blocker were included. All patients underwent dynamic PET of the pelvis followed by whole-body PET/CT. Quantitative analysis of kinetic data of the sacroiliac joints (SIJs) was performed, and the SUVmax of the SIJs and SUVmax of the spine were calculated. Clinical indexes related to AS disease activity (serum C-reactive protein level, Bath ankylosing spondylitis disease activity index [ BASDAI], and Bath ankylosing spondylitis functional index) were evaluated. Clinical response was defined as an improvement from the initial BASDAI score of 50% or more (BASDAI 50) within 2 years after baseline 18F-NaF PET/CT. RESULTS. The BASDAI score at 18F-NaF PET/CT was significantly different between the responders and nonresponders: 18F-NaF uptake at the spine was significantly higher in the responders than in the nonresponders. Only SUVmax of the spine had a significant positive correlation with BASDAI score at PET/CT (r = 0.38, p = 0.048). The BASDAI score at PET/CT (odds ratio [OR], 35.32; 95% CI, 2.09-57.84; p = 0.014) and SUVmax of the spine (OR, 14.69; 95% CI, 0.79-27.27; p = 0.027) were significantly associated with BASDAI 50 response prediction. CONCLUSION. The results of our study suggest that the SUVmax of the spine on whole-body 18F-NaF PET/CT is a reliable and noninvasive biomarker for predicting therapeutic response to TNF-α blocker and shows better performance for predicting response than quantitative pharmacokinetic parameters. Fluorine-18-labeled NaF PET/CT showed axial bone lesions with bone formation and can be used as a monitoring tool in patients with AS receiving anti-TNF-α drugs. However, these results need to be validated in a larger cohort.

Systemic TNF-α blockade attenuates anxiety and depressive-like behaviors in db/db mice through downregulation of inflammatory signaling in peripheral immune cells

Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on db/db mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor Leprdb) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in db/db mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in db/db mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence.

BackgroundCancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19.MethodsUsing Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig.Results89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19.ConclusionThe COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs.

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in vivo in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects.

TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells.

PurposeTo determine whether priming of bone marrow mesenchymal stem cells (MSCs) by signals from injured retina, particularly tumor necrosis factor α (TNFα), increase their exosomes’ neuroprotective efficacy on retinal ganglion cells (RGCs).MethodsMSCs were primed with retinal cell culture conditioned medium, with or without the TNFα blocker etanercept or TNFα prior to isolation of exosomes. MSC conditioned medium or exosomes were added to rat retinal cultures or human stem cell–derived retinal ganglion cell (hRGC) cultures, and RGC neuroprotective effects were quantified. Luminex assays were used to compare primed versus unprimed exosomes.ResultsMSC conditioned medium and exosomes exerted a significant neuroprotective effect on injured rat and hRGC. This effect was significantly increased after MSCs were primed with retinal conditioned medium or TNFα. Blocking of TNFα signaling with etanercept prevented priming-induced RGC neuroprotective efficacy. Priming increased Pigment epithelium-derived factor (PEDF) and VEGF-AA exosomal abundance.ConclusionsMSC exosomes promote RGC survival not just in rodent retinal cultures but also with hRGC. Their efficacy can be further enhanced through TNFα priming with the mechanism of action potentially mediated, at least in part, through increased levels of PEDF and VEGF-AA.

Rare paradoxical adverse event in Crohn’s disease: a case report

An 18-year-old male adolescent diagnosed with ileocolitis-type Crohn's disease received therapy involving an anti-tumor necrosis factor-α (TNF-α) blocker, which resulted in remission for 2 years. The patient presented with fever, stomatitis, and cough with respiratory distress. Chest radiography revealed bilateral hilar lymphadenopathy; bronchoalveolar lavage showed high lymphocyte level: 40.8% and CD4/8 value: 3.9. Transbronchial lung biopsy identified multiple non-caseating granulomas fused to each other with connective tissue septa, leading to the diagnosis of sarcoidosis. The sarcoidosis was defined as a paradoxical adverse event (PAE) due to the use of TNF-α blocker; therefore, cessation of TNF-α blocker administration was sufficient to induce remission. We report a rare case of PAE on Crohn's disease. The characteristics and distinguishing histologies of PAE and Crohn's disease are described. Biological agent therapy has been reported to cause several PAEs during the treatment of immune-mediated inflammatory disorders. PAEs are defined as pathological conditions that occur during biological agent therapy usually effective in treatment. The laboratory, radiography, and histological findings shown in this case are useful for differential diagnosis and management of PAE.

Interleukin 22 and 6 serum concentrations decrease under long-term biologic therapy in psoriasis.

IntroductionPsoriasis, affecting approximately 2% of the worldwide population, is a chronic, inflammatory skin disease in which overexpression of proinflammatory cytokines is observed. Most of the available data on the influence of antipsoriatic therapy on the cytokine serum concentration are inconsistent and based on short-term observations.AimTo evaluate the influence of long-term biologic therapy with tumor necrosis factor α (TNF-α) blockers (adalimumab, etanercept, infliximab) and IL-12/23 inhibitor (ustekinumab) on the level of IL-6, IL-22 in the sera of patients with psoriasis.Material and methodsBlood samples were collected from 42 psoriatic patients in order to determine IL-6 and IL-22 serum concentrations prior to and at the 3rd, 12th, 24th and 36th month of biologic therapy. Psoriasis Activity and Severity Index (PASI) was assessed at the same time points. The control group consisted of 30 sex- and age-matched healthy volunteers.ResultsMean PASI index at baseline was 14.49 ±3.69 and decreased significantly until the end of the observation. Mean IL-6 serum concentration decreased significantly in all study groups (p < 0.05). A statistically significant decrease in IL-22 concentrations was demonstrated during the treatment with adalimumab and infliximab but not etanercept or ustekinumab.ConclusionsAccording to obtained results, IL-6 and IL-22 serum concentration may be an accurate marker of response to antipsoriatic therapy, even though not correlated with PASI index. Biologic therapy in psoriasis allows for long-term clinical improvement expressed not only by the remission of skin lesions, but also by lowering serum concentrations of pro-inflammatory interleukins.

Assessment of the State of Cell Membranes against the Background of Prolonged Use of Anticytokine Therapy in Patients with Ulcerative Colitis

Biological therapy in the treatment of immune-mediated conditions has changed their course, the quality of life of patients and the prognosis of diseases. The accumulated by mankind 20 years of experience with the use of genetically engineered drugs has led to a number of questions regarding, among other issues, safety in the long-term administration of biological therapy. Patients suffering from ulcerative colitis revealed changes in cell membranes, reflecting their structural and energy characteristics. Long-term administration of Infliximab leads to the stabilization of energy processes in the erythrocyte membrane and improves homeostatic function of the kidneys.The aim of the studywas to evaluate the effect of long-term use of TNF-α blockers (Infliximab) on the structural and functional characteristics of cell membranes and the functional state of the kidneys in patients with moderate to severe ulcerative colitis.Materials and methods. We examined 103 patients with moderate to severe ulcerative colitis during the period of acute attack and remission, of which 28 patients received basic therapy using the drug Infliximab (IFX) for 10 years, 75 patients received standard basic treatment. The patients of the biological therapy group took the original drug Infliximab – Remicade. The comparison group consisted of 30 healthy volunteers, comparable by sex and age. The analysis of the state of erythrocyte membranes was carried out using a set of physicochemical methods: UV spectroscopy (SF-46m spectrophotometer), high-performance thin-layer reaction paper chromatography, membrane ultrafiltration, erythrocyte NMR spectroscopy on phosphoric (31P) and proton (1H) nuclei. The functional state of the kidneys was evaluated using a dynamic scintigraphic study (with the technemage –Tc-99m).Results.Prolonged use of anticytokine therapy with Infliximab for 10 years in patients with ulcerative colitis, upon reaching deep remission, improves endogenous intoxication, restores the structural and functional characteristics of cell membranes, normalizes cell energy metabolism and does not negatively affect the functional state of the kidneys.

SERUM LEVEL OF MMP-3 IN PATIENTS WITH PSORIATIC ARTRITIS TREATED WITH TNF-α BLOKERS

Background: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes whose primary function is to break down the extracellular matrix. MMPs are important for tissue remodeling and affect cell signaling. MMP-3 (Stromelysin-1, Transin-1) hydrolyzes natural collagen and extracellular matrix components such as proteoglycan, laminin, fibronectin, gelatin and collagen type III, IV and IX and activates the precursor of IL1-beta. Psoriatic arthritis (PsA) is a rapidly developing, debilitating disease, and it is important for patients with it to identify serum biomarkers to predict its development. Patients and Methods: MMP-3 has been studied in 21 patients with PsA, 16 patients with PsA receiving TNF-α blocker therapy, and 22 patients with gonarthrosis and 15 healthy age-matched adults. All patients were treated and monitored at the University Clinic of Rheumatology, UMHAT “Kaspela“ and UMHAT “Steti Georgi”, Medical University, Plovdiv. The study of MMPs was performed using an ELISA methodology. Statistical processing of the data was performed using the SPSS 23 program with confidence (p &lt;0.001). Results: The mean MMP-3 value in patients with PsA was 197.00 ± 35.90 pg / ml, in patients with AS 101.08 ± 15.76 ng / ml. The mean MMP-3 in patients with PsA receiving TNF-α blocker therapy and with low clinical disease activity was 50.48 ± 9.22 ng / ml. The mean MMP-3 in patients with gonarthrosis was 42.91 ± 11.72 ng / ml. The mean MMP-3 values in patients with active PsA were significantly different from those treated with TNF-α-blockers and patients with degenerative joint disease and controls (p &lt;0.05). Conclusion: MMP-3 was significantly increased in patients with PsA compared with patients with osteoarthritis and healthy subjects. Administration of TNF-α blockers gradually leads to a decrease in the serum level of MMP-3 and can serve as a biomarker for disease activity as well as for evaluating the effect of therapy. arthrosis disease

The protective effects of the GPR39 agonist TC-G 1008 against TNF-α-induced inflammation in human fibroblast-like synoviocytes (FLSs)

Rheumatoid arthritis (RA) is a common immune-mediated chronic inflammatory joint disease of unknown etiology. While tumor necrosis factor-α(TNF-α) blockers have proven to be a beneficial treatment option for many patients, not all respond to such treatments. In the present study, we investigate the role of the recently discovered zinc-sensing G protein-couple receptor GPR39. To our knowledge, this study is the first to investigate the role of GPR39 in the context of RA using human fibroblast-like synoviocytes (FLS). We found that agonism of GPR39 using its specific agonist TC-G 1008 significantly ameliorated important markers of RA, including oxidative stress, mitochondrial dysfunction, expression of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein 1 (MCP-1), and secretion of key matrix metalloproteinases (MMPs) including MMP-1, MMP-3 and MMP-13. Furthermore, we demonstrate that these may be mediated via the Janus-kinase (JNK), activating protein 1 (AP-1), and nuclear factor-κB (NF-κB) cellular signaling pathways. Our findings demonstrate for the first time the potential of GPR39 to mediate synovial inflammation, pannus invasion, and enzymatic degradation of articular extracellular matrix.

Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression.

BackgroundTumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported.MethodologyWe performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included.Principal findingsForty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers.ConclusionsThis data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

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

Kawasaki disease (KD) is an acute inflammatory vasculitis (inflammation of the blood vessels) that mainly affects children between six months and five years of age. The vasculitis primarily impacts medium-sized blood vessels, especially in the coronary arteries. In most children, intravenous immunoglobulin (IVIG) and aspirin therapy rapidly reduce inflammatory markers, fever, and other clinical symptoms. However, approximately 15% to 20% of children receiving the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that plays an important role in host defence against infections and in immune responses. Several studies have established that blocking TNF-α is critical for obtaining anti-inflammatory effects in children with KD, thus, there is a need to identify benefits and risks of TNF-α blockers for the treatment of KD. To evaluate the efficacy and safety of using TNF-α blockers (i.e. infliximab and etanercept) to treat children with Kawasaki disease. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 19 September 2018. We also undertook reference checking of grey literature. We included randomised controlled trials (RCTs) that compared TNF-α blockers (i.e. infliximab and etanercept) to placebo or other drugs (including retreatment with IVIG) in children with KD, reported in abstract or full-text. Two review authors independently applied the study selection criteria, assessed risk of bias and extracted data. When necessary, we contacted study authors for additional information. We used GRADE to assess the certainty of the evidence. We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD.Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence).Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence).Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence).Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence).One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence).No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.

Tumor Necrosis Factor-Alpha Antagonist Interferes With the Formation of Granulomatous Multinucleated Giant Cells: New Insights Into Mycobacterium tuberculosis Infection.

More than half of tuberculosis cases in the world are due to resuscitation of dormant Mycobacterium tuberculosis (Mtb) sequestered into cell-derived structures called granulomas. It is fairly admitted that cytokines and more particularly Tumor Necrosis Factor (TNF)-α is critical in the control of Mtb infections and that anti-TNF-α drugs constitute one of the main risk factors for reactivation of latent Mtb infection. The aim of this study was to evaluate the role of etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF receptor linked to the Fc portion of human IgG1, in an in vitro model of human tuberculous granuloma. We showed that etanercept slightly delayed the formation of granuloma and reduced the generation of multinuclear giant cells (MGCs). In addition, etanercept exacerbated the expression of M1 polarization genes but also induced interleukin (IL)-10 release. In addition, our results indicated that etanercept inhibited cell fusion in an IL-10-dependent manner. Moreover, adalimumab, a human monoclonal anti-TNF-α IgG1 inhibited MGC formation in granuloma, without altering IL-10 secretion and induced macrophage apoptosis. Taken together, our data provides new insights into the role of TNF-α blockers in MGCs formation and the impact of such immunomodulatory drugs on tuberculous granuloma maturation.

Learning From Success and Failure: Biologics for Non-approved Skin Diseases.

The impressive potential of biologics has been demonstrated in psoriasis, hidradenitis suppurativa, and urticaria. Numerous biologicals are entering the field for a restricted number of skin disorders. Off-label use of biologics in other recalcitrant skin diseases has increased. Mounting data point to the potential of already existing biologics acting on the IL-17/IL-23 pathway in skin disorders with epidermal hyperkeratosis (e.g., pityriasis rubra pilaris), acneiform inflammation (e.g., hidradenitis suppurativa), and loss of mucosal integrity (e.g., aphthosis). TNF-α blockers are also effective in the latter conditions but seem of particular value in granulomatous (e.g., granuloma annulare) and neutrophilic disorders (e.g., pyoderma gangrenosum). Failure of IL-17 blockade in skin diseases resulting from immune-mediated cell destruction (e.g., alopecia areata and vitiligo) illustrates its limited involvement in Th1-dependent skin immunology. Overall, disappointing results of TNF-α blockers in alopecia areata and vitiligo point to the same conclusion although promising results in toxic epidermal necrolysis suggest TNF-α exerts at least some in vivo Th1-related activities. Acting on both the Th1 and Th17 pathway, ustekinumab has a rather broad potential with interesting results in lupus and alopecia areata. The efficacy of omalizumab in bullous pemphigoid has revealed an IgE-mediated recruitment of eosinophils leading to bullae formation. Reconsidering reimbursement criteria for less common but severe diseases seems appropriate if substantial evidence is available (e.g., pityriasis rubra pilaris). For other disorders, investigator- and industry-initiated randomized clinical trials should be stimulated. They are likely to improve patient outcome and advance our understanding of challenging skin disorders.

C3 AND C4 COMPLEMENT – BIOMARKERS FOR PROGNOSIS OF TREATMENT OF TNF-BLOKERS

Introduction: The complement system adds antibodies and helps phagocytic cells to destroy pathogens from the body. This is part of a congenital immune system that is not adaptive and does not change over the individual life. However, complement can be "triggered" by the adaptive immune system. The complement system is the main effector of the humoral patr of the immune system. Activation of complement results in opsonization, chemotaxis and cytolysis. Regulation of the complement system can control inflammatory diseases including psoriatic arthritis and vice versa, complement fixation disorders can lead to illness. Treatment with anti-TNF blokers complement activity in patients with inflammatory joint diseases.Objective: To investigate C3, C4 fractions of complement, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complement the response prediction and monitoring of anti-TNF treatment in patients with psoriatic arthritis.Materials and Methods: 36 patients were included sequentially before treatment with TNF-a-blokers. C3, C4, ESR, CRP were assessed at baseline at 6 and 12 months after initiation of treatment with TNF-α blockers. The activity of the disease is measured by the DARSA disease activity scale, the responses being compared with a control group of persons similar in gender and age. Statistical data processing was performed using the SPSS v25.Results and conclusions: According to the results obtained, C3 and C4 were significantly higher than controls at initiation of treatment (C3 111.3 ± 30.8, C4 91.9 ± 12.4 mg / dl, controls 19.1 ± 8.3 mg / dl, 10.2 ± 5.6 mg / dl p = 0.001, p = 0.001). At 6 and 12 months of follow-up, 76.2% of patients had a reduction in the level of C3 and C4 (p = 0.002, 0.001, respectively). It was found that higher baseline levels of C3 were associated with higher DARSA values at 6 and 12 months.Conclusion: The study of the C3 and C4 complement fractions can be used as biomarkers to estimate the prognosis of TNF-blocker therapy.

Acute onset of psoriatic spondyloarthritis as a new manifestation of post-streptococcal reactive arthritis: a case series

Streptococcus is well associated with a myriad of inflammatory diseases. Among others, this bacterium is linked to the triggering of psoriasis and to post-streptococcal reactive arthritis (PSRA), an arthritis which is typically confined to peripheral joints. Three patients who developed acute psoriatic spondyloarthritis (SpA) following a recent streptococcal infection are described in this article. We searched the existing literature for cases of axial involvement in PSRA and reviewed the association between streptococcal infection and psoriasis or psoriatic arthritis )PsA). In all patients, psoriatic SpA occurred within 7-10days of a confirmed streptococcal infection. The main presenting syndrome was inflammatory back pain with evidence of acute axial spondyloarthritis on magnetic resonance imaging. One patient had guttate psoriasis, the second patient developed pustular psoriasis, and the third patient had exacerbation of pustular palmoplantar psoriasis. Two patients required treatment with tumor necrosis factor alpha (TNF-α) blockers. Axial involvement in PSRA is very rare. A potential association of streptococcal infection and development of PsA has been explored in several articles. However, to the best of our knowledge, acute psoriatic SpA as a manifestation of PSRA has yet to be described. Acute psoriatic SpA should be considered in the differential diagnosis of new-onset inflammatory back pain followed by psoriasis in young adults who had a recent throat infection. KEY POINTS: • Our case series describes three cases of acute psoriatic spondyloarthritis that occurred within 7--10 days of a confirmed streptococcal infection and progressed to full blown chronic disease. • Acute psoriatic spondyloarthritis as a manifestation of post streptococcal reactive arthritis should be considered in the differential diagnosis of new onset inflammatory back pain followed by psoriasis in young adults who had a recent throat infection.

Real-Life Tolerability and Effectiveness of Adalimumab Biosimilar in Rheumatoid Arthritis: ASPIRE Registry Data.

IntroductionThe TNF-α blocker adalimumab is a well-proven therapy for rheumatoid arthritis (RA). A biosimilar adalimumab (ZRC-3197; Exemptia™), a ‘fingerprint match’ to reference adalimumab, has been approved for prescription in India since 2014. Here, we report on the effectiveness and tolerability of this biosimilar adalimumab (bADA) from the Adalimumab Biosimilar Patient Registry [ASPIRE; ISRCTN16838474], which contains data from real-life RA patients from India.MethodsASPIRE is a post-marketing, observational registry that evaluates real-world experience across multiple centres in India. Patients with moderate to severe RA who were prescribed bADA 40 mg subcutaneously every fortnight were enrolled. Patients with complete data available until 24 weeks of bADA treatment were extracted and analyzed for standard disease activity measures and reported adverse events.ResultsThe registry included 149 patients with RA who had a median age of 41 (22–67) years; 65% of the patients were female. Disease outcome measures, i.e. ESR, DAS-ESR and VAS-pain scores, showed gradual and significant decreases (p < 0.0001 for all) in 73 analyzable patients who received 24 weeks of bADA therapy. ACR20, ACR50 and ACR70 responses were achieved in 48%, 48% and 34% of patients after 24 weeks of therapy, respectively, and about 58% and 15% of patients were moderate and good EULAR responders, respectively. Physician and patient ratings for the overall global assessment of efficacy and tolerability were ‘good’ to ‘excellent’ for the majority of the patients (≥ 96%). No new safety signals were observed when analyzing this registry data.ConclusionReal-life data from this post-marketing observational analysis demonstrate the clinical effectiveness and tolerability of 24 weeks of adalimumab biosimilar therapy in Indian patients with RA. This report also reflects upon the treatment strategies and prescription patterns for such therapies in Indian clinical practice.Trial RegistrationISRCTN16838474.FundingCadila Healthcare Limited, India.

DRUG-INDUCED NEUTRALIZING ANTIBODIES TO TNF-α BLOCKES IN PATIENTS WITH INFLAMMATORY JOINT DISEASES FOLLOWED BY 24-MONTHS

Introduction: The efficacy and safety of TNF-α blockers have been demonstrated in lot of clinical trials. The use of TNF-α blockers is associated with a significant improvement in the overall symptoms of patients with inflammatory joint diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). As a result of their use, the functions of affected joints and the quality of life of patients are improved. In recent years, it has been demonstrated that TNF-α blockers produce drug-induced neutralizing antibodies that reduce the effectiveness of these costly drugs. Objective: To investigate drug-induced neutralizing antibodies to TNF-α blockers in patients with inflammatory joint diseases followed by 24-months. Materials and Methods: 121 (56.8%) patients with PA, 50 (23.5%) patients with AS and 42 (19.7%) patients with PsA, treated with TNF-α blockers, were tested at 0, 6, 12, 24 months for drug-induced neutralizing antibodies. Detection of neutralizing antibodies to adalimumab (Humira) is performed by ELISA method, with Immundiagnostik - TNFα-Blocker-ADA, Antikorper gegen Adalimumab (Humira), Immundiagnostik AG, Stubenwald-Allee 8a, D 64625 Bensheim all requirements of the manufacturer. Determination of neutralizing antibodies to etanercept (Enbrel) were performed by ELISA method, with Immundiagnostik – TNF-α-Blocker-ADA, Antikorper gegen Etanercept (ENBREL), Immundiagnostik AG, Stubenwald-Allee 8a, D 64625 Bensheim, all requirements of the manufacturer. The SPSS v.24 statistical program was used. Results and conclusions: Drug-induced neutralizing antibodies in patients with RA, PsA, AS, treated with adalimumab, occurred in 11.5% of the patients 6th months after beginning of the treatment, at 12th months they were 17.64%, at the end of the second year 24.8 %. Patients treated with etanercept do not have proven neutralizing antibodies 6th months after beginning of the treatment, at the end of the first year they were 7.77%, at the end of the second year 9.63%. There is no significant difference between the number of males and females with drug-induced neutralizing antibodies (p=0.01). The number of patients with neutralizing antibodies to adalimumab and etanercept differ markedly in the 12th and 24th month (p=0.01). We recommend that the investigating of drug-induced neutralizing antibodies to TNF-α blockers have to be done every 12th months as a part of the routine work of rheumatologists.

IgA nephropathy associated with axial spondyloarthritis responding to treatment by etanercept: A case report

IntroductionImmunoglobulin A (IgA) nephropathy may be associated with spondyloarthritis (SpA). This association raises the possibility of a common pathogenesis. Tumor necrosis factor alpha (TNFα) blockers showed good efficiency in SpA and may be efficient in IgA nephropathy. Case reportA case of a 28-year-old man diagnosed with axial SpA is reported. The patient’s Bath ankylosing spondylitis disease activity index (BASDAI) was 7 and functional index (BASFI) 9. Laboratory investigations revealed: erythrocyte sedimentation rate (ESR) 38 mm/1st hour, C-reactive protein (CRP) 6 mg/L, serum creatinine 72 μmol/L with a clearance of 108 ml/min; proteinuria 1.55 g/24 h, leucocyturia at 60,000 cells/ml and haematuria 80,000 red cells/ml. The serum IgA level was normal (238.8 mg/dL). Salivary gland and subcutaneous fat biopsies were normal. The renal biopsy showed moderate focal interstitial fibrosis. The glomerular basement membranes were not thickened while the mesangium was slightly thickened. There was no vascular damage. Congo red staining was negative. By immunofluorescent microscopy, there were mesangial deposits of IgA mainly; leading to the diagnosis of IgA nephropathy. Infliximab was initially given with limited efficacy and the patient was switched to etanercept which was effective especially in the osteoarticular symptoms. Leucocyturia, haematuria and proteinuria decreased but did not disappear, and the renal function and blood pressure remained normal. After 2 years there remained a persistent efficacy and good profile of tolerance (BASDAI = 2.2, BASFI = 4, CRP = 2, ESR = 21, proteinurua = 0.5 g/24 h). ConclusionEtanercept may be a potentially effective option for treating IgA nephropathy associated with axial SpA.

Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment.

TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (TM) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector TM and a reduced central TM cell population when compared to GM untreated group. An increase in the frequencies of TNFα+, IL-2+, and IL-17+ CD8 TM cells was observed whereas only TNFα+CD4 TM cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses.