Initiation Of anti-TNF Treatment Research Articles

Genetic variability of three common NK and γδ T cell receptor genes (FCγ3R, NCR3, and DNAM-1) and their role in Polish patients with rheumatoid arthritis and ankylosing spondylitis

Various lymphocyte subpopulations, including NK cells as well as γδ T cells, have been considered an important element in the pathogenesis of autoimmune, inflammatory, rheumatic diseases, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). The aim of this study was to assess the potential role of polymorphic variations in the genes coding for three NK and γδ T cell receptors: NCR3, FCγR3A, and DNAM-1 (rs1052248, rs396991, and rs763361, respectively) in the disease susceptibility and the efficacy of treatment with TNF inhibitors. The study included 461 patients with RA, 168 patients with AS, and 235 voluntary blood donors as controls. The NCR3 rs1052248 AA homozygosity prevailed in RA in patients lacking rheumatoid factor (p = 0.044) as well as in those who manifested the disease at a younger age (p = 0.005) and had higher CRP levels after 12 weeks of anti-TNF therapy (p = 0.021). The FCγR3A rs396991 polymorphism was associated with pain visual analogue scale (VAS) values before the initiation of anti-TNF treatment. Lower VAS values were observed in the GG homozygous RA patients (p = 0.024) and in AS patients with the TT genotype (p = 0.012). Moreover, AS heterozygous patients with the TG genotype presented higher CRP levels in the 12th week of anti-TNF treatment (p = 0.021). The findings suggest that the NCR3 rs1052248 AA homozygosity may have an adverse effect on RA, while the T allele potentially plays a protective role in the development of AS. Moreover, the rs1052248 T allele and TT genotype appear to have a favorable impact on the response to anti-TNF therapy in RA patients.

The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study.

Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use-but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD. Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated. Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03). In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.

Early prediction of clinical response to anti-TNF treatment using multi-omics and machine learning in rheumatoid arthritis.

ObjectivesAdvances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for Rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF, the downstream mechanisms of immune suppression are not completely understood. The aim of this study was to detect biomarkers and expression signatures of treatment response to TNF inhibition.MethodsPeripheral blood mononuclear cells (PBMCs) from 39 female patients were collected before anti-TNF treatment initiation (day 0) and after 3 months. The study cohort included patients previously treated with MTX who failed to respond adequately. Response to treatment was defined based on the EULAR criteria and classified 23 patients as responders and 16 as non-responders. We investigated differences in gene expression in PBMCs, the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry and the level of proteins in plasma. Finally, we used machine learning models to predict non-response to anti-TNF treatment.ResultsThe gene expression analysis in baseline samples revealed notably higher expression of the gene EPPK1 in future responders. We detected the suppression of genes and proteins following treatment, including suppressed expression of the T cell inhibitor gene CHI3L1 and its protein YKL-40. The gene expression results were replicated in an independent cohort. Finally, machine learning models mainly based on transcriptomic data showed high predictive utility in classifying non-response to anti-TNF treatment in RA.ConclusionsOur integrative multi-omics analyses identified new biomarkers for the prediction of response, found pathways influenced by treatment and suggested new predictive models of anti-TNF treatment in RA patients.

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. Results: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <−0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

Long-term outcome of Crohn's disease patients with upper gastrointestinal stricture: A GETAID study

BackgroundThere are few data concerning patients with Crohn's disease (CD) complicated by a stricture of the upper gastrointestinal tract (UGT). AimsWe evaluated the outcome and management of CD patients complicated by a stricture of the UGT. MethodsWe performed a retrospective multicenter study including all CD patients with a non-passable symptomatic UGT stricture on endoscopy. Primary outcome measure was surgery-free survival from diagnosis of stricture. Efficacy of medical, endoscopic, and surgical treatments, and identification of predictors of surgery were also evaluated. Results60 CD patients with an UGT stricture were included. 60% of the strictures were located in the duodenum. With a median follow-up of 5.5 (IQR: 3.0–12.0) years since stricture diagnosis, surgical-free survival was 75% and 64% at 1 and 5 years, respectively. At the end of the follow up, 27 (45%) patients underwent surgery. 77 endoscopic procedures were performed in 30 patients with an immediate success of 81% and a clinical benefit in 84% of the procedures. In multivariate analysis, anti-TNF treatment initiation was associated with a reduced risk of surgery. ConclusionCD UGT strictures are mainly located in the duodenum. Medical and endoscopic treatments allow to avoid surgery in half of the patients

Evaluation of hepatitis B vaccine efficacy and factors affecting vaccine nonresponse in patients receiving anti-tumor necrosis factor agents.

The response rate of patients to hepatitis B virus (HBV) vaccination receiving anti-tumor necrosis factor (TNF) agents is quite low. We aimed to assess the efficiency of HBV vaccination in patients with chronic inflammatory diseases (CIDs) receiving anti-TNF agents as well as in healthy controls. We also evaluated the impact of different factors on the efficacy of HBV vaccination. Patients with CIDs receiving anti-TNF agents and healthy controls vaccinated for HBV were included in the study during 2018-2019. An adequate immune response and an effective immune response to HBV were defined as >10 IU/L and > 100 IU/L, respectively. Among 274 participants, 187 were patients with CID and 87 were healthy controls. The mean age of the patients with CID (43.9 ± 11.7 years) was significantly higher than that of the healthy controls (31.4 ± 7 years) (P = 0.000). Adequate immune response was 60.8 and 94.3% in patients with CID and healthy controls (P = 0.000), respectively, whereas effective immune response was 37.9 and 75.9% (P = 0.000), respectively. In logistic regression analysis, male sex [odds ratio (OR), 0.408; 95% confidence interval (CI), 0.201-0.830; P = 0.013), use of infliximab (OR, 2.694; 95% CI, 1.203-6.035; P = 0.016) and sertoluzimab (OR, 3.307; 95% CI, 1.287-8.498; P = 0.013), vaccination after anti-TNF treatment (OR, 0.224; 95% CI, 0.083-0.602; P = 0.003) were identified as risk factors of nonresponse to HBV vaccine. Infliximab and sertoluzimab usage, male sex, and vaccination after anti-TNF treatment were risk factors of nonresponse. HBV vaccination should be given to patients with CID before initiation of anti-TNF treatment and awareness should be spread on this subject.

Similar Clinical Outcomes of Early and Late Anti-TNF Initiation for Ulcerative Colitis: A Nationwide Population-Based Study.

PurposeThe optimal timing of anti-tumor necrosis factor (anti-TNF) initiation in patients with ulcerative colitis (UC) remains unclear. Very little is known about the clinical outcomes after the early versus late initiation of anti-TNF therapy, especially in Asian UC patients. Here we aimed to assess whether earlier anti-TNF treatment initiation results in favorable clinical outcomes in Korean UC patients.Materials and MethodsUsing the Korean National Health Insurance claims database, we studied patients who were diagnosed with UC and received anti-TNF therapy for more than 6 months between 2010 and 2016. Using a Cox proportional hazard model, clinical outcomes including colectomy, UC-related emergency room (ER) visits, UC-related hospitalizations, and the need for corticosteroids were compared between early (≤2 years of diagnosis) and late (>2 years of diagnosis) initiators of anti-TNF therapy.ResultsAmong 17167 UC patients, 698 patients who received anti-TNF therapy for more than 6 months were included (420 infliximab, 242 adalimumab, and 36 golimumab). Of the 698 patients, 299 (42.8%) initiated anti-TNF therapy within 2 years of diagnosis. There were no significant differences in the risk of colectomy [adjusted hazard ratio (aHR), 0.41; 95% confidence interval (CI), 0.04–3.90], ER visits (aHR, 0.98; 95% CI, 0.50–1.92), hospitalization (aHR, 0.76; 95% CI, 0.57–1.01), and corticosteroid use (aHR, 1.04; 95% CI, 0.71–1.50) between early and late initiators of anti-TNF therapy.ConclusionPatients receiving early anti-TNF therapy had similar clinical outcomes to those of late initiators, suggesting that early anti-TNF therapy initiation offers little benefit in patients with UC.

Diffusion-weighted magnetic resonance enterography for prediction of response to tumor necrosis factor inhibitors in stricturing Crohn's disease.

Distinguishing between fibrotic and inflammatory strictures in Crohn's disease (CD) is still challenging. The capacity of diffusion-weighted (DWI) magnetic resonance (MRE) to identify intestinal fibrosis was recently demonstrated; however, the therapeutic implications of this association have never been evaluated. The aim of the current study was to identify imaging features, including DWI, which can predict response to anti-inflammatory treatment in patients with stricturing CD. Consecutive CD patients with intestinal strictures that initiated treatment with anti-tumor necrosis alpha (anti-TNF) between June 2012 and April 2017 with MRE adjacent to treatment onset were retrospectively collected. The primary outcome was treatment failure, defined as drug discontinuation, CD-related surgery, or endoscopic dilatation of the stricture. Clinical, demographic, and imaging data were compared between patients who did and did not develop treatment failure within 12 months of anti-TNF treatment initiation. A total of 21 patients were included in the study; 9/21 (42.8%) developed treatment failure. None of the clinical/demographic parameters were associated with the risk of treatment failure. Among imaging parameters, only ADC value (< 1 × 10-3mm2/s) was significantly associated with the risk of treatment failure (AUC = 0.81, 66% vs. 0%, p = 0.015). Our results suggest that ADC value on DWI MRE may predict the risk of treatment failure in stricturing CD. If replicated in larger studies, these results may guide therapeutic decisions and suggest avoiding anti-TNF treatment.

RISK OF DEVELOPING ACTIVE TB IN IBD PATIENTS TREATED WITH ATNI-TNF

AIM. To develop an investigation complex for IBD-patients with the anti-TNF therapy to decrease the risk of active TB. METHODS. In Moscow Research and Clinical Center for TB Control 454 patients with IBD were screened prior to initiation of anti-TNF treatment and 167 (36,8%) of them - during the anti-TNF therapy. Tuberculin skin test (TST) and chest radiography were used for screening and evaluation of pulmonary adverse effects (every 6 months and additionally in cases of any respiratory signs). RESULTS. Of 454 patients investigated during screening X-ray, chest radiography findings were detected in 29 (6,4%), which required additional investigation, among them in 14 patients, findings considered as residual TB lesions. In the other 15 patients, the radiographic findings caused by previous non-specific pulmonary infections. Positive TST implicates preventive antituberculosis therapy, which was provided 37 patients (before and under anti-TNF therapy). During provided to 167 patients the anti-TNF therapy, were developed pulmonary adverse effects: 10 incidences of active TB lung infection 3 case of sarcoidosis, 1 case of fibrosing alveolitis, and two case of non-CONCLUSION. The patients with IBD, treated by anti-TNF therapy, have a risk of development of a wide variety of infectious and non-infectious pulmonary complications, including TB. It is therefore highly important to carefully monitor the patients prior and during the anti-TNF therapy (every 6 months) for a timely detection of pulmonary conditions potentially associated with the treatment.

Variations in the metabolome in response to disease activity of rheumatoid arthritis.

BackgroundAnti-Tumor Necrosis Factor (TNF) therapies are able to control rheumatoid arthritis (RA) disease activity and limit structural damage. Yet no predictive factor of response to anti-TNF has been identified. Metabolomic profile is known to vary in response to different inflammatory rheumatisms so determining it could substantially improve diagnosis and, consequently, prognosis.The aim of this study was to use mass spectrometry to determine whether there is variation in the metabolome in patients treated with anti-TNF and whether any particular metabolomic profile can serve as a predictor of therapeutic response.MethodsBlood samples were analyzed in 140 patients with active RA before initiation of anti-TNF treatment and after 6 months of Anti-TNF treatment (100 good responders and 40 non-responders). Plasma was deproteinized, extracted and analyzed by reverse-phase chromatography–QToF mass spectrometry. Extracted and normalized ions were tested by univariate and ANOVA analysis followed by partial least-squares regression-discriminant analysis (PLS-DA). Orthogonal Signal Correction (OSC) was also used to filter data from unwanted non-related effects. Disease activity scores (DAS 28) obtained at 6 months were correlated with metabolome variation findings to identify a metabolite that is predictive of therapeutic response to anti-TNF.ResultsAfter 6 months of anti-TNF therapy, 100 patients rated as good responders and 40 patients as non-responders according to EULAR criteria. Metabolomic investigations suggested two different metabolic fingerprints splitting the good-responders group and the non-responders group, without differences in anti-TNF therapies. Univariate analysis revealed 24 significant ions in positive mode (p < 0.05) and 31 significant ions in negative mode (p < 0.05). Once intersected with PLS results, only 35 ions remained. Carbohydrate derivates emerged as strong candidate determinants of therapeutic response.ConclusionsThis is the first study describing metabolic profiling in response to anti-TNF treatments using plasma samples. The study highlighted two different metabolic profiles splitting good responders from non-responders.

P387. Does standard therapy in paediatric Crohn’s disease really prevent our patients from the need of early initiation of anti-TNF treatment?

P387. Does standard therapy in paediatric Crohn’s disease really prevent our patients from the need of early initiation of anti-TNF treatment?

QuantiFERON-TB Gold In-Tube assay for screening arthritis patients for latent tuberculosis infection before starting anti-tumor necrosis factor treatment.

BackgroundPatients undergoing anti-tumor necrosis factor (TNF) treatment are at an increased risk of reactivating a latent tuberculosis infection (LTBI). This study evaluated the effectiveness of the QuantiFERON-TB Gold In-Tube (QFT) assay for diagnosing LTBI in arthritis patients undergoing anti-TNF treatment.MethodsWe enrolled 342 consecutive patients from August 2007 to October 2013: 176 (51.5%) patients with ankylosing spondylitis and 166 (48.5%) with rheumatoid arthritis. Screening tests included tuberculin skin test (TST) and QFT assay. Positive QFT results, regardless of TST results, were considered an indicator for LTBI treatment.ResultsBacillus Calmette-Guérin scars were found in 236 (69.0%) patients. Of 342 patients, TST and QFT were positive in 122 (35.7%) and 103 (30.1%) patients, respectively, and discordant in 101 (29.5%) patients. During a median follow-up duration of 41.7 months, five patients (1.5%) developed TB in a median of 20.8 months after initiation of anti-TNF treatment (428/100,000 person-years). TB did not occur in 62 TST+/QFT+ patients who received LTBI treatment. Of 41 TST−/QFT+ patients who received LTBI treatment, one (2.4%) developed TB 20.5 months after starting anti-TNF treatment (705/100,000 person-years). Of 60 TST+/QFT− patients who did not receive LTBI treatment, two (3.3%) developed TB 20.8 and 22.0 months after starting anti-TNF treatment (871/100,000 person-years). Of 179 TST−/QFT− patients, two (1.1%) developed TB 7.2 and 22.7 months, respectively, after initiating anti-TNF treatment (341/100,000 person-years). TB incidence rate during the follow-up period did not differ among TST−/QFT+, TST+/QFT−, and TST−/QFT− patients (P = 0.661).ConclusionQFT might be used instead of TST for diagnosing LTBI in patients before starting anti-TNF therapy in countries, such as Korea, where the TB prevalence is intermediate and the BCG vaccination is mandatory at birth. In the absence of a true gold standard test for LTBI, however, there is still a risk of TB development during anti-TNF treatment.

AB0672 Serological Neo-Epitope Biomarkers of Synovial Associated Collagen Can Assess Treatment Efficacy of Anti-TNF-A and Identify Benefiters

BackgroundNon Steroidal Anti-Inflammatory Drugs (NSAIDs) and anti-TNF biologics have been used in patients with ankylosing spondylitis (AS) to suppress inflammation and associated symptoms. Although symptom-modifying, the effects of these interventions...

AB0761 Prevalence of Enthesitis and Dactylitis, Impact on Disease Severity and Evolution over 12 Months in PSA Patients Treated with Anti-TNF in A Real-World Setting

BackgroundSpondyloarthritis, including psoriatic arthritis (PsA), is characterized by inflammatory arthritis affecting axial and peripheral joints. It is commonly associated with extra-articular and peri-articular manifestations (PAMs) including dactylitis and enthesitis.ObjectivesTo evaluate...

FRI0321 The Dynamics of Response to Rituximab in Rheumatoid Arthritis Patients with Moderate Disease Activity and Inadequate Response to Inhibitors of Tumor Necrosis Factor. Data from 3-Year REPEAT Study

BackgroundIn recent years, emphasis has shifted in rheumatoid arthritis (RA) to early intervention in the disease course. We have shown that patients with MDA should be further divided in three...

AB0302 Profile of Joint Involvement over Time in Rheumatoid Arthritis and Psoriatic Arthritis Patients Treated with Anti-TNF in A Real-World Setting

BackgroundUnlike rheumatoid arthritis (RA), the pattern of joint involvement in psoriatic arthritis (PsA) is usually asymmetric. Furthermore, PsA may demonstrate oligoarthritis or polyarthritis, while RA usually manifests in multiple joints.ObjectivesTo...

Tumor Necrosis Factor α Inhibition in Radiographic and Nonradiographic Axial Spondyloarthritis: Results From a Large Observational Cohort

To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA.

AB0186 BAFF levels in patients with ankylosing spondylitis and response to anti-tumor necrosis factor treatment

BackgroundAlthough B cells are not commonly associated with the pathogenesis of ankylosing spondylitis (AS), some findings corroborate their potential role in this chronic inflammatory rheumatic disease. Dense infiltrations of B...

AB1212 Skin-manifested adverse events in children treated with biologics: Single centre experience

BackgroundSite reactions are the most common but the least serious events of biological treatment. However, the first signs of the serious adverse events may be skin manifestations.ObjectivesThe aim of the...

THU0162 Patterns of Clinical Response Predict Failure of TNF Inhibitor Treatment in Rheumatoid Arthritis: Data from a Longitudinal Observational Study in Romania

BackgroundIn recent years, emphasis has shifted in rheumatoid arthritis (RA) to early intervention in the disease course. The introduction of tumour necrosis factor (TNF) inhibitors significantly changed the overall treatment...