Tumor Necrosis Factor Inhibitor Therapy Research Articles

Improving the design of RCTs in non-radiographic axial spondyloarthritis.

Concerns have been raised that randomized placebo-controlled trials (RCTs) in non-radiographic axial spondyloarthritis (nr-axSpA) might be failing to identify patients that best show differences in clinical response rates between those receiving active drug and those receiving placebo therapies; in addition, some studies might even be showing spurious differences in responses to TNF and IL-17 inhibitor therapies. In particular, the most recent phase III RCTs in nr-axSpA have reported variable and generally lower response rates than observed in phase III trials of patients with ankylosing spondylitis and in trials conducted a decade ago in patients with early axSpA who were selected on the basis of axial inflammation evident on MRI scans. We argue that these observations at least partly reflect an RCT design that does not take full advantage of MRI to select patients who are responsive to therapy because the current MRI-based inclusion criteria cannot identify patients with axSpA with sufficient specificity. We propose that future studies should be designed using revised patient inclusion criteria based on expanded MRI evaluation and the application of data-driven definitions of a positive MRI for inflammatory and structural lesions typical of axSpA reported in an international multicentre analysis of MRI scans from the Assessment of SpondyloArthritis International Society (ASAS) classification cohort.

Erratum to: Integrating molecular interactions and gene expression to identify biomarkers to predict response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients.

Erratum to: Integrating molecular interactions and gene expression to identify biomarkers to predict response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients.

P187 Pre-defined Gene Co-expression Modules in Rheumatoid Arthritis Transition towards Molecular Health following Tumour Necrosis Factor Inhibitor Therapy

Abstract Background/Aims Tumour necrosis factor inhibitors (TNFi) have advanced the clinical management of rheumatoid arthritis (RA); however, only 30-40% of patients who receive initial treatment with a TNFi experience a beneficial response. The discovery of biomarkers of TNFi response would facilitate improved response rates and more objective monitoring of inflammation. Gene transcript levels measured in the blood of RA patients represent an attractive source of biomarkers. For example, a study by Oswald et al demonstrated reproducible changes in gene expression modules in RA patients treated effectively with a TNFi. Such gene modules were previously defined by Chaussabel et al following the assessment of gene co-expression patterns, transcript clustering patterns and functional associations amongst transcripts from several inflammatory diseases. We aim to replicate the changes in modular gene co-expression reported to occur in response to TNFi therapy in RA in a UK cohort described by Oswald et al; to test if changes in modular expression are specific to TNFi therapy by analysing change in gene co-expression in response to methotrexate (MTX); and to determine if module expression transitions towards a disease-free state in responding patients. Methods Published whole blood transcriptomic data from disease-free controls (n = 10) and RA patients treated with either the TNFi adalimumab (n = 70) or MTX (n = 85) were studied. Transcriptomic data were available at pre-treatment and at 3-months (TNFi) and 4-weeks (MTX) post-treatment. Response to treatment was assessed using the EULAR response criteria following 3/6-months on-drug. For each of the 27 modules, the fraction of probes that significantly (p < 0.05) changed in expression between time-points was recorded. Linear mixed models were used to test if module expression transitioned towards a disease-free state following treatment. Results In the TNFi cohort, 25 of the 27 modules significantly changed in expression between pre- and post-treatment, replicating published findings by Oswald et al. Six of these 27 modules transitioned towards a disease-free state by 3-months. Transition in module expression was irrespective of treatment response in 5 of the 6 modules, however one module (module 3.2) appeared to be dependent on good response to adalimumab. This module was linked to pathways of inflammation and TNF signalling. Similar patterns of modular expression changes were observed in the MTX cohort, but with reduced significance compared to TNFi treated patients. Conclusion This study provides independent replication of changes in modular gene expression in TNFi treated RA patients. Gene expression changes were observed regardless of treatment response and were not specific to TNFi therapy. These results suggest that some factors of biological response are not detected by clinical classifiers of treatment response. Further research is now needed to test the utility of gene modules for prediction of clinical response, or for objective monitoring of molecular pathways that are responsive to treatment. Disclosure M.A. Sutcliffe: None. N. Nair: None. J. Oliver: None. A. Morgan: None. J. Isaacs: None. G. Wilson: None. S. Verstappen: None. S. Viatte: None. K. Hyrich: None. A. Morris: None. A. Barton: None. D. Plant: None.

Impact of serum interleukin-22 as a biomarker for the differential use of molecular targeted drugs in psoriatic arthritis: a retrospective study

BackgroundWe explored whether serum cytokines could be used as biomarkers for optimal use of tumor necrosis factor inhibitors (TNF-i) and interleukin (IL)-17 inhibitors (IL-17-i) in patients with psoriatic arthritis (PsA).MethodsIn cohort 1 (47 patients treated with IL-17-i [n=23] or TNF-i [n=24] for ≥1 year), we identified serum cytokines that predicted the achievement of Disease Activity in Psoriatic Arthritis-remission (DAPSA-REM), Psoriasis Area and Severity Index (PASI) 90, and Minimal Disease Activity after 1 year of TNF-i or IL-17-i therapy. Subsequently, we developed treatment strategies based on the identified cytokines; initiation of IL-17-i therapy in patients with low IL-22 concentrations (IL-22 <0.61376 pg/ml) and TNF-i therapy in patients with high IL-22 concentrations (0.61376< IL-22 pg/ml). In cohort 2 (34 patients), treatment responses were compared between the strategic treatment group (n=17), which was treated based on the treatment strategies, and the mismatched treatment group (n=17) to verify the validity of the treatment strategies developed using serum cytokines as biomarkers.ResultsIn cohort 1, serum IL-22 concentration was identified as a predictor of DAPSA-remission after 1 year of IL-17-i therapy. Regarding treatment strategies, we selected TNF-i for patients with high IL-22 concentrations and IL-17-i for those with low IL-22 concentrations. There were no significant differences in the baseline characteristics between the strategic and mismatched treatment groups. Regarding treatment effects, activity significantly improved at 1 year in both groups. Upon comparison of the treatment effects, the rate of achieving DAPSA-REM and Minimal Disease Activity at month 12 was significantly higher in the strategic treatment group.ConclusionsThe results of this pilot study suggest that IL-22 may be a biomarker of treatment response to TNF-i and IL-17-i in patients with PsA. Further large-scale studies in independent, prospectively collected datasets are required to verify that IL-22 is indeed a biomarker of treatment response in these patients.

Incidence Rates of Psoriasis in Children With Inflammatory Bowel Disease and Juvenile Arthritis Treated With Tumor Necrosis Factor Inhibitors and Disease-Modifying Antirheumatic Drugs.

To estimate the differential effect of tumor necrosis factor inhibitor (TNFi) therapies and presence or absence of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) on the incidence of psoriasis (PsO) in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic nonbacterial osteomyelitis (CNO). This was a retrospective cohort study from 2008 to 2020. TNFi and DMARD exposures were dichotomized as ever/never. The primary outcome was incident PsO. Incidence rates (IRs) of PsO were stratified by underlying diagnosis, TNFi agent, and DMARD use. Poisson regression was used to assess the IR ratios (IRRs) between exposure groups. There were 5088 children who met the inclusion criteria: 3794 (75%) had IBD, 1189 (23%) had JIA, and 105 (2%) had CNO. Of the 2023 children with TNFi exposure, 613 (30%) and 1410 (70%) were with or without a DMARD, respectively. When controlling for DMARD, sex, and family history of PsO, the IRR of developing PsO in patients exposed to adalimumab (ADA) was 2.70 times higher (95% CI 1.53-4.75; P < 0.001) than those who did not receive any TNFi treatment. IRR was lower, but not significantly different, for patients exposed to infliximab (IFX; IRR 2.34, 95% CI 1.56-3.51; P < 0.001) and etanercept (ETN; IRR 2.21; 95% CI 1.17-4.21; P = 0.006) compared to TNFi-unexposed patients. IRR of TNFi exposure was lower by 0.25 (P < 0.001) in DMARD-exposed patients compared to non-DMARD-exposed patients. IRR of TNFi-induced PsO was not significantly different among ADA, IFX, and ETN. However, for patients with exposure to any of the TNFi evaluated, the IRR was significantly lower in those also exposed to a DMARD.

Gender-Based Differences in Response to Tumor Necrosis Factor Inhibitor Therapies for Ulcerative Colitis: Individual Participant Data Meta-Analyses of Clinical Trials.

Gender-based differences are reported in inflammatory bowel diseases (IBD) pathogenesis, but their impacts on IBD outcomes are not well known. We determined gender-based differences in response to treatment with tumor necrosis factor inhibitor (TNFi) therapies in individuals with ulcerative colitis (UC). We used the Yale University Open Data Access (YODA) platform to abstract individual participant data from randomized clinical trials to study infliximab and golimumab as induction and maintenance therapies in moderately to severely active UC. Using multivariable logistic regression, we examined associations between gender and the endpoints of clinical remission, mucosal healing, and clinical response for each study individually and in a meta-analysis. Of 1639 patients included in induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Subcutaneous [PURSUIT-SC], active ulcerative colitis trials [ACT] 1 and 2) and 1280 patients included in maintenance trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment-Maintenance [PURSUIT-IM], ACT 1 and 2), 696 (42.5%) and 534 (41.7%) were women, respectively. In a meta-analysis of induction trials, the adjusted odds ratios (aORs) of clinical remission (aOR, 0.55; 95% CI, 0.31-0.97), mucosal healing (aOR, 0.47; 95% CI, 0.27-0.83), and clinical response (aOR, 0.51; 95% CI, 0.29-0.90) in the treatment arm and of clinical remission in the placebo arm (aOR, 0.34; 95% CI, 0.15-0.82) were lower in men compared to women. There were no differences in outcomes by gender in the treatment and placebo arms in the meta-analysis of maintenance trials. Men are less likely to achieve clinical remission, mucosal healing, and clinical response compared to women during induction treatment with TNFi for UC, but not during the maintenance phase. Future studies delineating the mechanisms underlying these observations would be informative.

Clinical Features and Drug Retention of TNF Inhibitors in Older Patients with Ankylosing Spondylitis: Results from the KOBIO Registry.

This study aimed to analyse the clinical features and outcomes of and reasons for discontinuing tumour necrosis factor (TNF) inhibitor therapy in older patients with ankylosing spondylitis (AS). Data were extracted from the nationwide Korean College of Rheumatology Biologics registry. Clinical variables and outcomes were compared, and drug retention rate was evaluated. Among 1524 patients with AS treated with TNF inhibitors, 306 were aged ≥ 50 years ('older patients'). Fewer patients were male, the incidence of hypertension and diabetes was higher (all p < 0.001), and the proportion of peripheral arthritis (35.6 vs. 27.1%), Ankylosing Spondylitis Disease Activity Score‒erythrocyte sedimentation rate (4.0 ± 1.1 vs. 3.6 ± 1.0), and Bath Ankylosing Spondylitis Functional Index (4.2 ± 2.6 vs. 3.3 ± 2.5) were all higher in older patients. Although the drug retention rate was lower (log-rank p = 0.018) and lack of efficacy and adverse events were more frequent in older patients (both p < 0.001), drug retention rates were not different after propensity score matching (log-rank p = 0.23). Improvements in disease activity and manifestations were comparable between groups, except for the incidence of peripheral arthritis, which decreased significantly less in older patients over 3 and 5 years. Improvements in disease-related clinical factors and drug retention rates were not different between older and younger patients with AS receiving TNF inhibitors. However, the incidence of adverse events was higher in older patients.

The beneficial effect of csDMARDs co-medication on drug persistence of first-line TNF inhibitor in rheumatoid arthritis patients: data from Czech ATTRA registry

The study aimed to compare treatment retention for first-line TNF inhibitor (TNFi) in the ATTRA registry patients receiving either combination with conventional synthetic DMARDs or TNFi as monotherapy. A retrospective multicenter study analyzed data of all adult patients with rheumatoid arthritis (n = 3032) starting TNF inhibitor as the first-line biological therapy in combination with csDMARDs or in monotherapy from January 1st 2012 to December 31st 2020. Kaplan–Meier method was employed to calculate drug retentions. Survival curves of treatment retentions were compared through Log-rank test between the studied subgroups. The hazard ratio for drug discontinuation was assessed through univariate cox regression models. In patients who started the first line TNFi therapy, the median treatment retention was 47.7 (42.2; 53.1) months for combination therapy and 22.7 (14.9; 30.6) months for TNFi monotherapy (p < 0.001). Estimated one-year survival was higher in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy (75.3% vs 65.7%); two-year survival rate was 63.2% vs 49.2%, three-year survival rate was 55.4% vs 42.4% and five-year survival 44.9% vs 26.4% of patients. The estimated survival on the first TNFi was higher in patients taking combination therapy with methotrexate than with other csDMARDs (p = 0.003). Use of csDMARDs co-medication was associated with significantly better first TNFi drug survival compared to monotherapy. The combination of TNFi with MTX is more effective than the combination with leflunomide, which did not demonstrate a significant effect.

Reduced Serological Response to COVID-19 Vaccines in Patients with IBD is Further Diminished by TNF Inhibitor Therapy; Early Results of the VARIATION study [VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON

Background and AimsEvidence suggests patients with inflammatory bowel disease (IBD) receiving TNF-antagonists have attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for treatment of IBD on antibody responses to vaccination against COVID-19.MethodsPatients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses assessed following COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated.Results100% of HC seroconverted post-complete vaccination with two vaccine doses. 2% of patients with IBD failed to seroconvert. Median anti-spike protein (SP) immunoglobulin (Ig)G levels post-complete vaccination in our IBD cohort was significantly lower than HC (2,613 AU/mL versus 6,871 AU/mL, p=<0.001). A diagnosis of IBD was independently associated with lower anti-SP IgG levels (β coefficient -0.2, p = 0.001). Use of mRNA vaccines was independently associated with higher anti-SP IgG levels (β coefficient 0.25, p = < 0.001). Patients with IBD receiving TNF-inhibitors had significantly lower anti-SP IgG levels (2,445AU/mL) than IBD patients not receiving TNF-inhibitors (3868AU/mL)(p = < 0.001). Patients with IBD not receiving TNF-inhibitors still showed attenuated responses compared to HC (3868AU/mL versus 8747AU/mL p = 0.001).ConclusionsPatients with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy negatively impacts anti-SP IgG levels further. Patients who do not seroconvert post-vaccination are a particularly vulnerable cohort. Impaired responses to vaccination in our study highlight the importance of booster vaccination programmes for patients with IBD.

Psoriasis rate is increased by the exposure to TNF inhibition in children with JIA

ObjectiveWe aimed to investigate the relationship between tumour necrosis factor inhibitors (TNFi) therapy and the onset of new psoriasis in children with juvenile idiopathic arthritis (JIA) using Childhood Arthritis and...

Association between depression, anxiety, chronic pain, or opioid use and tumor necrosis factor inhibitor persistence in inflammatory arthritis.

Depression, anxiety, and chronic pain are common comorbidities in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and may substantially impact patient outcomes. We aimed to determine whether these comorbidities were associated with earlier TNF-inhibitor (TNFi) discontinuation. This retrospective cohort study using Optum's de-identified Clinformatics® Data Mart Database 2000-2014 identified patients with RA, PsA, and AS initiating a first TNFi. Depression/anxiety, chronic pain, and opioid use were identified using diagnosis codes and prescription fill data. Cox proportional hazards models were used to compare time to medication discontinuation in patients with or without each of these risk factors and to assess the additive effect of having multiple risk factors. Among 33,744 patients initiating a TNFi (23,888 RA, 6443 PsA, 3413 AS), depression/anxiety, chronic pain, and opioid use were common, with ≥ 1 risk factor in 48.1%, 42.5%, and 55.4% of patients with RA, PsA, and AS respectively. Each risk factor individually was associated with a 5-7-month lower median treatment persistence in each disease (all p < 0.001). Presence of multiple risk factors had an additive effect on time to discontinuation with HR (95% CI) 1.19 (1.14-1.24), 1.41 (1.33-1.49), and 1.47 (1.43-1.73) for 1, 2, or 3 risk factors respectively in RA. Findings were similar in PsA and AS. Depression, anxiety, chronic pain, and opioid use are common in inflammatory arthritis and associated with earlier TNFi discontinuation. Recognizing and managing these risk factors may improve treatment persistence, patient outcomes, and cost of care. Key Points • Depression, anxiety, chronic pain, and opioid use are common in patients with inflammatory arthritis. • In patients initiating treatment with a TNF-inhibitor, depression, anxiety, chronic pain, or recent opioid use are associated with sooner discontinuation of TNFi therapy. • Patients with multiple of these risk factors are even more likely to discontinue therapy sooner.

P040 Reduced serological response to COVID-19 vaccines in patients with IBD is further diminished by TNF inhibitor therapy; Early results of the VARIATION study (VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON)

BackgroundPatients with inflammatory bowel disease (IBD) have attenuated responses to current vaccinations. There is a limited body of evidence suggesting patients with IBD receiving TNF antagonists have an attenuated response to vaccination against COVID-19. We sought to determine the impact of IBD and various medications for the treatment of IBD on antibody responses to vaccination against COVID-19.MethodsPatients with IBD (n=270) and healthy controls (HC, n=116) were recruited prospectively and quantitative antibody responses were assessed following 1st and 2nd doses of COVID-19 vaccination. The impact of IBD and medications for treatment of IBD on vaccine response rates was investigated.ResultsAll HC seroconverted post complete vaccination [100%]. A small proportion of patients with IBD failed to seroconvert [2%]. Median IgG spike protein (SP) antibody levels post-complete vaccination in our IBD cohort was significantly lower than HC [2,613 AU/mL versus 6,871 AU/mL, p=<0.001]. A diagnosis of IBD and viral-vector vaccine use were independently associated with lower IgG SP antibody levels. Patients with IBD receiving anti-TNF therapy had significantly lower IgG SP antibody levels [2444.6 AU/mL] than IBD patients not receiving these agents [3867.6 AU/mL]. Patients with IBD not receiving TNF inhibitors still showed attenuated responses compared to HC receiving a similar vaccine [p = < 0.001].[Figure 1]. IgG SP antibody levels in our IBD cohort reduced rapidly during follow up. ConclusionPatients with IBD who do not seroconvert post-vaccination against COVID-19 are a vulnerable cohort. Patient with IBD have attenuated serological responses to SARS-CoV-2 vaccination. Use of anti-TNF therapy further impacts IgG SP antibody levels. Impaired response to vaccination in our study highlights the importance of booster vaccination programmes for patients with IBD.

New onset of Juvenile Dermatomyositis during Tumor Necrosis Factor Inhibitor (Adalimumab) Therapy

New onset of Juvenile Dermatomyositis during Tumor Necrosis Factor Inhibitor (Adalimumab) Therapy

The Complement System in Spondyloarthritis: What Do We Know?

Spondyloarthritis (SpA) encompasses a group of rheumatologic diseases, including axial spondyloarthritis (axSpA), psoriatic arthritis, arthritis with associated inflammatory bowel disease (i.e. Crohn’s disease and ulcerative colitis), reactive arthritis and undifferentiated SpA, which all share certain clinical, biological and genetic features. However, the pathogenesis remains largely unexplained. Recent evidence suggests an autoinflammatory component of the disease. The complement system is a cornerstone of the innate immune system. This review aims to evaluate the current knowledge of the complement system in SpA. Animal models have shown that complement activation is associated with axSpA. Complement proteins L-ficolin and H-ficolin levels are elevated in patients with axSpA, and complement factor C3 levels decrease after the initiation of tumour necrosis factor-inhibitor therapy. Associations with disease activity are inconsistent, as one study found that the serum levels of complement factors C3 and C4 did not differ in patients with different Bath Ankylosing Spondylitis Disease Activity Index scores but, in another study, were associated with baseline Ankylosing Spondylitis Disease Activity Score with C-reactive protein and Bath Ankylosing Spondylitis Disease Activity Index improvement after treatment with a tumour necrosis factor inhibitor. Future studies should focus on the complement system in various SpA entities, involvement in pathogenesis and disease progression under clinically relevant conditions.

Clinical course of Covid-19 in a cohort of patients with Behçet disease

ObjectiveThe implications of Covid-19 in patients with Behçet's disease (BD) are unknown. Patients with BD usually take long-term therapy with therapeutic agents that have been tested in Covid-19 patients. We aimed to assess the prevalence of Covid-19 in a cohort of patients with BD and investigate whether those patients with a long-term treatment with colchicine, tumor necrosis factor inhibitors (TNFi) or glucocorticoids are at reduced or increased prevalence of Covid-19 related clinical outcomes. MethodsA retrospective study was conducted among 244 patients with BD (86.1% females; mean age 43.95±11.11 years). Each participant completed an online questionnaire regarding demographics, medical conditions, dispensed colchicine, TNFi or oral glucocorticoids, Covid-19 infection, clinical symptoms and recovery. ResultsThe prevalence of Covid-19 infection was 14.75%. Regarding dose of colchicine, the presence of ageusia was lower in patients taking 0.5mg/day of colchicine compared to those taking 1.5mg/day (p=0.021). The prevalence of dyspnea was significantly higher in patients taking TNFi compared with those without therapy (p=0.032). With regards to oral glucocorticoids, no significant differences were found. ConclusionsThe prevalence of Covid-19 among patients with BD seems to be higher than that among the general population in Spain. Continuous TNFi therapy might increase the prevalence of worse clinical outcomes such as dyspnea; oral glucocorticoids and colchicine apparently provided no protection against the Covid-19 related clinical outcomes of patients with BD.

The Association Between TNF Inhibitor Therapy Availability and Hospital Admission Rates for Patients with Ankylosing Spondylitis. A Longitudinal Population-Based Study.

BackgroundTNF inhibiting drugs (TNFi) provide symptomatic relief for patients with ankylosing spondylitis (AS), but uncertainty remains about long-term benefits. We compared hospital admissions, emergency department (ED) presentations, and direct health care costs before and after the availability of subsidized TNFi therapy for AS patients.MethodsState-specific dispensing and cost data for TNFi therapy for AS in Western Australia (WA) were obtained from Pharmaceutical Benefits Scheme (PBS) and expressed as the number of defined daily doses (DDD)/1000 population/day. Linked admission and ED data for 1783 AS patients followed for 14,257 person-years between 1990 and 2015 were extracted. Pre- and post-2005 admission rates/100,000 population were compared by rate ratio (RR).ResultsTNFi uptake in WA reached a DDD/1000 population/day 0.45 at an annual cost of AU$17.7 million in 2020. Hospital admission rates remained unchanged (RR: 0.95, CI 0.71–1.27, p = 0.66) but increased slightly in female patients (RR 1.22; CI 0.91–1.64, p = 0.20). While there was no change in cardiovascular admissions (6.3 vs. 6.2%, p = 0.6) or ED visit rates since 2005, frequency for cancer (2.7 vs. 3.8%, p < 0.01), infection (1.1 vs. 1.7%, p < 0.01) and mental health (4.0 vs. 4.5%, p < 0.02) admissions increased. Associated direct health care costs (2020 values) averaged AU$14.7 million before and AU$ 24.7 million per year after 2005.ConclusionsThe introduction of subsidized TNFi therapy did not change all-cause hospital admission or ED visit rates for existing AS patients. Whether the significantly increased direct health care costs are offset by reductions in other health care costs remains to be determined.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00393-x.

The risk factors and incidence of major infectious diseases in patients with ankylosing spondylitis receiving tumor necrosis factor inhibitors

Objectives This study aimed to evaluate the risk factor and incidence of infections in patients receiving tumor necrosis factor inhibitor (TNFi) therapy for ankylosing spondylitis using data from the national health insurance service. Methods This was a retrospective cohort study. Data regarding patients with ankylosing spondylitis prescribed TNFis were obtained from an insurance claims database of the Health Insurance Review & Assessment Service in Korea. Outcomes used were incidence rates of serious infection, pneumonia, tuberculosis, and herpes zoster during the follow-up period as well as the relationship between each TNFi and sex, hazard ratio (HR) of infection-related risk factors, and incidence of infections. Results A total of 2515 patients were included. There were no significant differences among the hazard ratios of TNFis for serious infection, pneumonia, and herpes zoster. However, the hazard ratio of tuberculosis was significantly higher for infliximab than for etanercept (adjusted HR 8.40 [95% confidence interval: 1.06–66.91]). In the subgroup analysis by sex, women treated with golimumab had a significantly higher hazard of herpes zoster than those treated with etanercept (adjusted HR 12.40 [95% confidence interval: 1.40–109.58]). Conclusion We recommend that risk factors for these infectious diseases be identified prior to prescribing TNFis in these patients.

Tumor necrosis factor inhibitor (TNFi) persistence and reasons for discontinuation in a predominantly male cohort with axial spondyloarthritis

Although tumor necrosis factor inhibitors (TNFi) have favorably altered the treatment landscape for patients with axial spondyloarthritis (axSpA), there is limited data regarding TNFi persistence and reasons for discontinuation. This is an observational time-to-event study utilizing data collected for a prospective multiple-disease registry of US Veterans with axSpA treated with TNFi therapies and recruited over a 10year period. Clinical, serological, and comorbid parameters were collected. Corporate Data Warehouse Pharmacy files provided courses of the 5 TNFi agents, and response to treatment was documented. Individual TNFi persistence was established utilizing univariate and multivariate Cox proportional models, and reasons for discontinuation were obtained by physician chart review. Two-hundred and fifty-five axSpA patients received 731 TNFi courses. A majority of patients (84.3%) had TNFi persistence at 12months; 63.5% and 47.1% at 24 and 36months, respectively. Compared to adalimumab, infliximab demonstrated greater persistence, certolizumab the least. Age, smoking status, BMI, comorbidity burden, inflammatory markers and HLA-B27 did not predict TNFi persistence or discontinuation. Stroke and peripheral arterial disease increased the probability of TNFi discontinuation. Secondary non-response (SNR) was the most common reason for discontinuation (46% of all courses); non-adherence (6%) and clinical remission (2%) were uncommon. Pain score at enrollment, myocardial infarction, African American race and inflammatory bowel disease (IBD) predicted TNFi response. While initial persistence of TNFi treatment was high, a large proportion of the patients discontinued initial TNFi therapy by 3years, primarily due to loss of efficacy. While further research identifying potential predictors of TNFi discontinuation in axSpA is warranted, access to alternate disease-modifying therapies is needed.

Determinants of Tumor Necrosis Factor Inhibitor Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomess.

ObjectiveThe objectives of this study were to characterize the reasons for tumor necrosis factor inhibitor (TNFi) initiation in patients with juvenile spondyloarthropathy (JSpA) and identify clinical correlates and to assess the effect of TNFi therapy on JSpA disease activity.MethodsWe conducted a retrospective cohort study of 86 patients with JSpA with first‐time use of a TNFi over a 7‐year period at Stanford Children's Health. We assessed the physician's reason for TNFi initiation, disease activity at 6 months, and clinical disease status at 12 months following TNFi start. Changes in active joint count, enthesitis count, and pain were measured. Demographics, physician reasons for TNFi initiation, and clinical characteristics were summarized.ResultsThe mean age at JSpA diagnosis was 12.4 years (SD 4.0 years), and the mean time from diagnosis to TNFi initiation was 1.6 years (SD 2.3 years). The most common reason for initiating a TNFi was active disease on physical examination (61%). At 6 months post TNFi initiation, patients on average had three fewer active joints and one fewer active enthesitis point. Patient‐reported pain improved from moderate/severe to mild. After 12 months, 54% of patients had active disease.ConclusionThe physician's decision to initiate a TNFi relied mostly on physical examination findings. Despite improvement in arthritis, enthesitis, and patient‐reported pain at 6 months post TNFi initiation, the majority of the patients still had active disease after 1 year of therapy.

The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial.

The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). Academic and community-based rheumatology, gastroenterology, and dermatology practices. Adults aged 50 years or older receiving TNFis for any indication. Random assignment to ZVL versus placebo. Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. Potentially limited generalizability to patients receiving other types of immunomodulators. This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.