Tumor Necrosis Factor Inhibitor Therapy Research Articles

Translated article] Immune-Mediated Skin Reactions to Tumor Necrosis α Inhibitors: A Review of 30 Cases

BackgroundTumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions. Material and methodsRetrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain. ResultsWe collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution. ConclusionsParadoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases.

Effect of Secukinumab and Tumor Necrosis Factor Inhibitors on Humoral Response to BNT162b2 mRNA Vaccine in Patients With Spondyloarthritis Compared to Immunocompetent Controls.

To assess the humoral response to the BNT162b2 mRNA vaccine among patients with spondyloarthritis (SpA) receiving secukinumab (SEC) compared to those receiving tumor necrosis factor inhibitors (TNFi) and immunocompetent controls. Consecutive patients with psoriatic arthritis or axial SpA receiving SEC (n = 37) or TNFi (monotherapy, n = 109; + methotrexate [MTX], n = 16), immunocompetent controls (n = 122), and patients with rheumatoid arthritis (RA) receiving TNFi therapy (controls, n = 50) were vaccinated with 2 or 3 doses of the BNT162b2 vaccine. We evaluated humoral response, adverse events, and disease activity, and monitored for breakthrough coronavirus disease 2019 (COVID-19) postvaccination. The 2-dose vaccine regimen induced a comparable seropositive response in all study groups. S1/S2 antibody titers (in binding antibody units/mL; mean [SD]) were higher in the SEC group vs the TNFi + MTX-SpA and TNFi-RA groups (192.5 [68.4] vs 104.6 [46.9], P < 0.001, and 143.1 [81.9], P = 0.004). After 6 months, 96.3%, 96.6%, and 80.9% of the SEC, immunocompetent, and TNFi monotherapy-SpA groups (P = 0.10), respectively; 66.7% of the TNFi + MTX-SpA group (P = 0.03); and 63% of the TNFi-RA group (P = 0.004) remained seropositive. S1/S2 antibody titer decline was steeper in the TNFi groups than the SEC group. After the third dose, 100% of the SpA and immunocompetent and 88.9% of the TNFi-RA (P = 0.25) groups were seropositive. Rate of breakthrough COVID-19 infection was higher in the TNFi groups than in the SEC group (36-37.5% vs 10.8%). No significant between-group differences were observed for postvaccination disease activity and adverse events. SEC did not interfere with the immunogenic response to BNT162b2 vaccine in patients with SpA; however, TNFi therapy was associated with lower S1/S2-antibody titers, faster decline, and higher rate of breakthrough infections.

Occurrence and prediction of flare after tapering of TNF inhibitors in patients with axial spondyloarthritis.

Patients with axial spondyloarthritis (axSpA) in clinical remission tapered Tumor Necrosis Factor inhibitor (TNFi) therapy according to a clinical guideline. During 2-years' follow-up, we aimed to investigate flare frequency, dose at which flare occurred, type of flare and predictors thereof. Patients in clinical remission (Bath ankylosing spondylitis disease activity index (BASDAI)<40, physician global score<40 and without disease activity the previous year) tapered TNFi to 2/3 standard dose at baseline, 1/2 at week (w) 16, 1/3 at w32 and discontinuationed at w48. Flare was defined as: BASDAI flare (BASDAI≥40 and Δ≥20) and/or clinical flare (development of inflammatory back pain, musculoskeletal or extra-articular manifestations and/or ASDAS-CRP increase ≥0.9) and/or MRI flare (≥2 new/worsened inflammatory lesions). Of 108 patients, 106 (99%) flared before 2 years: 29 patients (27%) at 2/3 standard dose, 21 (20%) at 1/2 dose, 29 (27%) at 1/3 dose and 27 (25%) after discontinuation. One-hundred-and-five (99%) had clinical flare, 25 (24%) BASDAI flare and 23 (29% of patients with MRI) MRI flare. Forty-one patients (41%) fulfilled the ASAS-definition of clinically important worsening (≥0.9 increase since baseline). Higher baseline physician global score was an independent predictor of flare after tapering to 2/3 (Odds ratio=1.19 (95% Confidence Interval=1.05-1.41);p=0.011). Changes in clinical and/or imaging variables in the 16 weeks prior to tapering did not predict flare. Almost all (99%) axSpA patients in clinical remission flared during tapering to discontinuation, but above half not before receiving 1/3 dose or less. Higher physician global score was an independent predictor of flare.

Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial

ObjectivesMany patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in...

Retention rate of tumor necrosis factor inhibitors, anti-interleukin 17, and anti-interleukin 12/23 drugs in a single-center cohort of psoriatic arthritis patients.

The objective of this study was to evaluate biological disease-modifying anti-rheumatic drugs (bDMARDs) survival in several therapy courses of patients affected by psoriatic arthritis (PsA) and to compare tumor necrosis factor inhibitors (TNFi) and non-TNFi retention rates. A total of 241 bDMARD therapy courses (155 TNFi drugs, 65 anti-interleukin (IL)-17 drugs, and 21 anti-IL12/23) were analyzed. Bivariate analyses were performed to assess the presence of demographic and clinical features, as well as comorbidities, associated with bDMARD discontinuation in TNFi and non-TNFi groups. In the bivariate analyses of TNFi and non-TNFi groups, we found a lower age at the start of TNFi therapy in the former group [46 years, interquartile range (IQR) 45-54 vs 50.5 years, IQR 42-61; p=0.004] as well as a lower proportion of patients with skin psoriasis (65.8% vs 88.4%; p<0.001). Survival analysis showed no significant differences between TNFi and non-TNFi groups. Cox regression found fibromyalgia as a predictor of drug failure [hazard ratio (HR) 3.40, confidence interval (CI) 1.92-6.03; p<0.001] and first-line bDMARDs as a protective factor (HR 0.46, CI 0.25-0.88; p=0.019). Lastly, among TNFi courses, fibromyalgia was associated with drug suspension (HR 6.52, CI 3.16-13.46; p<0.001), while only a trend of significance for skin psoriasis as a risk factor for drug failure was shown (HR 2.38, CI 1.00-5.66, p=0.05). This study provides information about clinical and demographic factors associated with retention rates of bDMARDs from a real-life, single-center cohort of PsA patients.

Efectos adversos cutáneos inmunomediados por los anti-TNF: revisión de 30 casos

BackgroundTumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions. Material and methodsRetrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain. ResultsWe collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution. ConclusionsParadoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases.

Predictors of DAPSA28 remission in patients with psoriatic arthritis initiating a first TNF inhibitor: results from 13 European registries.

In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98-0.99). Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme

ObjectiveIncreased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular...

Incident psoriasis under treatment with tumor necrosis factor-α inhibitors in juvenile idiopathic arthritis patients-analysis of the BiKeR registry.

The efficacy of tumor necrosis factor inhibitors (TNFi) for the treatment of psoriasis is well established, but patients may develop psoriasis for the first time while on TNFi as a paradoxical effect. Limited data on this association in patients with juvenile idiopathic arthritis (JIA) are available. Safety data from patients registered to the German Biologics registry (BiKeR) were analyzed. Patients were grouped by treatment regime: single TNFi, multiple TNFi, non-TNFi biologics or bDMARD-naïve control group receiving methotrexate. TNFi-associated psoriasis was defined as incident diagnosis of psoriasis after starting TNFi treatment. Patients with a history of psoriasis or psoriasis arthritis prior to TNFi therapy were excluded. Event rates using AEs reported after first dose were compared by Wald's test. A total of 4149 patients were treated with a TNFi (etanercept, adalimumab, golimumab, infliximab), 676 with a non-TNFi biologic (tocilizumab, abatacept, anakinra, canakinumab) and 1692 with methotrexate only. A total of 31 patients were diagnosed with incident psoriasis while on one of the above treatments. Compared with methotrexate, psoriasis was more frequent in the TNFi cohorts (RR 10.8, p = 0.019), specifically in the subgroup of TNF antibodies (RR 29.8, p = 0.0009), whereas no significant signal was observed with etanercept. Also, non-TNFi-treated patients presented high incident psoriasis rates (RR 25.0, p = 0.003). Our findings indicate a higher rate of incident psoriasis in JIA patients treated with TNFi monoclonal antibodies or non-TNFi biologic treatment. JIA patients receiving monoclonal antibody TNFi or non-TNFi bDMARD should be monitored for incident psoriasis. Medication change, if topical skin treatment remains insufficient, may be considered.

Acute heart failure as an adverse event of tumor necrosis factor inhibitor therapy in inflammatory bowel disease: A review of the literature.

Tumor necrosis factor inhibitors (anti-TNFs) are widely used therapies for the treatment of inflammatory bowel diseases (IBD); however, their administration is not risk-free. Heart failure (HF), although rare, is a potential adverse event related to administration of these medications. However, the exact mechanism of development of HF remains obscure. TNFα is found in both healthy and damaged hearts. Its effects are concentration- and receptor-dependent, promoting either cardio-protection or cardiomyocyte apoptosis. Experimental rat models with TNFα receptor knockout showed increased survival rates, less reactive oxygen species formation, and improved diastolic left ventricle pressure. However, clinical trials employing anti-TNF therapy to treat HF had disappointing results, suggesting abolishment of the cardioprotective properties of TNFα, making cardiomyocytes susceptible to apoptosis and oxidation. Thus, patients with IBD who have risk factors should be screened for HF before initiating anti-TNF therapy. This review aims to discuss adverse events associated with the administration of anti-TNF therapy, with a focus on HF, and propose some approaches to avoid cardiac adverse events in patients with IBD.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study

Objectives To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs).Methods In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP)) &lt;3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed.Results In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p&lt;0.01 for both comparisons). Achievement of DAS28 (CRP) &lt;3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patientreported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group.Conclusions Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNFi-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor.

TNF inhibitors significantly attenuate the humoral immune response to COVID-19 vaccination in patients with rheumatoid arthritis.

Several studies on the immunogenicity of vaccination against coronavirus disease 2019 (COVID-19) in patients with immune-mediated inflammatory diseases have evaluated the influence of DMARDs. The aim of the work presented here was to compare the humoral vaccine response after two vaccinations between patients with RA undergoing TNF inhibitor therapy and healthy controls. We assessed the humoral immune response, as measured by titres of neutralizing antibodies against the S1 antigen of severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), in patients with RA and anti-TNF treatment vs. controls without immunomodulatory medication. One hundred and seven fully vaccinated individuals were included at 6 ± 1 weeks after the second vaccination [BioNTech/Pfizer (72.9%), AstraZeneca (17.8%) and Moderna (9.3%)]. Immune responses in terms of antibody titres were compared between both subgroups with (n = 45) and without (n = 62) exposure to anti-TNF medication. The comparison was performed as a cross-sectional, single-centre study approach using non-parametric tests for central tendency. Anti-TNF medication produced a significantly impaired humoral immune response to vaccination against COVID-19. The maximum immune response was detected in 77.4% of control patients, whereas this decreased to 62.2% in participants treated with TNF inhibitors (P = 0.045; effect size, d = 0.194). Patients on combination treatment (anti-TNF medication and MTX, 17 of 45 subjects in the treatment group) did not differ significantly regarding humoral immune response compared with patients on monotherapy with TNF inhibitors only (P = 0.214). TNF inhibitors significantly reduce the humoral response following dual vaccination against COVID-19 in patients with RA.

The effect of TNF treatment uptake on incident hospital admission in Western Australia

ObjectiveTreatment strategies for juvenile idiopathic arthritis (JIA) have shifted significantly over the last 20 years. We examined the effect of the introduction of government-subsidised TNF inhibitor (TNFi) treatment on incident hospitalisation for JIA.MethodsWestern Australian (WA) hospital data were used to identify patients < 16 years hospitalised with JIA between 1990 and 2012. Changes in the number of patients with an incident hospitalisation, overall admissions and admissions for joint aspiration were examined using join-point regression TNFi dispensing data from 2002–2012 was used to describe defined daily doses (DDD)/1000 population/day.ResultsWe included 786 patients (59.2% girls, median age 8 years) with a first-time admission with JIA. The annual incident admission rate was 7.9 per 100,000 person-years (95%CI: 7.3, 8.4) which did not change significantly between 1990 and 2012 (annual percentage change (APC): 1.3, 95%CI: -0.3, 2.8). Annual hospital-based prevalence of JIA reached 0.72/1000 in 2012. DDD for TNFi usage rose steadily from 2003 indicating TNFi usage by 1/2700 children in 2012, while overall admission rates (APC 3.7; 95%CI: 2.3, 5.1) and admission rates for joint injections (APC 4.9%; 95%CI: 3.8, 6.0) also increased significantly in that period.ConclusionIncident inpatient admission rates for JIA were stable over a 22-year period. The uptake of TNFi was not associated with lower admission rates for JIA, due mainly to an increase in admissions for joint injection. These results indicate a notable but unexpected change in hospital-based management of JIA since the introduction of TNFi therapy in WA, where hospital-based prevalence of JIA is slightly higher than in North America.

Subclinical atherosclerosis in patients with hidradenitis suppurativa treated with TNF inhibitors.

Hidradenitis suppurativa (HS) is an independent risk factor for the development of subclinical atherosclerosis. Tumour necrosis factor (TNF) inhibitors are effective for the treatment of recalcitrant moderate-to-severe HS. However, the effect of treatment with TNF inhibitors on subclinical atherosclerosis in HS patients has not been previously investigated. In this study, we aimed to assess changes in biochemical parameters (fasting blood glucose and lipid levels) and carotid intima-media thickness (CIMT) values in Hurley stage II and III HS patients undergoing treatment with TNF inhibitors. This was a single center prospective study including 30 patients with Hurley stage II and III HS and 30 healthy controls (HCs). Baseline values of biochemical parameters and CIMT were compared to the values recorded after at least 6 months of TNF inhibitor therapy. CIMT values of the HS patients significantly exceeded those of HCs (for right p=0.011 and for left p=0.017). After at least 6 months of TNF inhibitor therapy, there was a statistically significant decrease in fasting blood glucose (p=0.001), whereas total cholesterol levels significantly increased (p=0.001). CIMT values also significantly increased (for right p=0.02 and for left p=0.01). Small sample size is limitation of the current study. Our study shows that patients with Hurley stage II and III HS undergoing TNF inhibitor therapy are under risk for progression of subclinical atherosclerosis.

Dva roky pandemie covidu-19 v populaci českých pacientů s idiopatickými střevními záněty léčenými bio­logickou léčbou – zkušenosti terciárního IBD centra

Summary: Background: Inflammatory bowel disease (IBD) may be associated with a more severe course of infections and a different response to vaccination, especially in complicated IBD course and in association with immune-modifying IBD treatment. The aim of this study was to describe COVID-19 pandemic during years 2020–2022 in IBD patients with long-term bio­logical therapy. Methods: A retrospective analysis of SARS-CoV-2 infection incidence in the population of 1,177 IBD (Crohn’s disease or ulcerative colitis) patients with long-term bio­logical therapy (IBD cohort) was performed. The incidence rate, crude incidence rate and standardized incidence ratio of COVID-19 in the IBD cohort, the odds ratio of infection depending on the type of bio­logic therapy administered, the dynamics of COVID-19 incidence depending on the predominant SARS-CoV-2 variant in the population and the current vaccination coverage of the IBD cohort were calculated. Results: From January 2020 to April 2022, 548 confirmed cases of COVID-19 (46.6%) were reported in the IBD cohort, with 39% share of PCR positivity in vaccinated individuals and with 95% occurrence of infection in unvaccinated part of the IBD cohort. Standardized incidence rate ratio of COVID-19 was 27% higher in the IBD cohort compared to the general Czech population. The dynamics of the development of the number of positive cases of COVID-19 in the IBD cohort was identical to the situation in the entire country. A higher odds ratio of the chances of infection was demonstrated in patients treated with tumor necrosis factor inhibitors, but not in patients treated with anti-integrins or monoclonal antibodies against interleukins. In the IBD cohort, 85.2% of patients were properly vaccinated, which was significantly more than the vaccination rate of the entire Czech population. Discussion and conclusion: During the two pandemic years, the incidence of COVID-19 in patients with severe IBD and long-term bio­logical treatment was higher compared to the general Czech population, despite the favorable vaccination coverage of this high-risk patients’ group. A higher risk was associated with tumor necrosis factor inhibitor therapy. Key words: inflammatory bowel disease – Crohn’s disease – ulcerative colitis – COVID-19 – SARS-CoV-2 – vaccination – bio­logical therapy

Changes in Bone Metabolism in Patients with Rheumatoid Arthritis during Tumor Necrosis Factor Inhibitor Therapy.

Tumor necrosis factor alpha (TNF-α), which enhances osteoclast activity and bone resorption, is one of the key inflammation mediators in rheumatoid arthritis (RA). The aim of this study was to assess the influence of yearlong TNF-α inhibitor application on bone metabolism. The study sample comprised 50 female patients with RA. Analyses involved the osteodensitometry measurements obtained using a "Lunar" type apparatus and the following biochemical markers from serum: procollagen type 1 N-terminal propeptide (P1NP), beta crosslaps C-terminal telopeptide of collagen type I (b-CTX) by ECLIA method, total and ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone and vitamin D. Analyses revealed changes in bone mineral density (BMD) at L1-L4 and the femoral neck, with the difference in mean BMD (g/cm2) not exceeding the threshold of statistical significance (p = 0.180; p = 0.502). Upon completion of 12-month therapy, a significant increase (p < 0.001) in P1NP was observed relative to b-CTX, with mean total calcium and phosphorus values following a decreasing trend, while vitamin D levels increased. These results suggest that yearlong application of TNF inhibitors has the capacity to positively impact bone metabolism, as indicated by an increase in bone-forming markers and relatively stable BMD (g/cm2).

Biologic Abatement and Capturing Kids’ Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA): study protocol for a randomized pragmatic trial

BackgroundThe effectiveness of biologic therapies, primarily tumor necrosis factor inhibitors (TNFi), for children with spondyloarthritis (SpA) has made inactive disease a realistic patient outcome. However, biologic therapies are costly, primarily delivered by subcutaneous or intravenous route, and have non-trivial side effects. Many patients and families want to know if biologic medications can be discontinued after inactive disease is achieved. It remains unclear whether medication dose should remain unchanged, tapered (increase the time between doses), or discontinued once when inactive disease is attained.MethodsThe Biologic Abatement and Capturing Kids’ Outcomes and Flare Frequency in Juvenile SpA (BACK-OFF JSpA) trial is a multicenter pragmatic trial that will randomize 198 participants ages 8–21 years old with SpA and sustained inactive disease on standard TNFi dosing to (1) continue standard TNFi dosing, (2) fixed longer dosing intervals of TNFi, or (3) stop TNFi. The trial will compare the hazard rate of protocol-defined flare and participants’ emotional health among the 3 groups over 12 months. Innovative aspects of this trial are the involvement of patient and parent stakeholders in the design and conduct of the study as well as an electronic health record-based enhanced recruitment strategy.DiscussionThis is the first randomized pragmatic trial to assess the efficacy of TNFi de-escalation strategies in children with JSpA with sustained inactive disease. This research will improve the evidence base that patients, caregivers, and rheumatologists use to make shared decisions about continued treatment versus de-escalation of TNFi therapy in this population.Trial registrationClinicalTrials.gov NCT04891640. Registered on 18 May 2021.

A tissue atlas of ulcerative colitis revealing evidence of sex-dependent differences in disease-driving inflammatory cell types and resistance to TNF inhibitor therapy.

Although literature suggests that resistance to TNF inhibitor (TNFi) therapy in patients with ulcerative colitis (UC) is partially linked to immune cell populations in the inflamed region, there is still substantial uncertainty underlying the relevant spatial context. Here, we used the highly multiplexed immunofluorescence imaging technology CODEX to create a publicly browsable tissue atlas of inflammation in 42 tissue regions from 29 patients with UC and 5 healthy individuals. We analyzed 52 biomarkers on 1,710,973 spatially resolved single cells to determine cell types, cell-cell contacts, and cellular neighborhoods. We observed that cellular functional states are associated with cellular neighborhoods. We further observed that a subset of inflammatory cell types and cellular neighborhoods are present in patients with UC with TNFi treatment, potentially indicating resistant niches. Last, we explored applying convolutional neural networks (CNNs) to our dataset with respect to patient clinical variables. We note concerns and offer guidelines for reporting CNN-based predictions in similar datasets.

Cancer incidence in immunocompromised patients: a single-center cohort study

BackgroundDiminished immune defense plays an important role in cancer development. Cancer risk in immunocompromised patients may differ. Identifying individuals with elevated cancer risk can inform strategies for routine cancer screening. This study aimed to understand and compare cancer incidence and risk in three patient groups: recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT); diagnosis of primary or secondary immunodeficiency disorder (PID/SID); and recipients of tumor necrosis factor inhibitor (TNF-i) therapy.MethodsThis retrospective cohort study used the University of Utah Health System database and Huntsman Cancer Institute tumor registry. Patients aged ≥18 years with SOT/HSCT, PID/SID or ≥ 3 months of TNF-i therapy were included. The date of transplant, diagnosis of PID/SID, or 1st TNF-i medication order date was defined as the index date. We calculated cumulative cancer incidence by Kaplan-Meier method. A Cox-proportional hazard regression model with a stepwise variable selection process was used to identify independent risk factors associated with the time to onset of a new primary cancer.ResultsIn total, 13,887 patients were included which comprised of 2982 (21%) SOT/HSCT, 7542 (54%) PID/SID and 3363 (24%) patients receiving TNF-i. The mean (SD) age ranged from 46.8 (15) years - 50.4 (18.2) years. The proportion of white patients ranged from 72.3–84.8%. The estimated cumulative cancer incidence was 11.5% in the SOT/HSCT cohort, 14.3% in the PID/SID cohort, and 8.8% in the TNF-i cohort. The multivariable model adjusted for age, benign in-situ disease, Charlson Comorbidity Index, hypertension/cardiovascular disease/end stage renal disease, gender, race/ethnicity, and renal cyst as significant risk factors. The adjusted hazard ratios for cancer development in SOT/HSCT and PID/SID cohorts compared to the TNF-i cohort over the full follow-up period were 1.57 (95% CI: 1.16–2.13) and 2.14 (95% CI: 1.65–2.77), respectively.ConclusionA significantly increased risk of cancer was observed in PID/SID patients and SOT/HSCT patients compared to TNF-i patients. Age ≥ 50 years, male gender, and clinical comorbidities were additional factors impacting cancer risk. PID/SID and SOT/HSCT patients may benefit from more intensive cancer screening.

The predictability of ASDAS on drug survival in patients with ankylosing spondylitis on biologic therapy: data from the KOBIO registry.

The Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS) is largely used for assessing disease activity in patients with AS. We aimed to investigate the predictability of ASDAS on drug survival in patients with low Bath AS Disease Activity Index (BASDAI) during biologic therapy. Using data from multi-center, prospective, observational prospective cohort, Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. The study population consisted of patients enrolled in the KOBIO registry from December 2012 to December 2018. The baseline demographic data and variables such as extra-articular manifestations, HLA-B27 positivity, family history of spondyloarthritis, ASDAS C-reactive protein (CRP), BASDAI, and Bath AS Functional Index scores were collected from the database. The disease activity indices were followed yearly after initiating a tumor necrosis factor (TNF) inhibitor (TNFi). Disease activities were defined as high (ASDAS-CRP ⩾ 2.1, BASDAI ⩾ 4) and low (ASDAS-CRP < 2.1, BASDAI < 4). Data from 1773 patients were analyzed. Among 269 patients with low BASDAI at baseline, 151 (56.1%) patients had high ASDAS-CRP, yet in 142 patients with low ASDAS-CRP at baseline, only 24 (16.9%) patients had a high BASDAI. High ASDAS-CRP captured more patients who had initiated or switched to a TNFi than those with high BASDAI (92.5% versus 84.8%, respectively, p < 0.001). Moreover, among AS patients with low BASDAI after 1 year of therapy, drug persistence in the following year was significantly lower in patients with high ASDAS than in those with low ASDAS (68.7% versus 82.5%, p < 0.001). ASDAS-CRP not only has its advantages over BASDAI in assessing disease activity but also low ASDAS-CRP at 1 year can be a marker of long-term drug survival of TNFi therapy.