Anti-Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease.

Importance: Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD. Objective: To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality. Design, Setting, and Participants: This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024. Exposures: Incident use of TNF inhibitors. Main Outcomes and Measures: The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Results: Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses. Conclusions and Relevance: In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.

Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF-α and IL-23p19 bioactivities.

BACKGROUND: Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non-response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF-α (tumour necrosis factor-α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond. METHODS: We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage-expressed membrane TNF-α (hmTNF-α) and IL-23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb-Fc.  Our study encompassed in vitro and in vivo characterization of BsNb and BsNb-Fc. RESULTS: BsNb-Fc exhibited an improved serum half-life, targeting capability and effector function than BsNb. It's demonstrated that BsNb-Fc exhibited superior anti-inflammatory effects compared to the anti-TNF-α mAb (infliximab, IFX) combined with anti-IL-12/IL-23p40 mAb (ustekinumab, UST) by Transwell co-culture assays. Notably, in murine models of acute colitis brought on by 2,4,6-trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb-Fc effectively alleviated colitis severity. Additionally, BsNb-Fc outperformed the IFX&UST combination in TNBS-induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS. CONCLUSION: These findings highlight an enhanced efficacy and improved biostability of BsNb-Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF-α inhibition. KEY POINTS: A bispecific nanobody (BsNb) was created to target TNF-α and IL-23p19, exhibiting high affinity and remarkable stability. BsNb-Fc inhibited the release of cytokines in CD4+T cells during co-culture experiments. BsNb-Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.

Is the use of secukinumab after anti-TNF therapy greater than expected for the risk of developing inflammatory bowel disease?

OBJECTIVE: In this study, our objective was to present real-life data on the incidence of inflammatory bowel disease (IBD) among patients receiving secukinumab treatment. METHODS: The study consisted of 209 patients who had prior exposure to anti-tumor necrosis factor (TNF) or were biologically naive. Patients with a pre-existing history of IBD were excluded from the study. RESULTS: Of the 209 patients in the study, 176 (84.3%) had ankylosing spondylitis, while 33 (15.7%) had psoriatic arthritis. 112 (53.6%) patients had prior exposure to at least one anti-TNF treatment before initiating secukinumab. IBD developed in 10 (4.8%) of the 209 patients. The incidence of IBD among patients who initiated secukinumab as their first biologic agent was 1%. For patients who had previously received any anti-TNF treatment and subsequently transitioned to secukinumab, the incidence of IBD was 8% (p=0.018, odds ratio (OR): 8.38, 95% CI: 1.04-67.45). A mean of 3.67 months (±4.3) after anti-TNF use, whereas IBD symptoms developed in the biologically naive patient after 15 months. CONCLUSION: Our study observed IBD incidence in 4.8% of patients using secukinumab. Patients who initiated secukinumab after previous anti-TNF treatment exhibited a significantly higher rate and risk of developing IBD. The onset of IBD occurred earlier in these patients (mean 3.67 months), whereas a single case of IBD showed a longer duration (15 months). Further studies with larger patient numbers are warranted to provide a more comprehensive understanding of our findings.

Persistence and safety of anti-TNF biosimilars versus originators in immune-mediated inflammatory diseases: an observational study on the French National Health Data System.

OBJECTIVES: Biosimilar-originator equivalence has been demonstrated in phase 3 trials in a few indications of infliximab, etanercept and adalimumab. The objective of our study was to compare the persistence and safety of biosimilars versus originators in all the licensed indications of these molecules. METHODS: We used data from the French National Health Data System (SNDS), covering 99% of the French population, to identify infliximab, etanercept and adalimumab initiators from biosimilar launch (January 2015, May 2016 and October 2018, respectively) to 30 June 2021. Patients were then followed for 1 year. Treatment persistence (duration without treatment discontinuation or modification) and safety (including severe infections, all-cause hospitalisation and death) were compared between originator and biosimilar users by Cox regressions weighting the populations on the inverse probability of treatment. Analyses were performed by molecule, by disease and by biosimilar product. RESULTS: From January 2015 to June 2021, 86 776 patients were included in the study: 22 670, 24 442 and 39 664 patients had initiated infliximab, etanercept and adalimumab, respectively; 49 752 (53%) were biosimilar initiators. We did not find any risk of discontinuation (HRs were below or around 1, here all pathologies and products together: infliximab 0.88 (0.80-0.97), etanercept 0.85 (0.81-0.90) and adalimumab 0.96 (0.91-1.00)) or safety event (infection: infliximab 0.97 (0.78-1.21), etanercept 1.04 (0.81-1.33) and adalimumab 0.98 (0.83-1.16); hospitalisation: infliximab 1.08 (0.96-1.23), etanercept 0.99 (0.87-1.11) and adalimumab 0.91 (0.83-0.99)) associated with biosimilar versus originator use. CONCLUSIONS: Our study shows reassuring results regarding the persistence and safety of biosimilar tumour necrosis factor-alpha inhibitors compared with originators in all licensed indications.

A Case Series of TNF Inhibitor-Induced Psoriasis Successfully Treated With Upadacitinib.

Tumor necrosis factor-alpha inhibitors (TNF-i) are commonly used to treat immune-mediated diseases such as psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD), spondyloarthritis (SpA) and rheumatoid arthritis (RA). However, paradoxical psoriasis induced by TNF-i has been described and is not uncommon, particularly with infliximab and etanercept. The presentation of TNF-i-induced psoriasis is most commonly plaque or palmoplantar morphology. Optimal treatment strategies for recalcitrant psoriatic disease are not well understood. In this case series, we report three patients with TNF-i-induced psoriasis who were treated with upadacitinib and experienced complete resolution of their psoriatic eruptions. The efficacy of Janus kinase inhibitors (JAK-i) is possibly explained by mechanisms involving uncontrolled production of type 1 IFNs as well as increases in IL-23 and T-helper 17 cells upstream of relevant JAK/STAT pathways. We also offer a proposed treatment algorithm that includes the use of JAK-i as a promising management option in patients with recalcitrant disease. However, larger studies are needed to confirm the efficacy and safety of JAK-i in this patient population. J Drugs Dermatol. 2024;23(2): doi:10.36849/JDD.7645.

Risk of major adverse cardiovascular events and all-cause mortality among patients with psoriatic disease treated with tumor necrosis factor-α and interleukin-12/23 inhibitors: a nationwide population-based cohort study in Korea.

PURPOSE: Few studies have investigated the impact of biologics on the risk of major adverse cardiovascular events (MACEs) among Korean patients with psoriatic diseases. We compared the risk of MACEs and all-cause mortality among patients with psoriatic disease treated with tumor necrosis factor (TNF)-α and interleukin (IL)-12/23 inhibitors in Korea. METHODS: Patients with psoriatic disease prescribed with TNF-α and IL-12/23 inhibitors since 2016 were selected from the Korean National Health Insurance Service (NHIS) Database. Follow-up data for MACEs and all-cause mortality between 2016 and 2020 were collected. A total of 2886 individuals were included, including 1987 IL-12/23 inhibitor users and 899 TNF-α inhibitor users. RESULTS: Compared with IL-12/23 inhibitor users, TNF-α inhibitor users had a higher prevalence of dyslipidemia and a significantly higher risk of all-cause mortality but not MACE. After controlling for age, female TNF-α inhibitor users had a significantly increased risk of all-cause mortality. Meanwhile, after controlling for sex, TNF-α inhibitor users aged 60 years or older demonstrated a significantly elevated risk of all-cause mortality. In conclusion, No statistically significant difference in MACE risk was observed between patients who used TNF-α and IL-12/23 inhibitors. Nevertheless, the use of IL-12/23 inhibitors, especially among older and female patients, resulted in a lower overall mortality.

Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis.

BACKGROUND: Dysregulation of several inflammatory cytokines including tumour necrosis factor (TNF) in dementia patients has also been identified as a key factor in the pathogenesis of rheumatoid arthritis (RA). We aimed to investigate the association of disease-modifying antirheumatic drugs (DMARDs) therapy for RA with risk of incident dementia. METHODS: Electronic database searches of PubMed, EMBASE and Cochrane Library were performed. Observational studies that assessed the association of dementia with DMARDs in RA were included. Pooled risk ratios (RRs) with 95% CIs were used as summary statistic. The certainty of evidence was judged by using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Overall, 14 studies involving 940 442 patients with RA were included. Pooled RR for developing dementia was 0.76 (95% CI 0.72 to 0.80) in patients taking biological DMARDs overall versus those taking conventional synthetic DMARDs, with 24% for TNF inhibitors (RR 0.76, 95% CI 0.71 to 0.82), 24% for non-TNF biologics (RR 0.76, 95% CI 0.70 to 0.83), separately. There was a significant subgroup effect among different types of TNF inhibitors (RR 0.58 [95%CI 0.53 to 0.65], 0.65 [95% CI 0.59 to 0.72], 0.80 [95% CI 0.72 to 0.88] for etanercept, adalimumab, infliximab, respectively; p value between groups=0.002). However, compared with non-users of DMARDs or investigative treatment, no significant effect on dementia incidence was observed in those receiving conventional synthetic DMARDs overall (RR 0.84, 95% CI 0.59 to 1.20), methotrexate (RR 0.78, 95% CI 0.54 to 1.12), hydroxychloroquine (RR 0.95, 95% CI 0.63 to 1.44), except for sulfasalazine (RR 1.27, 95% CI 1.06 to 1.50). CONCLUSIONS: Biological DMARDs for RA are associated with decreased dementia risk, while protective effect is not observed in conventional synthetic DMARDs. Controlled clinical trials on TNF inhibitors are necessary to test their neuroprotective potentials.

Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Withdrawal of immunomodulators (IMMs) or tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases (IBDs) in remission on combination therapy is attractive. We evaluated the efficacy and safety of (1) IMM, or (2) TNF antagonist withdrawal in patients with IBD in sustained remission on combination therapy. METHODS: Through a systematic review till March 31, 2023, we identified randomized controlled trials (RCTs) that compared the efficacy and safety of IMM or TNF antagonist withdrawal vs continued combination therapy, in patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy. Primary outcome was risk of relapse and serious adverse events at 12 months. We conducted meta-analysis to calculate relative risk (RR) and 95% confidence interval (CI) and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: We identified 8 RCTs with 733 patients (77% with Crohn's disease, 91% on infliximab-based combination therapy). On meta-analysis of 5 RCTs, there was no difference in the risk of relapse between patients with IMM withdrawal (continued TNF antagonist monotherapy) vs continued combination therapy (16.8% vs 14.9%; RR, 1.15; 95% CI, 0.75-1.76) without heterogeneity (low certainty of evidence). TNF antagonist withdrawal (continued IMM monotherapy) was associated with 2.4-times higher risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38-4.01), with minimal heterogeneity (low certainty of evidence). There was no difference in the risk of serious adverse events with IMM or TNF antagonist withdrawal vs continued combination therapy. CONCLUSIONS: In patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy, de-escalation with TNF antagonist withdrawal, but not IMM withdrawal, was associated with an increased risk of relapse.

Factors that predict development of chronic kidney disease in patients with rheumatoid arthritis receiving biologic DMARDs and mortality rates.

OBJECTIVES: We aimed to determine the choice of biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/ts-DMARDs), factors associated with the development of chronic kidney disease (CKD), and mortality in RA patients with CKD receiving b/ts-DMARDs. METHODS: Two thousand one hundred forty-one RA (79.4% female) patients were included in the analysis from the HUR-BIO prospective registry. Patients were divided into the CKD group and the non-CKD group. Age and gender-matched patients were selected from the non-CKD group, and then three main groups were determined. CKD was staged according to the glomerular filtration rate criteria. The clinical characteristics of the patients, disease activities, treatment choices, drug retention rate, and mortality rates were compared between the groups. RESULTS: CKD was detected in 90/2141 (4.2%) RA patients on b/ts-DMARDs. Forty patients (2.3%) developed CKD during follow-up after the initiation of b/ts-DMARDs. In the CKD group, anti-TNF agents were chosen as the first-line b/ts-DMARDs therapy in 64.4% of patients, with etanercept leading in 31 (34.4%) patients. In multivariate analysis, age at the start of treatment, DAS-28-ESR at last visit, amyloidosis, hypertension, and history of smoking were the factors associated with the development of CKD in RA patients receiving b/ts-DMARDs. The mortality rate in RA-CKD patients until the onset of the pandemic was 15.41 per 1000 patient years, whereas it was 85.9 per 1000 patient years after the pandemic. CONCLUSION: Comorbidities and control of disease activity are critical in the development of CKD in RA patients receiving b/ts-DMARDs. While there was no significant difference in mortality rate between CKD and non-CKD patients, the overall mortality rate increased after the COVID-19 pandemic duration in both groups.

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Etanercept Ameliorates Vascular, Endocrine, and Ovarian Changes in a Rat Model of DHEA-Induced Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder affecting women of reproductive age. This study examined the efficacy of etanercept (ETA), an anti-TNF-α drug, in alleviating endocrine, metabolic, and vascular dysfunction in a rat model of PCOS. Prepubertal female Wistar rats were divided into three groups: control, PCOS, and PCOS+ETA. The PCOS groups received dehydroepiandrosterone (DHEA) treatment, whereas the PCOS+ETA group received both DHEA and ETA. After 35 days, various biomarkers were evaluated, including systemic blood pressure, endothelial function, and eNOS and TNF-α expression levels in the thoracic aorta and ovaries. The PCOS group exhibited ovarian morphological changes, increased body weight, and hormonal imbalances, whereas the PCOS+ETA group showed restored levels of these parameters. Systemic blood pressure, urinary albumin levels, and protein excretion did not differ significantly differ among the groups. Endothelium-dependent relaxation, eNOS expression, TNF-α expression in the thoracic aorta, and TNF-α expression in the ovaries were restored to normal levels in the PCOS+ETA group. Furthermore, ovarian morphology was improved in the PCOS+ETA group. In conclusion, etanercept treatment shows promise in mitigating hormonal disturbances and vascular dysfunction in patients with PCOS, suggesting potential therapeutic advantages.

Is low-dose tumor necrosis factor inhibitor effective and safe in patients with ankylosing spondylitis flare-up after renal transplantation? A case report and literature review.

Rheumatic diseases, the immunosuppressant drugs used after solid organ transplantation to prevent graft rejection, and the biologics used for controlling rheumatic disease, especially tumor necrosis factor inhibitors (TNFi)-all of these could increase the risk of malignancy. The roles of biologics for disease control in rheumatic disease patients after kidney transplantation (KT) are not well established because only a few cases are reported, and the possibility of increasing infection and malignancy rates. Here, we present the first case of ankylosing spondylitis (AS) successfully treated with low-dose TNFi for disease activity flare-up 5 months after KT and review the literature to see whether the use of biologics, especially TNFi, in AS patients with disease activity flare-ups after receiving KT is effective and safe.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). METHODS: We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. RESULTS: The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). CONCLUSIONS: In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

Efficacy and safety of proactive drug monitoring in inflammatory bowel disease treated with anti-TNF agents: A systematic review and meta-analysis.

BACKGROUND AND AIMS: A systematic review and a meta-analysis of the literature was conducted to assess efficacy and safety of proactive therapeutic drug monitoring (TDM) versus conventional management during maintenance treatment with anti-tumour necrosis factor (anti-TNFα) in patients with inflammatory bowel disease (IBD). METHODS: A search was conducted up to January 2022 (MEDLINE, EMBASE, and the Cochrane Library). The primary outcome was the ability to maintain clinical remission at 12 months. The certainty of evidence was determined using the GRADE approach. RESULTS: Nine studies were identified: one systematic review, six randomised clinical trials, and two cohort studies. No superior efficacy of proactive TDM [relative risk 1.16; 95% confidence interval (CI): 0.98-1.37, n=528; I2=55%] was shown. Proactive TDM could improve the durability of anti-TNFα treatment [odds ratio (OR) 0.12; 95%CI: 0.05-0.27; n=390; I2=45%), prevent acute infusion reactions (OR 0.21; 95%CI: 0.05-0.82; n=390; I2=0%), decrease adverse events (OR 0.38; 95%CI: 0.15-0.98; n=390; I2=14%), and reduce the probability of surgery, at lower economical expenditure. CONCLUSIONS: The analysed evidence did not confirm the superiority of proactive TDM of anti-TNFα treatment over conventional management in patients with IBD, so proactive TDM should not currently be recommended.

Infliximab abrogates adenine-induced chronic kidney disease via modulation of the MAPK/JNK/ASK signaling pathway in rats.

Chronic kidney disease (CKD) is a prominent cause of death worldwide. Infliximab is one of the anti-TNF-α; herein, we studied the effect of infliximab on adenine-induced CKD. To inspect the role of infliximab, either ameliorative or curative, on CDK induced with adenine. Thirty Wistar albino rats were separated into five groups of 6 rats' each: rats of group Ι were kept as control given saline, rats of group II were treated with infliximab (5 mg/kg, i.p.) for 5 weeks, rats of group ΙΙΙ (the diseased group) had an adenine containing diet (0.25% W/W in feed) for 5 weeks, rats of group ΙV (the ameliorative group) had an adenine-containing diet and infliximab (5 mg/kg, i.p.) for 5 weeks simultaneously, and rats of group V (the curative group) had adenine containing diet then a single dose of infliximab (5 mg/kg, i.p.) was given in the 6th week. Infliximab treatment revealed a decrease in the plasma levels of urea, creatinine, NGAL, and MDA with a substantial increase in TAC. Also, inflammatory mediators such as IL-6 and NF-κB were significantly decreased with the down-regulation of the ASK1/MAPK/JNK pathway. Caspase 3 was downregulated. Also, infliximab treatment exhibited improvement in the histological and immunohistochemical kidney changes. Through its involvement in reducing oxidative stress, inflammation, and apoptosis, infliximab has an ameliorative and curative effect on CKD induced with adenine.

Frailty and Risk of Serious Infections in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted-Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted-synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. METHODS: Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients' baseline frailty risk score was calculated using a Claims-Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time-to-any infection and all-cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. RESULTS: A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non-TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2-1.9) and 40% higher risk of inpatient admissions (1.4 [1.3-1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1-1.3]) or non-TNFi (1.2 [1.0-1.4]) or JAKi (1.4 [1.0-2.0]). CONCLUSION: Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted-synthetic DMARDs.

Rituximab as possible therapy in TNF inhibitor-induced IgA vasculitis with severe renal involvement.

BACKGROUND: We observe the increasing use of tumor necrosis factor (TNF) inhibitors in patients affected by chronic inflammatory diseases. These drugs provide good control of symptoms, contributing to significant improvement in the quality of life in individuals with high disease burden. On the other hand, along with their wider use and longer follow-up periods the number of reports regarding their adverse effects is also increasing. The reported complications include drug-induced vasculitis with possible kidney involvement. In the literature we can distinguish more frequently described ANCA-associated vasculitis and more rarely occurring immunoglobulin A vasculitis. Although uncommon, such complications may present with potentially life-threatening vital organ dysfunction; therefore, adequate monitoring and effective therapy are necessary. CASE PRESENTATION: We report two cases of TNF inhibitor-induced vasculitis with severe acute worsening of renal function and significant proteinuria. The first patient was receiving golimumab therapy for ankylosing spondylitis and the second patient was treated with adalimumab for psoriasis and psoriatic arthritis. In the second case dialysis treatment was necessary and the patient presented recurrence of vasculitis after rechallenge with adalimumab. Both patients underwent renal biopsy which showed findings compatible with drug-induced IgA vasculitis and both were treated successfully with corticosteroids and rituximab. CONCLUSIONS: To the best of our knowledge this is the first report of rituximab use in drug-induced IgA vasculitis with renal involvement. Combination of corticosteroids and rituximab can be an effective therapy in case of vasculitis with kidney failure and a preferable option for selected patients with drug-induced IgA vasculitis compared to cyclophosphamide. More studies are necessary to establish suitable short- and long-term treatment. Given the rarity of this disorder, case reports and case series can provide practical guidance until additional studies become available.