Tumor Necrosis Factor Alpha Inhibitors Research Articles

Improving Hepatitis B Vaccination Rates among At-risk Children and Adolescents with Inflammatory Bowel Disease.

Introduction:Patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor alpha inhibitors (TNFai) may be at higher risk for hepatitis B virus (HBV) infection. We conducted a quality improvement (QI) initiative to improve HBV vaccination rates in seronegative children with IBD.Methods:This QI initiative implemented an HBV vaccination strategy from September 2018 to March 2020 in patients with newly diagnosed IBD with hepatitis B surface antibody (HBsAb) <10 mIU/mL. The project aimed to (1) increase HBV vaccination rates in seronegative patients and (2) document immunogenicity after completing a three-dose vaccine series. Outcome measures included the percentage of seronegative patients who received HBV vaccines (dose 1 and three-dose series). Interventions included applying a standardized vaccination protocol, and creating a vaccine workflow in two clinical areas, previsit planning and stakeholder engagement.Results:One hundred seventy-four children and adolescents with IBD were evaluated during the study period, and 132 (76%) were HBsAb negative. After plan-do-study-act (PDSA) 1, the proportion of eligible patients who received HBV vaccine dose 1 increased from a baseline of 7% to 100% and was sustained for over 12 months. During PDSA 2, the proportion of patients completing the three-dose vaccine series improved from a baseline of 0% to 82% (n = 100); among 93 children in this subgroup who had repeat serology performed, 86 (92%) demonstrated serologic evidence of HBV protection.Conclusions:A multidisciplinary approach applying QI methodology allowed for improved and sustained HBV vaccination rates in at-risk seronegative children and adolescents with IBD. A three-dose HBV vaccine series proved immunogenic in 92% of eligible patients.

TNF-α Inhibitors and Other Biologic Agents for the Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis.

With anti-PD-1 antibodies serving as a representative drug, immune checkpoint inhibitors (ICIs) have become the main drugs used to treat many advanced malignant tumors. However, immune-related adverse events (irAEs), which might involve multiple organ disorders, should not be ignored. ICI-induced myocarditis is an uncommon but life-threatening irAE. Glucocorticoids are the first choice of treatment for patients with ICI-induced myocarditis, but high proportions of steroid-refractory and steroid-resistant cases persist. According to present guidelines, tumor necrosis factor alpha (TNF-α) inhibitors are recommended for patients who fail to respond to steroid therapy and suffer from severe cardiac toxicity, although evidence-based studies are lacking. On the other hand, TNF-α inhibitors are contraindicated in patients with moderate-to-severe heart failure. This review summarizes real-world data from TNF-α inhibitors and other biologic agents for ICI-induced myocarditis to provide more evidence of the efficacy and safety of TNF-α inhibitors and other biologic agents.

Psoriasis, inflammatory bowel disease, and uveitis as paradoxical adverse effects induced by TNF inhibitors in patients with immune-inflammatory rheumatic conditions

Despite their known benefits, tumor necrosis factor alpha inhibitors (TNFi) may cause certain unexpected side effects, such as the aggravation of pre-existing autoimmune conditions or inducing the onset of new inflammatory conditions, these reactions being called “paradoxical adverse effects’’ (PAEs). The spectrum of TNFi-induced PAEs is vast and may include dermatological disease (frequently - psoriasiform skin reactions), gastroenterological disease (inflammatory bowel disease), ophthalmological disease (uveitis) and other autoimmune conditions (lupus-like reactions, vasculitis). PAEs are characterized by complex physio-pathological mechanisms which remain a matter of further research and may significantly impact the patients’ evolution and quality of life. Importantly, a large number of patients require the cessation of TNFi treatment, as well as other types of therapeutic interventions. The present review aimed to analyze recent findings regarding certain paradoxical adverse effects (psoriasis, inflammatory bowel disease, and uveitis) in patients with RA, ankylosing spondylitis (AS), and PsA treated with TNFi.

Tumor Necrosis Factor-Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is an autoimmune disease that, if untreated or poorly controlled, can cause significant morbidity in terms of loss of physical function and higher mortality due to higher cardiovascular risk. The standard of care for this disease is the use of disease-modifying antirheumatic drugs (DMARDs). However, patients unable to reach low disease activity or remission and patients unable to tolerate conventional DMARDs will be switched to biologic therapy, a subset of which includes anti-tumor necrosis factor-alpha inhibitors. Since tumor necrosis factor-alpha inhibitors (TNFi) inhibit the inflammatory cascade, they also play an essential role in dampening the progression of atherosclerosis and altering the risk of cardiovascular outcomes in RA.In this study, we assessed the risk of cardiovascular diseases, namely, congestive heart failure, nonfatal myocardial infarction, cerebrovascular disease, and coronary artery disease. We carried out the analysis by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and conducted a literature search utilizing the following databases: PubMed, Science Direct, and Cochrane Library. Using the search strategy, we found a total of 19 articles that fit the inclusion and exclusion criteria, in addition to passing the risk of bias assessment. This is composed of three systematic reviews with meta-analyses, three randomized control studies, four narrative reviews, and nine cohort studies. In this systematic review, it was found that treatment with TNFi causes a corresponding reduction in the risk of cardiovascular events. This review encourages further dissection into the inner workings of TNFi in reducing the risk of cardiovascular disease among patients with RA.

Recurrence of Relapsing Polychondritis on Tumor Necrosis Factor Antagonist Cessation and Starting an Interleukin-17 A Inhibitor

Relapsing polychondritis (RP) is a rare autoimmune disorder that has been associated with various other autoimmune conditions. There have been no reported cases about any patient with psoriasis who has experienced RP recurrence associated with a change in biologic therapy. This is only the second case of a patient developing RP or RP recurrence associated with an Interleukin-17 A inhibitor or Tumor Necrosis Factor alpha inhibitor cessation. We present this case to increase physician awareness of a relationship between IL-17 A inhibitor use and the induction of relapsing polychondritis. In addition, we explore current literature related to IL-17 A inhibitor use in psoriasis.

Discontinuation and Switchback After Non-Medical Switching from Originator Tumor Necrosis Factor Alpha (TNF) Inhibitors to Biosimilars: A Meta-Analysis of Real-World Studies from 2012 to 2018.

IntroductionTo examine the prevalence rates of biosimilar discontinuation and switchback to the originator tumor necrosis factor alpha (TNF) inhibitors following non-medical switch (NMS) in patients.MethodsReal-world studies reporting biosimilar discontinuation and switchback rates following NMS published between January 2012 and August 2018 were identified through a systematic literature review. A meta-analysis estimated the annualized discontinuation and switchback rates. A subsequent meta-analysis assessed annualized incremental discontinuation rate among studies reporting both discontinuation rates in patients who underwent an NMS (switchers) and patients who remained on originators (non-switchers).ResultsA total of 66 publications were identified: 31 in gastroenterology, 32 in rheumatology, and 3 in both. Half of the studies reported switchback rates; only 9 studies reported discontinuation rates for both switchers and non-switchers. Across studies, the mean/range sample size of the NMS patient population was 136/9–1641; mean/range follow-up was 10/3–24 months. Annualized biosimilar discontinuation rate was 21% (95% confidence interval [CI] 18%, 25%). Switchback rate was 14% (95% CI 10%, 17%) among all NMS patients and 62% (95% CI 44%, 80%) among discontinuers. The mean/range sample size of switchers and non-switchers was 344/89–1621 and 768/19–2870, respectively; mean/range follow-up was 11/6–18 and 12/6–8 months, respectively. Annualized incremental biosimilar discontinuation rate was 18% (95% CI 4%, 31%).ConclusionBiosimilar discontinuation was found to be prevalent among patients who underwent an NMS from an originator TNF inhibitor to its biosimilar(s) in the real world. In addition, switchback to the originator TNF inhibitors was common following biosimilar discontinuation. Careful consideration is necessary when switching patients already on an originator TNF inhibitor to its biosimilar(s). Main limitations included the heterogeneity of the studies and the limited comparability of the data.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02173-7.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUNDTumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.AIMTo determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODSIn this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test.RESULTSOne hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].CONCLUSIONHigher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

The Utility of Frequent Laboratory Monitoring for Patients on Tumor Necrosis Factor-Alpha Inhibitors in Dermatology.

IntroductionTumor necrosis factor-alpha inhibitors (TNF-ai) are becoming increasingly common to use among patients with skin disease. To safely take these medications, it is recommended to monitor laboratory values routinely; however, the utility of this practice and the risk-benefit of frequent laboratory monitoring has not been explored fully in patients with skin disease. The purpose of this study was to evaluate the necessity of routine laboratory monitoring in patients taking a TNF-ai with a dermatological disease.MethodsRetrospective chart review evaluated laboratory abnormalities (complete blood counts and liver function tests) in adult patients who took a TNF-ai for a dermatologic disease at The University of Kansas Hospital.ResultsThere were 27 patients included for a total of 45 entries. The most common skin disease was hidradenitis suppurativa (23/45) and infliximab (22/45) was most the commonly used medication. Of the 45 entries, there were only seven patients that developed abnormal monitoring laboratory values related to initiation of TNF-ai. These abnormalities were transient and most frequently occurred after 12 months, with 2 of the 45 resulting in no discontinuation or dose reduction of TNF-ai. One patient discontinued medication due to anemia that did not improve after medication withdrawal.ConclusionsLaboratory abnormalities due to TNF-ai were infrequent and when they did occur were transient and mild. The study was limited by the small sample size of patients, and larger prospective studies are needed to evaluate these findings fully. However, dermatologists may be able to employ less frequent laboratory monitoring safely for patients on TNF-ai.

Co-administration of Lactobacillus gasseri KBL697 and tumor necrosis factor-alpha inhibitor infliximab improves colitis in mice

Inflammatory bowel disease (IBD) refers to disorders involving chronic inflammation of the gastrointestinal tract. Well-established treatments for IBD have not yet to be suggested. To address this gap, we investigated the effects of co-administration of Lactobacillus gasseri (L. gasseri) KBL697 and infliximab (IFX), the first approved tumor necrosis factor (TNF)-alpha inhibitor, on the dextran sodium sulfate-induced colitis mouse model. 2 × 109 colony-forming units/g of L. gasseri KBL697 were administered to seven-week-old female C57BL/6J mice daily by oral gavage. On day three, IFX (5 mg/kg) suspended in 1 × PBS (200 µL) was intravenously injected in the IFX-treated group and all mice were sacrificed on day nine. Co-administration of L. gasseri KBL697 and IFX improved colitis symptoms in mice, including body weight, disease activity index, colon length, and histology score. Additionally, pro-inflammatory cytokines, such as interferon-gamma, interleukin (IL)-2, IL-6, IL-17A, and TNF were significantly decreased, while IL-10, an anti-inflammatory cytokine, was increased. Expression levels of tight junction genes and CD4 + CD25 + Foxp3 + T regulatory cells in the mesenteric lymph nodes were synergistically upregulated with the combined treatment. Furthermore, co-administered mice displayed altered cecum microbial diversity and composition with increases in the genus Prevotella. Related changes in the predicted amino and nucleic acid metabolic pathways were also evident, along with increased acetate and butyrate level. Therefore, the synergistic effect of L. gasseri KBL697 and IFX co-administration is a possible method of prevention and treatment for IBD.

Long-term Efficacy of TNF-alpha Inhibitors on Persistent Uveitic Macular Edema: A Swiss Multicenter Cohort Study

ABSTRACT Purpose To assess the efficacy of tumor necrosis factor-alpha inhibitors (TNFi) on uveitic macular edema (ME) unresponsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Methods This multicenter retrospective study included patients with uveitic ME persisting despite csDMARDs. The effect of an additional TNFi on central retinal thickness (CRT), best corrected visual acuity (BCVA) and corticosteroid need was evaluated. Results Thirty-five eyes (26 patients, mean age 42.9 ± 15.2 years) were included. CRT decreased from 425 ± 137 µm to 294 ± 66 µm (p < .001) and 280 ± 48 µm (p < .001) at 1 and 4 years of follow-up, respectively. BCVA improved from 0.28 ± 0.22 to 0.21 ± 0.48 (1 year, p = .013) and 0.08 ± 0.13 logMAR (4 years, p = .002). The proportion of patients requiring systemic corticosteroids decreased from 88.5% to 34.8% (1 year) and 15.4% (4 years). Conclusion The addition of a TNFi resulted in an improvement of CRT and BCVA for up to 4 years in uveitic ME but rescue treatments were needed for some patients.

A retrospective, longitudinal study of rheumatoid arthritis treatment patterns with Janus kinase inhibitors and other disease-modifying antirheumatic drugs in Japan.

There is limited information on the clinical use of Janus kinase inhibitors (JAKis) for rheumatoid arthritis treatment in Japan. The aim of this study was to identify disease-modifying antirheumatic drug (DMARD) treatment patterns in Japan. This retrospective, longitudinal study extracted data from the Japan Medical Data Center database. Patients with rheumatoid arthritis diagnosis were enrolled 2016-19, during which patients had a first prescription of a major DMARD, split into six mutually exclusive classes: methotrexate (MTX); other conventional synthetic DMARDs; tumour necrosis factor alpha inhibitors; cytotoxic T-lymphocyte-associated antigen-4-immunoglobulin; anti-interleukin-6 receptor therapies; and JAKis. The primary objective was to describe DMARD treatment patterns, especially for JAKis. Overall, 10,399 patients were included in the analysis. The most common treatments were MTX, other conventional synthetic DMARDs, and tumour necrosis factor alpha inhibitors. The total number of JAKi prescriptions increased approximately 8-fold during 2016-19. Most (61.1%) patients who received JAKis had prior MTX or tumour necrosis factor alpha inhibitor treatment. The duration of JAKi treatment was longer than for biologics and other conventional synthetic DMARDs and comparable to that of MTX. The sequence of drug class prescriptions for rheumatoid arthritis in Japan during 2016-19 followed clinical guidelines. Over this period, JAKis were increasingly used as a second-line treatment following MTX.

Risks of Biologic Therapy and the Importance of Multidisciplinary Approach for an Accurate Management of Patients with Moderate-Severe Psoriasis and Concomitant Diseases.

Simple SummaryPsoriasis is a chronic multisystem inflammatory disease associated with a wide range of comorbidities including cardiovascular disease, hypertension, diabetes, hyperlipidemia, obesity, metabolic syndrome, anxiety, depression, chronic kidney disease, and malignancy. Currently available novel therapeutic options for moderate-severe psoriasis include tumor necrosis factor alpha inhibitors, inhibitors of the interleukin 17, and inhibitors of the interleukin 23. Apart from the concomitant diseases psoriasis patients may have, biologic therapy may cause significant complications requiring close collaboration between dermatologists and physicians of different specialties. Consequently, it was our main purpose to provide an overview of each class of biologic agents, as well as of the most frequent adverse events they may cause in psoriasis patients with concomitant diseases.Psoriasis is a chronic multisystem inflammatory disease associated with a plethora of comorbidities including metabolic syndrome, cardiovascular disease, hypertension, diabetes, hyperlipidemia, obesity, anxiety, depression, chronic kidney disease, and malignancy. Advancement in unveiling new key elements in the pathophysiology of psoriasis led to significant progress in the development of biologic agents which target different signaling pathways and cytokines involved in the inflammatory cascade responsible for the clinical manifestations found in psoriasis. Currently available novel therapeutic options for moderate-severe psoriasis include tumor necrosis factor alpha inhibitors, inhibitors of the interleukin 17, and inhibitors of the interleukin 23. Nevertheless, concerns have been raised with respect to the possible risks associated with the use of biologic therapy requiring close collaboration between dermatologists and physicians of different specialties. Our aim was to perform an in-depth literature review and discuss the potential risks associated with biologic therapy in patients with psoriasis and concurrent diseases with a focus on the influence of novel therapeutic agents on liver function in the context of hepatopathies, particularly viral hepatitis. A multidisciplinary teamwork and periodic evaluation of psoriasis patients under biologic therapy is highly encouraged to obtain an accurate management for each case.

Amyotrophic Lateral Sclerosis as an Adverse Drug Reaction: A Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System

Amyotrophic lateral sclerosis is a fatal progressive disease with a still unclear multi-factorial etiology. This study focused on the potential relationship between drug exposure and the development of amyotrophic lateral sclerosis by performing a detailed analysis of events reported in the FDA Adverse Event Reporting System database. The FDA Adverse Event Reporting System quarterly data (January 2004-June 2020) were downloaded and deduplicated. The reporting odds ratios and their 95% confidence intervals were calculated as a disproportionality measure. The robustness of the disproportion was assessed accounting for major confounders (i.e., using a broader query, restricting to suspect drugs, and excluding reports with amyotrophic lateral sclerosis as an indication). Disproportionality signals were prioritized based on their consistency across analyses (reporting odds ratio stability). We retained 1188 amyotrophic lateral sclerosis cases. Sixty-two drugs showed significant disproportionality for amyotrophic lateral sclerosis onset in at least one analysis, and 31 had consistent reporting odds ratio stability, including tumor necrosis factor-alpha inhibitors and statins. Disproportionality signals from ustekinumab, an immunomodulator against interleukins 12-23 used in autoimmune diseases, and the anti-IgE omalizumab were consistent among analyses and unexpected. For each drug emerging as possibly associated with amyotrophic lateral sclerosis onset, biological plausibility, underlying disease, and reverse causality could be argued. Our findings strengthened the plausibility of a precipitating role of drugs primarily through immunomodulation (e.g., tumor necrosis factor-alpha, ustekinumab, and omalizumab), but also by impacting metabolism and the musculoskeletal integrity (e.g., statins and bisphosphonates). Complement and NF-kB dysregulation could represent interesting topics for planning translational mechanistic studies on amyotrophic lateral sclerosis as an adverse drug effect.

Review of guideline for the management of large vessel vasculitis presented in 2021 by the American College of Rheumatology / Vasculitis Foundation

The main statements of the recommendations of the American College of Rheumatology and the Vasculitis Foundation on the treatment of patients with systemic vasculitis of large vessels, published in August 2021, are discussed. As a result of a detailed review of current data, a group of experts proposed 22 recommendations and 2 ungraded position statements for giant cell arteritis (GCA), as well as 20 recommendations and 1 ungraded position statement for Takayasu arteritis (AT), on the basis of which algorithms for the treatment of patients with these diseases are presented. An expansion of the value of genetically engineered biological therapy, primarily tocilizumab in GCA and tumour necrosis factor alpha inhibitors in AT, has been recorded. The new recommendations should not be considered as final standards, but are intended to become the basis for choosing a personalized treatment strategy for patients with large vessels vasculitis and serve as a starting point for further research.

The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era.

Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the “treat-to-target” approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs.

MicroRNA‐195 regulates blood pressure by inhibiting NKCC2A

We previously showed that inhibition of renal tumor necrosis factor‐alpha (TNF) production induced by high salt intake increases Na+‐K+‐2Cl−cotransporter isoform A (NKCC2A) mRNA, protein, and phospho (p)NKCC2 expression. MicroRNA (miRNA) contributes to blood pressure regulation, however no studies have addressed the regulation of NKCC2 by miRNA. miR‐195 is one of the most abundant miRNAs expressed in the kidney and qRT‐PCR experiments showed that injection of TNF (5ng/g bw) directly into the kidney of male mice up‐regulates miR‐195 in the renal outer medulla (OM) by approximately 3.5‐fold (p&lt;0.05). Subsequently, a potential miR‐195 binding site in the 3′‐UTR of NKCC2A was identified using the prediction tool TargetScan v5.1, and luciferase reporter gene assays confirmed that NKCC2A mRNA is directly targeted and repressed by miR‐195. Primary cultures of medullary thick ascending limb (mTAL) cells and freshly isolated mTAL tubules express NKCC2 isoforms A and F. However, only miR‐195 and NKCC2A, but not NKCC2F mRNA, were up‐regulated in mTAL cells exposed for 2 h to a change in osmolality from 300 to 500 mOsmol/kgH₂O, produced with NaCl. Transient transfection of mTAL cells with an shRNA vector targeting TNF prevented increases in miR‐195 induced by high NaCl concentration. Moreover, transfection of a miR‐195 mimic into mTAL cells suppressed NKCC2A mRNA, but not NKCC2F mRNA, by approximately 83% (p&lt;0.05) in cells exposed to high NaCl. In contrast, transfection with anti‐miR‐195 increased NKCC2A mRNA without altering NKCC2F mRNA abundance. Laser‐scanning cytometry detected a 1.5 fold (p&lt;0.05) increase in pNKCC2 protein expression in mTAL cells transfected with anti‐miR‐195, and a miR‐195 mimic prevented the increase of pNKCC2 induced by silencing TNF in cells exposed to high NaCl. Next, we determined whether miRNA‐195 regulates HS‐dependent changes in blood pressure by inhibiting NKCC2A. Both TNF and miR‐195 expression increased in OM from mice given 1% NaCl in the drinking water (HS) for 7 days. Intrarenal injection of a lentivirus construct that specifically silenced TNF in the kidney (U6‐TNF‐ex4) inhibited the expression of miR‐195 (p&lt;0.05), while increasing NKCC2A mRNA expression in mice ingesting HS. However, intrarenal injection of murine recombinant TNF significantly upregulated the expression of miR‐195 and suppressed the increases of NKCC2A mRNA in mice ingesting HS. Intrarenal administration of miR‐195 prevented the increase of NKCC2A mRNA abundance in the OM from mice injected with the TNF silencing lentivirus (U6‐TNF‐ex4) compared with the control lentivirus. Moreover, the HS‐induced increase in blood pressure detected by radiotelemetry after renal silencing of TNF was markedly attenuated in mice given an intrarenal injection of miR‐195. Collectively, the study identifies miR‐195 as a salt‐sensitive and TNF inducible miRNA that inhibits HS‐mediated increases in blood pressure by inhibiting NKCC2A.

Steroid-Resistant Central Nervous System Sarcoidosis: Use of Immunosuppressants and Biologic Drugs

Sarcoidosis is a systemic non-caseating granulomatous disease of unknown origin, and involvement of the nervous system may result in irreversible neurological deficits. Corticosteroids (CSs) are commonly used as first-line agents for neurosarcoidosis. In steroid-refractory patients, immunosuppressants (ISs) have been used as second-line agents, and tumor necrosis factor-alpha (TNF-alpha) inhibitors as third-line agents. However, evidence regarding the treatment of steroid-refractory neurosarcoidosis is scarce, and treatment strategies for such patients have not been established. In this article, we review the evidence regarding treatments for neurosarcoidosis and strategies for refractory patients. We also discuss the practical uses of CS, IS, and TNF-α inhibitors, providing specific cases treated with such agents.

Adalimumab-Induced Lupus Nephritis: Case Report and Review of the Literature.

Tumor necrosis factor-alpha inhibitors are known causative agents of systemic lupus erythemato- sus but have rarely been implicated in lupus nephritis. A patient with Crohn's disease on long-term adalimumab treatment presented with new-onset Raynaud's phenomenon and was found to have hematuria and proteinuria. Elevated antinuclear, anti-dsDNA, and MPO antibodies were found. A renal biopsy confirmed the diagnosis of lupus nephritis. Adalimumab was discontinued ensuing improvement in urine studies and resolution of dsDNA and MPO antibodies. Adalimumab can induce systemic lupus erythematosus and lupus nephritis.

P272 Pregnancy outcomes in women receiving biological therapy for axial spondyloarthritis

Abstract Background/Aims Axial spondyloarthritis (axSpA) is a chronic inflammatory disease affecting the spine and sacroiliac joints. It is typically diagnosed before the age of thirty-five in patients presenting with pain and stiffness of the lower back. Treatment of axSpA is multidisciplinary and medical management initially consists of non-steroidal anti-inflammatory medications. For patients with high disease activity or poor symptomatic control, treatment may be escalated to biological therapies including, tumour necrosis factor (TNF) alpha inhibitors. Thus, treatment with these powerful medications is likely to coincide with the time that patients may wish to start a family. Currently, there is very limited evidence regarding the safety of biological therapies during pregnancy and the advice to patients is unclear. The aim of this paper is to identify the current evidence regarding pregnancy outcomes following exposure to biological therapy during pregnancy for the treatment of axSpA. Methods Methods: A literature search was conducted through Ovid Medline and Embase to identify relevant studies in line with a patient population, intervention, comparator, and outcomes (PICO) model identified prior to this study. An adapted version of the PRISMA 2020 flow diagram guided screening of manuscripts identified during database searches. Data gathered were summarised in a narrative review. Results From 15,121 papers identified, 101 were assessed for eligibility and six full papers were included in this study. Five of these studies reported 117 pregnancy outcomes following exposure to TNF-alpha inhibitors (adalimumab, etanercept, certolizumab pegol) for treatment of axSpA during pregnancy. Of these, five pregnancies were reported to have birth defects, for example cerebral ventricle dilatation and premature birth. The final study reported a high proportion of Caesarean sections among women treated with TNF-alpha inhibitors: 83 deliveries (61%) from 136 pregnancies. Conclusion There is very little published evidence on the safety of TNF-alpha inhibitors during pregnancy for axSpA and no papers were identified describing pregnancy outcomes in non-TNF biologics. Some additional literature was identified, examining biologic use in pregnancy across a variety of other rheumatological conditions, although it was often not possible to extract data on axSpA separately. However, existing evidence suggests no increased risk of adverse pregnancy outcomes associated with TNF inhibition in axSpA. There is some evidence that pregnant women may be more likely to undergo Caesarean section rather than vaginal delivery, although it is not clear whether this is due to increased elective or emergency Caesarean section. This review highlights the need for more studies to be conducted on this topic. This would enable more robust evidence-based guidelines to be produced and implemented confidently in clinical practice. Funding Statement: ELB supported by University of Aberdeen Summer Research Scholarship Programme. Disclosure E.L. Brandie: None. G.T. Jones: None.

Inflammatory Bowel Disease Patients' Treatment Preferences Using a Discrete Choice Experiment Technique: The InPuT Study.

IntroductionThe aim of this study was to investigate patients’ preferences regarding the evolving treatment landscape in Crohn’s disease (CD) and ulcerative colitis (UC) based on a discrete choice experiment.MethodsEligible patients (aged 18 years or older) had a confirmed diagnosis of CD or UC and were willing and able to participate in telephone interviews. The survey design is based on a prior literature review, a pilot study, and clinical expert discussions. Preferences related to clinical and practical features of advanced therapies, like tumor necrosis factor alpha inhibitors, anti-integrins, anti-interleukins, and Janus kinase inhibitors, were assessed. Patients were asked to choose between two different hypothetical treatment alternatives visualized in up to 11 choice scenarios. Based on these choices, the relative importance of treatment characteristics was derived from regression coefficients estimated by a conditional logit model.ResultsOf the 291 patients included, 219 (75%) were eligible for this analysis. Among the evaluated attributes in CD, 1-year remission rate was ranked highest, with 42.3% relevance for the overall decision. The second most important attribute was the frequency of serious adverse events (AE) (25.1%), followed by sustained remission over 2 years (17.8%). Lower importance was assigned to the administration mode (14.6%) and none to the frequency of non-serious AE (0.1%). In UC, preferences were driven by efficacy (25.3% for mucosal healing; 23.4% for corticosteroid-free remission) and the frequency of serious AE (18.3%), followed by the administration mode (18.1%). Also, non-serious AE were classified as relevant factors for decision-making (10.7%), while maintaining remission for at least 2 years showed no significant impact (4.4%).ConclusionFor both indications, efficacy outcomes were rated most important, followed by the frequency of serious AE. Variations were mainly found in the evaluation of non-serious AE and sustained remission. Considering patient preferences may improve the effectiveness of available therapies for moderate to severe CD and UC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02143-z.