Patient and health professional views on risk-stratified monitoring of immune-suppressing treatment in adults with inflammatory diseases.

OBJECTIVE: To explore the acceptability of an individualised risk-stratified approach to monitoring for target-organ toxicity in adult patients with immune-mediated inflammatory diseases established on immune-suppressing treatment(s). METHODS: Adults (≥18 years) taking immune-suppressing treatment(s) for at-least six months, and healthcare professionals (HCPs) with experience of either prescribing and/or monitoring immune-suppressing drugs were invited to participate in a single, remote, one-to-one, semi-structured interview. Interviews were conducted by a trained qualitative researcher and explored their views and experiences of current monitoring and acceptability of a proposed risk-stratified monitoring plan. Interviews were transcribed verbatim and inductively analysed using thematic analysis in NVivo. RESULTS: Eighteen patients and 13 HCPs were interviewed. While participants found monitoring of immune-suppressing drugs with frequent blood-tests reassuring, the current frequency of these was considered burdensome by patients and HCPs alike, and to be a superfluous use of healthcare resources. Given abnormalities rarely arose during long-term treatment, most felt that monitoring blood-tests were not needed as often. Patients and HCPs found it acceptable to increase the interval between monitoring blood-tests from three-monthly to six-monthly or annually depending on the patients' risk profiles. Conditions of accepting such a change included: allowing for clinician and patient autonomy in determining an individuals' frequency of monitoring blood-tests, the flexibility to change monitoring frequency if someone's risk profile changed, and endorsement from specialist societies and healthcare providers such as the National Health Service. CONCLUSION: A risk-stratified approach to monitoring was acceptable to patients and HCPs. Guideline groups should consider these findings when recommending blood-test monitoring intervals.

Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Venous thromboembolism risk is lower in patients with atopic dermatitis than other immune-mediated inflammatory diseases: A retrospective, observational, comparative cohort study using US claims data.

BACKGROUND: Certain immune-mediated inflammatory diseases (IMIDs) may increase patients' risk for venous thromboembolisms (VTEs), yet how atopic dermatitis (AD) influences VTE risk remains unclear. OBJECTIVE: Describe VTE incidence in patients with AD compared with other IMIDs and unaffected, AD-matched controls. METHODS: This retrospective, observational, comparative cohort study used Optum Clinformatics United States claims data (2010-2019) of adults with AD, rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). Unaffected control patients were matched 1:1 with patients with AD. RESULTS: Of 2,061,222 patients with IMIDs, 1,098,633 had AD. Patients with AD had a higher VTE incidence (95% CI) than did unaffected, AD-matched controls (0.73 [0.72-0.74] versus 0.59 [0.58-0.60] cases/100 person-years). When controlling for baseline VTE risk factors, however, AD was not associated with increased VTE risk (HR 0.96 [0.90-1.02]). VTE risk was lower in patients with AD versus RA, UC, CD, AS, or PsA; VTE risk was similar to patients with PsO. LIMITATIONS: Disease activity and severity were not accounted for. CONCLUSION: AD did not increase VTE risk when accounting for underlying risk factors. AD was associated with lower VTE risk compared with several rheumatologic and gastrointestinal IMIDs.

Susceptibility to COVID-19 and Immunologic Response to Vaccination in Patients With Immune-Mediated Inflammatory Diseases.

Immune-mediated inflammatory diseases (IMIDs) are a highly heterogeneous group of diseases that share a common etiology of immune dysregulation, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, among others. It is estimated that the prevalence of IMIDs ranges between 5% and 7% in developed countries. As current management of IMIDs includes the use of immunomodulatory medications, the resulting weakened immune response can increase the risk of infection, including with SARS-CoV-2 (the causative agent of COVID-19) and reduce response to vaccination, placing these individuals at continued risk of severe outcomes from COVID-19. In this article, we summarize the current literature related to COVID-19 outcomes and the immunogenicity and reactogenicity of COVID-19 mRNA vaccination among patients with rheumatologically dominated IMIDs, as well as the effect of immunomodulatory therapies on these outcomes. We conclude by providing current COVID-19 vaccination recommendations for individuals with IMID.

Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis.

Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.

The Characteristics and Functionalities of Mobile Apps Aimed at Patients Diagnosed With Immune-Mediated Inflammatory Diseases: Systematic App Search.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are systemic conditions associated with a high social and health impact. New treatments have changed the prognosis of IMIDs and have increased patient autonomy in disease management. Mobile apps have enormous potential to improve health outcomes in patients with IMIDs. Although a large number of IMID apps are available, the app market is not regulated, and functionality and reliability remain uncertain. OBJECTIVE: Our aims are to review available apps for patients with IMIDs or caregivers and to describe the main characteristics and functionalities of these apps. METHODS: We performed an observational, cross-sectional, descriptive study of all apps for patients with IMIDs. Between April 5 and 14, 2021, we conducted a search of the App Store (iOS) and Play Store (Android) platforms. We used the names of the different IMIDs as search terms. The inclusion criteria were as follows: content related to IMIDs, English or Spanish language, and user population consisting of patients and health care consumers, including family and caregivers. The variables analyzed were as follows: app name, type of IMID, platform (Android or iOS), country of origin, language, category of the app, cost, date of the last update, size, downloads, author affiliation, and functionalities. RESULTS: We identified 713 apps in the initial search, and 243 apps met the criteria and were analyzed. Of these, 37% (n=90) were on Android, 27.2% (n=66) on iOS, and 35.8% (n=87) on both platforms. The most frequent categories were health and well-being/fitness apps (n=188, 48.5%) and medicine (n=82, 37.9%). A total of 211 (82.3%) apps were free. The mean time between the date of the analysis and the date of the most recent update was 18.5 (SD 19.3) months. Health care professionals were involved in the development of 100 (41.1%) apps. We found differences between Android and iOS in the mean time since the last update (16.2, SD 14.7 months vs 30.3, SD 25.7 months) and free apps (85.6% vs 75.8%; respectively). The functionalities were as follows: general information about lifestyles, nutrition, or exercises (n=135, 55.6%); specific information about the disease or treatment (n=102, 42%); recording of symptoms or adverse events (n=51, 21%); agenda/calendar (n=44, 18.1%); reminder medication (n=41, 16.9%); and recording of patient-reported outcomes (n=41, 16.9%). A total of 147 (60.5%) apps had more than one functionality. CONCLUSIONS: IMID-related apps are heterogeneous in terms of functionality and reliability. Apps may be a useful complement to IMID care, especially inpatient education (their most frequent functionality). However, more than half of the IMID apps had not been developed by health care professionals or updated in the last year.

Safety of recombinant zoster vaccine: a retrospective study of 622 rheumatology patients.

OBJECTIVES: To provide insight into the safety of recombinant zoster vaccine (RZV) in patients with immune-mediated inflammatory diseases (IMID). METHODS: Patients who received RZV in a single-centre rheumatology department were retrospectively included. An IMID flare was defined as (i) a documentation of flare in the office notes or patient portal communication or (ii) new prednisone prescription, in the 12 weeks after each dose. RESULTS: Six-hundred and twenty-two patients were included (67% female, median age 67 years), 8.5% of them experienced adverse events (AEs) and herpes zoster (HZ) incidence was 0.6% after median follow-up of 36 weeks. Of 359 IMID patients: 88 had RA (25%), 50 vasculitis (14%) and 29 PMR (8%). At vaccination, 35% were on glucocorticoids (GC). Fifty-nine patients (16%) experienced a flare, 18 flares occurred in temporal relation to a treatment change (31%). RA patients had the highest flare rate (n = 21, 24%), 25% of patients who flared required adjustment of immunosuppression. In a multivariate analysis, use of GC at time of vaccination was associated with flare after vaccination [odds ratio (OR) 2.31 (1.3-4.1), P =0.004]. A time-to-flare survival analysis (Cox-model) showed that GC was a significant predictor of IMID flare after first RZV dose [hazard ratio (HR) 2.4 (1.3-4.5), P =0.0039] and that a flare after the first dose was associated with flaring after the second RZV dose [HR 3.9 (1.7-9), P =0.0015]. CONCLUSION: RZV administration in patients with IMIDs was generally well-tolerated, though mild flares were not uncommon in the first 12 weeks after vaccination. These data may provide useful information for patient education when considering RZV administration.

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets.

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn's disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

Sex-Specific Cardiovascular Comorbidities with Associations in Dermatologic and Rheumatic Disorders.

Cardiology, dermatology, and rheumatology form a fascinating triad. Many skin and joint disorders are associated with cardiovascular comorbidities because they share etiologic elements. Female predominance is often remarkable and likely related to autoimmune pathology. Although studies have shown that X-encoded genes may be involved in the differences in immunity between males and females, other studies have also shown that sex chromosomes are irrelevant and that estrogens and androgens are responsible for the differences. The elevated immune activity in females provides a beneficial position in coping with a pathogenic stimulus but may also enhance their susceptibility to autoimmunity. The complexity of the immune system and its role as a defensive force against infection requires an armamentarium to precisely identify and selectively control inflammatory processes or cells which promote atherosclerosis. On the other hand, the inflammation in skin diseases seems to be an active source of diverse proinflammatory cytokines and chemokines which can predispose to cardiovascular comorbidities. Also, it has been shown that comorbidity disproportionately accelerates risk in women.The skin offers a readily available window to facilitate detection of risk factors or even to assist the diagnostic process regarding a variety of disorders, including those with cardiovascular involvement. Current imaging techniques provide exquisite capabilities for diagnosing and possibly even counteracting atherosclerotic plaque formation, before serious cardiovascular events occur. Combining imaging approaches (such as videocapillaroscopy, intravascular ultrasound, and FDG positron emission tomography) with insights based on immunology will likely accelerate advances in this area.We review major dermatologic manifestations and rheumatologic disorders which are associated with cardiac and vascular abnormalities. In particular we discuss sex-specific aspects concerning incidence and severity of cardiovascular disease associated with systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Untreated Psoriasis Impairs Male Fertility: A Case-Control Study.

BACKGROUND: Recent evidence indicates that a systemic state of inflammation may impair fertility, but data about psoriatic males are scarce. OBJECTIVES: The aim of this study was to assess gonadal function in psoriatic males implementing our knowledge about fertility in these subjects. METHODS: Male psoriatic patients, aged between 18 and 55 years, and a group of healthy subjects matched for age, BMI and geographic origin were enrolled. All subjects underwent a complete physical and andrological examination, standard semen analysis, complete microbiological analysis and ultrasound evaluation of sexual glands. Seminal levels of soluble urokinase-type plasminogen activator receptor (suPAR) and serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone and follicle-stimulating hormone were also assessed. RESULTS: Fifty patients and 50 controls fulfilled the inclusion criteria and were enrolled in our study. Testosterone and SHBG were found to be significantly decreased in patients with psoriasis compared with the control group. Higher levels of E2 were also reported in psoriatic patients. Total sperm count, sperm motility and percent of spermatozoa with normal morphology were significantly reduced in patients compared to controls. suPAR levels were significantly increased in patients compared to controls and found to be above the reference limits. Ultrasound signs of inflammation of the accessory glands were observed in 35/50 patients with psoriasis and in none of the controls. CONCLUSION: Our study suggests that untreated psoriasis may impair male fertility. We also found that this might be due to an impact of systemic inflammation on the hormonal profile and on sexual accessory gland inflammation.

Immune-mediated inflammatory diseases and other comorbidities in patients with psoriasis: baseline characteristics of patients in the AQUILES study.

INTRODUCTION AND OBJECTIVES: Patients with psoriasis often have comorbidities, including other immune-mediated inflammatory diseases (IMIDs), and cardiovascular risk factors. In this article we describe the baseline prevalence of comorbidities-including other IMIDs-in a cohort of patients with psoriasis. PATIENTS AND METHODS: AQUILES was a prospective observational multicenter study of 3 patient cohorts (patients with psoriasis, spondyloarthritis, or inflammatory bowel disease) undertaken to investigate the prevalence of comorbidities, including other IMIDs, in these settings. The psoriasis cohort comprised patients aged at least 18 years who were seen in hospital dermatology clinics. A predefined protocol was used to collect demographic and clinical data. RESULTS: The study enrolled 528 patients with psoriasis (60.2% men and 39.8% women). Mean age was 46.7 years; 89.8% of the participants had plaque psoriasis, and the median Psoriasis Area Severity Index score (PASI) was 3.2 (1.5-7.4). Comorbid IMIDs were present in 82 (15.5%) of the patients (CI 95%, 12.7%-18.9%). Spondyloarthritis was observed in 14% of patients (95% CI, 11.3%-17.2%), mostly in the form of psoriatic arthritis, for which the overall prevalence was 13.1% (95% CI, 10.5%-16.2%). Inflammatory bowel disease was present in 1.3% (95% CI, 0.6%-2.7%) and uveitis in .2% (95% CI, 0.1%-1.4%). Psoriatic arthritis was associated with male sex (odds ratio, 1.75 [.98-2.98]) and a disease duration of over 8 years (OR, 4.17 [1.84-9.44] vs a duration of < 4 years). In 73.1%, at least 1 cardiovascular risk factor was identified: smoking (40.5%), obesity (26.0%), dyslipidemia (24.8%), hypertension (24.3%), and diabetes mellitus (12.3%). CONCLUSION: In patients with psoriasis the prevalence of other IMIDs was 15.5%, a level slightly higher than that found in the general population. Nearly three-quarters of these patients had at least 1 cardiovascular risk factor.

Contraceptive Recommendations for Women with Immune-Mediated Inflammatory Diseases: A Delphi Consensus.

INTRODUCTION: Immune-mediated inflammatory diseases (IMID) are a group of disorders characterized by chronic inflammation caused by an altered immune regulation in targeted organs or systems. IMID itself could have an implied increased risk of venous thromboembolism (VTE) and this risk varies throughout the course of the disease as well as with some contraceptive methods and treatments. The aim of this study was to present some key considerations in relation to contraception in women with IMID. METHODS: This was an exploratory study conducted in Spain following the online modified Delphi methodology with two rounds of participation. Four questionnaires were designed for each medical specialty: gastroenterology, rheumatology, dermatology, and gynecology. Each questionnaire was divided in three domains: general recommendations about IMID, specific recommendations, and contraceptive methods for patients with IMID. A 5-point Likert scale measured agreement with each statement, with an 80% agreement threshold. Following the first round, the percentage of each response was calculated for every item. Subsequently, a second round was conducted to reach a consensus on the items for which discrepancies were observed. RESULTS: A total of 52 and 50 experts participated in the first and second round, respectively. Participants agreed on the existence of a higher risk of VTE in inflammatory bowel diseases, psoriasis, and rheumatoid arthritis diseases. Regarding recommendations for contraceptive methods in patients with IMID, experts considered the hormonal intrauterine device (IUD) as a first-line contraceptive (80.0%) and low doses of progesterone-only pills if the latter is not recommended (88.0%). Most of the interviewees concurred on the importance of the patients' contraceptive needs during the disease course (98.1%). CONCLUSION: Raising awareness and promoting a multidisciplinary relationship among the physicians involved in the therapeutic decisions by considering all the risk factors when prescribing a contraceptive method is important to prevent VTE in women with IMID.

Continued JAK inhibitor treatment on the risk of recurrent herpes zoster reactivation in patients with immune-mediated inflammatory diseases: A nationwide population-based study in South Korea.

BACKGROUND: To investigate the risk of recurrent herpes zoster (HZ) reactivation under continued Janus kinase inhibitor (JAKi) therapy in patients with immune-mediated inflammatory diseases (IMID) who developed HZ reactivation. METHODS: Data from the Korean Health Insurance Review and Assessment Service (HIRA) of patients with rheumatoid arthritis (RA) or ulcerative colitis (UC) gathered from 2007 to 2021 were analyzed. RESULTS: A total of 3947 (RA 3540, UC 407) receiving JAKi were included. After median 0.95 years (IQR, 0.93-2.58) of therapy, 611 (15.5%) patients developed HZ reactivation (incidence rate: 8.38/100 person-years [PY]). After excluding 151 patients with lack of data after HZ reactivation, 460 patients (JAKi continuation group, n = 386 [83.9%]; JAKi discontinuation group, n = 74 [16.1%]) were analyzed for the risk of subsequent recurrent HZ reactivation. During further follow-up of median 1.11 years (IQR, 0.53-1.91), 36 (9.3%) and 6 (8.1%) patients in the JAKi continuation group and JAKi discontinuation group experienced a recurrence of HZ, respectively. The incidence rate of subsequent recurrent HZ reactivation was not significantly different between the two groups (5.3/100 vs. 5.9/100 PY; P = 0.52). After adjusting for age, sex, usage of corticosteroids, and antiviral agents, continued use of JAKi was not a significant risk factor for subsequent HZ reactivation (adjusted hazard ratio, 0.71 [CI, 0.29-1.72], P = 0.45). CONCLUSION: In this nationwide population-based study on patients with RA or UC, continued use of JAKi was not associated with a significant risk of subsequent recurrent HZ reactivation. JAKi therapy may be maintained in patients with IMID even after HZ reactivation.

scDrugPrio: a framework for the analysis of single-cell transcriptomics to address multiple problems in precision medicine in immune-mediated inflammatory diseases.

BACKGROUND: Ineffective drug treatment is a major problem for many patients with immune-mediated inflammatory diseases (IMIDs). Important reasons are the lack of systematic solutions for drug prioritisation and repurposing based on characterisation of the complex and heterogeneous cellular and molecular changes in IMIDs. METHODS: Here, we propose a computational framework, scDrugPrio, which constructs network models of inflammatory disease based on single-cell RNA sequencing (scRNA-seq) data. scDrugPrio constructs detailed network models of inflammatory diseases that integrate information on cell type-specific expression changes, altered cellular crosstalk and pharmacological properties for the selection and ranking of thousands of drugs. RESULTS: scDrugPrio was developed using a mouse model of antigen-induced arthritis and validated by improved precision/recall for approved drugs, as well as extensive in vitro, in vivo, and in silico studies of drugs that were predicted, but not approved, for the studied diseases. Next, scDrugPrio was applied to multiple sclerosis, Crohn's disease, and psoriatic arthritis, further supporting scDrugPrio through prioritisation of relevant and approved drugs. However, in contrast to the mouse model of arthritis, great interindividual cellular and gene expression differences were found in patients with the same diagnosis. Such differences could explain why some patients did or did not respond to treatment. This explanation was supported by the application of scDrugPrio to scRNA-seq data from eleven individual Crohn's disease patients. The analysis showed great variations in drug predictions between patients, for example, assigning a high rank to anti-TNF treatment in a responder and a low rank in a nonresponder to that treatment. CONCLUSIONS: We propose a computational framework, scDrugPrio, for drug prioritisation based on scRNA-seq of IMID disease. Application to individual patients indicates scDrugPrio's potential for personalised network-based drug screening on cellulome-, genome-, and drugome-wide scales. For this purpose, we made scDrugPrio into an easy-to-use R package ( https://github.com/SDTC-CPMed/scDrugPrio ).

Methotrexate and Tumor Necrosis Factor Inhibitors Independently Decrease Neutralizing Antibodies after SARS-CoV-2 Vaccination: Updated Results from the SUCCEED Study.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied the effects of methotrexate and tumor necrosis factor inhibitor (TNFi) on neutralization responses after COVID-19 vaccination in immune-mediated inflammatory disease (IMID). Methods: Prospective data and sera of adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and systemic lupus (SLE) were collected at six academic centers in Alberta, Manitoba, Ontario, and Quebec between 2022 and 2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between five laboratories, and each lab's results were analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for the effects of methotrexate and TNFi were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID-19 vaccinations (number/type), and infections in the 6 months prior to sampling. The adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for the ancestral strains and the Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) were RA, and the remainder were PsA, SpA, and SLE. The mean age was 57 (62.2% female). For both the individual labs and the meta-analyses, the adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval (CI) 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Global burden and cross-country inequalities in six major immune-mediated inflammatory diseases from 1990 to 2021: A systemic analysis of the Global Burden of Disease Study 2021.

BACKGROUND: This study aims to describe the global burden trends of six immune-mediated inflammatory diseases (IMIDs), including asthma, atopic dermatitis (AD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis and rheumatoid arthritis (RA), from 1990 to 2021, and analyze patterns of cross-country inequalities. METHODS: The estimates for the number of disability-adjusted life-years (DALYs) and age-standardized DALYs rates (ASDR), along with the 95 % uncertainty intervals (UI) for asthma, AD, IBD, MS, psoriasis and RA, were obtained from the Global Burden of Diseases Study 2021. The estimated annual percentage change (EAPC) was used to quantify the global burden trends of these six IMIDs from 1990 to 2021. Additionally, slope index of inequality and concentration index were employed to quantify the distributional inequalities in the burden of IMIDs. RESULTS: From 1990 to 2021, the global ASDR of psoriasis (EAPC = 0.23 %, 95 % UI: 0.21 to 0.25) and RA (EAPC = 0.05 %, 95 % UI: 0.01to 0.10) showed an increasing trend, while the global ASDRs of asthma (EAPC = -1.91 %, 95 % UI: -1.98 to -1.84), AD (EAPC = -0.26 %, 95 % UI: -0.27 to -0.26), IBD (EAPC = -0.52 %, 95 % UI: -0.60 to -0.43) and MS (EAPC = -0.39 %, 95 % UI: -0.45 to -0.33) demonstrated declining trends. The cross-country inequality analysis reveals pronounced heterogeneity in the burden of these six IMIDs. CONCLUSIONS: The global distribution of the DALYs burden attributable to IMIDs exhibits significant disparities across regions, underscoring an urgent need for innovative and comprehensive management strategies to address this heterogeneous landscape.

Propensity-Matched Analysis of the Risk of Age-Related Macular Degeneration with Systemic Immune-Mediated Inflammatory Disease.

PURPOSE: The pathogenesis of age-related macular degeneration (AMD) involves aberrant complement activation and is a leading cause of vision loss worldwide. Complement aberrations are also implicated in many systemic immune-mediated inflammatory diseases (IMIDs), but the relationship between AMD and these conditions remains undescribed. The aim of this study is to first assess the association between AMD and IMIDs, and then assess the risk of AMD in patients with specific IMIDs associated with AMD. DESIGN: Cross-sectional study and cohort study. SUBJECTS AND CONTROLS: Patients with AMD were compared with control patients with cataracts and no AMD to ensure evaluation by an ophthalmologist. Patients with IMIDs were compared with patients without IMIDs but with cataracts. METHODS: This study used deidentified data from a national database (2006-2023), using International Classification of Diseases 10 codes to select for IMIDs. Propensity score matching was based on patients on age, sex, race, ethnicity, and smoking. Odds ratios were generated for IMIDs and compared between AMD and control patients. For IMIDs associated with AMD, the risk of AMD in patients with the IMID versus patients without IMIDs was determined utilizing a cohort study design. MAIN OUTCOME MEASURES: Odds ratio of IMID, risk ratios (RRs), and 95% confidence intervals (CIs) of AMD diagnosis, given an IMID. RESULTS: After propensity score matching, AMD and control cohorts (n = 217 197 each) had a mean ± standard deviation age of 74.7 ± 10.4 years, were 56% female, and 9% of patients smoked. Age-related macular degeneration showed associations with systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis, rheumatoid arthritis (RA), psoriasis, sarcoidosis, scleroderma, giant cell arteritis, and vasculitis. Cohorts for each positively associated IMID were created and matched to control cohorts with no IMID history. Patients with RA (RR, 1.40; 95% CI, 1.30-1.49), SLE (RR, 1.73; 95% CI, 1.37-2.18), Crohn's disease (RR, 1.42; 95% CI, 1.20-1.71), ulcerative colitis (RR, 1.45; 95% CI, 1.29-1.63), psoriasis (RR, 1.48; 95% CI, 1.37-1.60), vasculitis (RR, 1.48; 95% CI, 1.33-1.64), scleroderma (RR, 1.65; 95% CI, 1.35-2.02), and sarcoidosis (RR, 1.42; 95% CI, 1.24-1.62) showed a higher risk of developing AMD compared with controls. CONCLUSIONS: The results suggest that there is an increased risk of developing AMD in patients with RA, SLE, Crohn's disease, ulcerative colitis, psoriasis, vasculitis, scleroderma, and sarcoidosis compared with patients with no IMIDs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Maternal-fetal outcomes in patients with immune-mediated inflammatory diseases, with consideration of comorbidities: a retrospective cohort study in a large U.S. healthcare system.

Background: Immune-mediated inflammatory diseases (IMIDs) are likely to complicate maternal health. However, literature on patients with IMIDs undergoing pregnancy is scarce and often overlooks the presence of comorbidities. We aimed to evaluate the impact of IMIDs on adverse pregnancy outcomes after assessing and addressing any discrepancies in the distribution of covariates associated with adverse pregnancy outcomes between patients with and without IMIDs. Methods: We conducted a retrospective cohort study using data from an integrated U.S. community healthcare system that provides care across Alaska, California, Montana, Oregon, New Mexico, Texas, and Washington. We used a database containing all structured data from electronic health record (EHRs) and analyzed the cohort of pregnant people who had live births from January 1, 2013, through December 31, 2022. We investigated 12 selected IMIDs: psoriasis, inflammatory bowel disease, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, systemic lupus erythematosus, psoriatic arthritis, antiphospholipid syndrome, Sjögren's syndrome, vasculitides, sarcoidosis, and systemic sclerosis. We characterized patients with IMIDs prior to pregnancy (IMIDs group) based on pregnancy/maternal characteristics, comorbidities, and pre-pregnancy/prenatal immunomodulatory medications (IMMs) prescription patterns. We 1:1 propensity score matched the IMIDs cohort with people who had no IMID diagnoses prior to pregnancy (non-IMIDs cohort). Outcome measures were preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), and caesarean section. Findings: Our analytic cohort had 365,075 people, of which 5784 were in the IMIDs group and 359,291 were in the non-IMIDs group. The prevalence rate of pregnancy of at least 20 weeks duration in people with a previous IMID diagnosis has doubled in the past ten years. 17% of the IMIDs group had at least one prenatal IMM prescription. Depending on the type of IMM, 48%-70% of the patients taking IMMs before pregnancy continued them throughout pregnancy. Overall, patients with one or more of these 12 IMIDs had increased risk of PTB (Relative risk (RR) = 1.1 [1.0, 1.3]; p = 0.08), LBW (RR = 1.2 [1.0, 1.4]; p = 0.02), SGA (RR = 1.1 [1.0, 1.2]; p = 0.03), and caesarean section (RR = 1.1 [1.1, 1.2], p < 0.0001) compared to a matched cohort of people without IMIDs. When adjusted for comorbidities, patients with rheumatoid arthritis (PTB RR = 1.2, p = 0.5; LBW RR = 1.1, p = 0.6) and/or inflammatory bowel disease (PTB RR = 1.2, p = 0.3; LBW RR = 1.0, p = 0.8) did not have significantly increased risk for PTB and LBW. Interpretation: For patients who have been pregnant for 20 weeks or greater, the association between IMIDs and adverse pregnancy outcomes depends on both the nature of the IMID and the presence of comorbidities. Because this study was limited to pregnancies resulting in live births, results must be interpreted together with other studies on early pregnancy loss and stillbirth in patient with IMIDs. Funding: National Institutes of Health.