Contributions of Synthetic Chemicals to Autoimmune Disease Development and Occurrence.

PURPOSE OF REVIEW: Exposure to many synthetic chemicals has been linked to a variety of adverse human health effects, including autoimmune diseases. In this scoping review, we summarize recent evidence detailing the effects of synthetic environmental chemicals on autoimmune diseases and highlight current research gaps and recommendations for future studies. RECENT FINDINGS: We identified 68 recent publications related to environmental chemical exposures and autoimmune diseases. Most studies evaluated exposure to persistent environmental chemicals and autoimmune conditions including rheumatoid arthritis (RA), systemic lupus (SLE), systemic sclerosis (SSc), and ulcerative colitis (UC) and Crohn's disease. Results of recent original research studies were mixed, and available data for some exposure-outcome associations were particularly limited. PFAS and autoimmune inflammatory bowel diseases (UC and CD) and pesticides and RA appeared to be the most frequently studied exposure-outcome associations among recent publications, despite a historical research focus on solvents. Recent studies have provided additional evidence for the associations of exposure to synthetic chemicals with certain autoimmune conditions. However, impacts on other autoimmune outcomes, particularly less prevalent conditions, remain unclear. Owing to the ubiquitous nature of many of these exposures and their potential impacts on autoimmune risk, additional studies are needed to better evaluate these relationships, particularly for understudied autoimmune conditions. Future research should include larger longitudinal studies and studies among more diverse populations to elucidate the temporal relationships between exposure-outcome pairs and to identify potential population subgroups that may be more adversely impacted by immune modulation caused by exposure to these chemicals.

Pre-existing Autoimmune Diseases and Immune Checkpoint Inhibitors for Cancer Treatment: Considerations About Initiation, Flares, Immune-Related Adverse Events, and Cancer Progression.

Immune checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancer types. Patients with preexisting autoimmune diseases may be vulnerable to underlying disease flare as well as immune-related adverse events from ICIs. There has also been concern that immunosuppression needed to control the autoimmune disease may blunt ICI efficacy. Much of the literature is focused on diverse preexisting autoimmune diseases, which may limit conclusions to specific diseases. There is a growing literature of specific diseases, such as preexisting rheumatoid arthritis, investigating outcomes after ICI.

Analysis of Nanoparticles' Potential to Induce Autoimmunity.

Autoimmune responses are characterized by the presence of antibodies and lymphocytes specific to self or so-called autoantigens. Among such autoantigens is DNA; therefore, screening for antibodies recognizing single- and/or double-stranded DNA is commonly used to detect and classify autoimmune diseases. While autoimmunity affects both sexes, females are generally more affected than males, which is recapitulated in some animal models. A variety of factors, including genetic predisposition and the environment, contribute to the development of autoimmune disorders. Since certain drug products may also contribute to the development of autoimmunity, understanding a drug's potential to trigger an autoimmune response is of interest to immunotoxicology. However, models to study autoimmunity are limited, and it is generally agreed that no model can accurately predict autoimmunity in humans. Herein, we present an in vivo protocol utilizing the SJL/J mouse model to study nanoparticles' effects on the development of autoimmune responses. The protocol is adapted from the literature describing the use of this model to study chemically induced lupus.

Rituximab in the Management of Autoimmune Bullous Diseases: A Treatment-Resistant Case Series from a Single Central European Referral Center.

Background and Objectives: Rituximab (RTX) has been the predominant treatment for autoimmune bullous diseases (AIBDs). The objective of this research was to assess the advantages and safety characteristics of RTX treatment in individuals with AIBD. This assessment focused on clinical remission and a reduction in glucocorticosteroid usage, its effect on the titers of autoantibodies targeting desmoglein-1 (DSG-1) and desmoglein-3 (DSG-3), and adverse occurrences during a 12-month follow-up period in a dermatology department within a Central European university context. Materials and Methods: Our case series involved eleven patients, including eight patients with pemphigus vulgaris, two with pemphigus foliaceus, and one with epidermolysis bullosa acquisita. They received a 1 g dose of rituximab, repeated over a two-week interval. Results: The reduction in a prednisone-equivalent dosage after 2, 6, and 12 months following the second RTX infusion was 65.05%, 73.99%, and 76.93%, in that order. The titers of antibodies against DSG-1 exhibited reductions of 43.29%, 75.86%, and 54.02% at 2, 6, and 12 months, respectively. By contrast, the antibody concentrations targeting DSG-3 displayed a decrease of 27.88%, 14.48%, and 5.09% at the corresponding time points. Over the course of the 12-month monitoring period, 18.18% of patients experienced disease relapse, while the remaining individuals achieved either complete or partial remission with minimal or no therapy. Adverse effects were noted in 36.36% of the patient population; they were mild, and no serious adverse effects were reported. Conclusions: RTX represents an efficacious and well-tolerated therapeutic option for the management of AIBD and merits consideration in cases of refractory AIBD. However, further research is imperative to delineate the most optimal dosage, dosing frequency, and total quantity of maintenance infusions required. Additionally, there is a compelling need for studies that explore the impact of RTX on individuals with AIBD who do not exhibit a significant reduction in anti-desmoglein autoantibody levels.

Patient preference, efficacy, and compliance with zoledronic acid for glucocorticoid-induced osteoporosis in patients with autoimmune diseases.

PURPOSE: We evaluated the preference, patient satisfaction, and efficacy of zoledronic acid compared with oral bisphosphonates (BPs) for glucocorticoid-induced osteoporosis (GIOP) in patients with autoimmune diseases. METHODS: We enrolled 50 patients with new fractures or osteoporosis detected on follow-up bone densitometry after at least 1 year of oral BP use among patients diagnosed with GIOP during treatment for autoimmune diseases. After 1 year of zoledronic acid treatment, patients completed a survey for preference and satisfaction assessment. Treatment efficacy was analysed by comparing bone mineral density changes and fractures with those in a control group of patients who continued oral BP use. RESULTS: Age, sex, treatment duration, and medication history did not differ significantly between the two groups. Among the participants, 86.7% preferred and were more satisfied with intravenous zoledronic acid than with oral BPs, primarily because of the convenience of its administration interval. Only two patients (4%) reported infusion-related adverse events with zoledronic acid. Furthermore, no significant differences were observed in the annualized percentage change in the bone mineral density of the lumbar spine, femur neck, and hip between patients receiving zoledronic acid and those receiving oral BPs. The occurrence of new fractures was consistent across both groups, with two cases in each, showing no significant differences. CONCLUSION: Patients showed a preference for and greater satisfaction with zoledronic acid, and its efficacy in treating osteoporosis was comparable to that of oral BPs. Therefore, zoledronic acid is a suitable treatment option for GIOP in patients with autoimmune diseases.

Autoimmune Movement Disorders Complicating Treatment with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) may trigger autoimmune neurological conditions, including movement disorders (MD). OBJECTIVES: The aim of this study was to characterize MDs occurring as immune-related adverse events (irAEs) of ICIs. METHODS: A systematic literature review of case reports/series of MDs as irAEs of ICIs was performed. RESULTS: Of 5682 eligible papers, 26 articles with 28 patients were included. MDs occur as a rare complication of cancer immunotherapy with heterogeneous clinical presentations and in most cases in association with other irAEs. Inflammatory basal ganglia T2/fluid attenuated inversion recovery abnormalities are rarely observed, but brain imaging is frequently unrevealing. Cerebrospinal fluid findings are frequently suggestive of inflammation. Half of cases are associated with a wide range of autoantibodies. Steroids and ICI withdrawal usually lead to improvement, even though some patients experienced relapses or a severe clinical course. CONCLUSION: MDs are a rare complication of ICIs that should be promptly recognized to offer patients a correct diagnosis and treatment.

Autoimmune disorders reported following COVID-19 vaccination: A disproportionality analysis using the WHO database.

PURPOSE: Owing to adverse event following immunization (AEFI) related to autoimmune disorders and coronavirus disease 2019 (COVID-19) vaccines sharing common biological mechanisms, identifying the risk of AEFIs associated with COVID-19 vaccines remains a critical unmet need. We aimed to assess the potential safety signals for 16 AEFIs and explore co-reported adverse events (AEs) and drugs using the global database of the World Health Organization, VigiBase. METHODS: We assessed the occurrence of 16 AEFIs following COVID-19 vaccination through the Standardized MedDRA Queries group "Immune-mediated/Autoimmune Disorders" from MedDRA and performed a disproportionality analysis using reporting odds ratio (ROR) and information component (IC) with 95% confidence intervals (CIs). RESULTS: We identified 25,219 events associated with COVID-19 vaccines in VigiBase. Although rare, we detected four potential safety signals related to autoimmune disorders following COVID-19 vaccination, including ankylosing spondylitis or psoriatic arthritis (ROR 1.86; 95% CI 1.53-2.27), inflammatory bowel disease (ROR 1.77; 95% CI 1.60-1.96), polymyalgia rheumatica (ROR 1.42; 95% CI 1.30-1.55), and thyroiditis (ROR 1.40; 95% CI 1.30-1.50), with positive IC025 values. The top co-reported AEs were musculoskeletal disorders, and immunosuppressants were the most representative co-reported drugs. CONCLUSION: In addressing the imperative to comprehend AEFI related to autoimmune disorders following COVID-19 vaccination, our study identified four potential safety signals. Thus, our research underscores the importance of proactive safety monitoring for the identification of the four AEFIs following COVID-19 vaccination, considering the associated advantages.

Immune Checkpoint Inhibitor-induced Pancreatitis with Pancreatic Enlargement Mimicking Autoimmune Pancreatitis: A Case Report and Review of the Literature.

A 61-year-old woman was administered 35 cycles of pembrolizumab for the treatment of recurrent endometrial cancer, achieving a complete response. She presented with asymptomatic pancreatic enlargement and elevated hepatobiliary enzymes, but amylase and lipase levels were within the normal ranges. Intrapancreatic bile duct stenosis due to pancreatic enlargement was present, mimicking autoimmune pancreatitis on computed tomography performed before the onset of clinical manifestations. A histological examination of a biopsy specimen showed lymphocyte and plasma cell infiltration with dense fibrosis in the stroma. The patient was successfully treated with oral prednisolone. There were no manifestations of recurrent pancreatitis after tapering the prednisolone dose.

Adherence to medication during pregnancy in systemic autoimmune diseases: results from a prospective study.

OBJECTIVES: To evaluate adherence to medication in patients with systemic autoimmune diseases (SAD), comparing pregnant and non-pregnant women. METHODS: 200 patients with SAD were consecutively enrolled, 100 pregnant and 100 non-pregnant women. Each patient completed the 8-item Morisky Medication Adherence Scale (MMAS-8), one copy for hydroxychloroquine (HCQ) and one for other treatments for rheumatic disease, and Hospital Anxiety and Depression Scale (HADS). RESULTS: No significant differences were found in ongoing therapies between pregnant and non-pregnant women. 148 patients (74.0%) were taking HCQ and 160 (80.0%) other therapies for rheumatic disease. The mean MMAS-8 score was >6 in all groups indicating a good adherence, on average. The rate of patients with good medication adherence was higher in pregnant patients (73.9% vs. 63.3% and 76.5% vs. 64.5%, for HCQ and other therapies, respectively) although this difference was not statistically significant. Eight patients had very poor medical adherence, and all were non-pregnant women. Anxiety (15% of patients) was associated to low medication adherence for drugs other than HCQ (p=0.02), while depression (4% of patients) did not seem to have an impact on adherence. CONCLUSIONS: In our cohort we recorded a good adherence to prescribed medication, although adequate adherence was not achieved in about 30% of patients, confirming that non-adherence is an important issue in SAD. It is difficult to define a profile of patients at risk of poor adherence, but it appears important to implement communication and adherence monitoring strategies since strict monitoring also during pregnancy could improve medical adherence.

Alemtuzumab-induced immune-mediated thrombotic thrombocytopenic purpura: A newly described drug-related autoimmune disease.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment.

The "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) after COVID-19 infection: A case report.

The term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) describes a variety of autoimmune conditions triggered by exposure to substances with adjuvant activity. We present the case of a patient with a history of biopolymer infiltration in both glutes, who years later experienced progressive weakness and pain in the lower limbs, myalgias, cramps, and progressive functional impotence following a mild COVID-19 infection. Laboratory test results were not consistent with any autoimmune disease. Physical examination revealed diffuse bilateral subcutaneous nodules. After an extensive etiological study, a gluteal biopsy was performed, which showed findings compatible with sclerosing lipogranuloma. Our patient required treatment with high-dose glucocorticoids and showed significant improvement in symptoms during long-term follow-up. We suggest the role of COVID-19 infection as a possible trigger for ASIA, as it has already been described as a trigger for several other autoimmune diseases.

Daratumumab for autoimmune diseases: a systematic review.

OBJECTIVE: Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases. METHODS: A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome. RESULTS: 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%). CONCLUSION: Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases.

Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Secondary exposure to heavy metal in genetically susceptible mice leads to acceleration of autoimmune response.

Exposure to mercury (Hg) and silver (Ag) has been shown to induce autoimmune diseases in genetically susceptible rodents. Here, A.SW mice were initially exposed to HgCl2, AgNO3 or tap water (control) for 3 weeks. After 13 weeks of stoppage, all mice had secondary exposure to 203HgCl2. After secondary exposure, higher and earlier ANoA titers were observed in mice initially exposed to Hg or Ag compared to control. Further, mice initially exposed to Ag showed higher total IgG1 and IgG2a, Whole Body Retention and lymph nodes and spleen accumulation of Hg compared to mice initially exposed to Hg and controls. These findings showed an earlier and stronger immunological response in A.SW mice compared with control, following re-exposure to heavy metals indicating an immunological memory. Additionally, secondary exposure to a different heavy metal may aggravate the effects of exposure of at least one of the metals indicating cross-reactivity.

Polybrominated biphenyls (PBBs) and prevalence of autoimmune disorders among members of the Michigan PBB registry.

BACKGROUND: Polybrominated biphenyls (PBBs), a class of endocrine disrupting chemicals, were the main chemicals present in one of the largest industrial accidents in the United States. We investigated the association between serum PBB-153 levels and autoimmune disorders among members of the Michigan PBB Registry. METHODS: Eight hundred and ninety-five members of the registry had both a serum PBB-153 measurement and had completed one or more questionnaires about autoimmune disorders. Autoimmune disorders were examined collectively and within specific organ systems. Sex-stratified unadjusted and adjusted log-binomial models were used to examine the association between tertiles of serum PBB-153 levels and autoimmune disorders. Models were adjusted by lifestage at exposure (in utero, childhood, adulthood), smoking history (never, past, current), and total serum lipid levels (continuous). We utilized cubic spline models to investigate non-linearity between serum PBB-153 levels and the prevalence of autoimmune disorders. RESULTS: Approximately 12.9% and 20.7% of male and female participants reported having one or more autoimmune disorders, respectively. After adjustment for potential confounders, we observed no association between PBB-153 tertiles and the composite classification of 'any autoimmune disorder' in either sex. We observed some evidence for an association between serum PBB-153 levels and rheumatoid arthritis in males and females; however, this was not statistically significant in females. We also observed some evidence for an association between serum PBB-153 levels and neurological- and thyroid-related autoimmune disorders in females, but again this was not statistically significant. Additionally, we identified dose-response curves for serum PBB-153 levels and the prevalence of autoimmune disorders that differed by lifestage of exposure and sex. CONCLUSIONS: We observed some evidence that increasing serum PBB-153 levels were associated with three specified autoimmune disorders. Studies focusing on these three autoimmune disorders and the potential non-linear trend differences by lifestage of exposure warrant further investigation.

Intravenous Immunoglobulin for Autoimmune Bullous Diseases: A Case Series from a Central European Referral Center.

Background and Objectives: Autoimmune bullous diseases (AIBDs) may be treated with intravenous immunoglobulin (IVIG) infusions. This study aimed to evaluate the benefits and safety profiles of high-dose IVIG therapy in AIBD patients, as determined by clinical remission, the glucocorticosteroid-sparing effect, and adverse events at 12 months follow-up in a Central European university dermatology department setting. Materials and Methods: Our case series included 10 patients: five patients with pemphigus vulgaris, one with pemphigus herpetiformis, one with pemphigus foliaceus, one with bullous pemphigoid, two with epidermolysis bullosa acquisita. They underwent 4-12 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. Results: The prednisone dosage reduction after 2, 6, and 12 months following the final IVIG course was 65.45%, 70.91%, and 76.37%, respectively. During the 12-month observation period, disease relapse was observed in 20% of patients, while others achieved complete or partial remission without or with minimal therapy. Side effects were seen in 80% of patients; they were transient and did not necessitate discontinuation of IVIG. Conclusions: IVIG demonstrates effectiveness as a treatment with a favorable safety profile. Nevertheless, its high cost remains a significant drawback, particularly in low-income countries. IVIG should be considered, especially in patients opposed to standard therapies or with contraindications to their use.

Aggravation of TGFß1-Smad Pathway and Autoimmune Myocarditis by Fungicide (Tebuconazole) Exposure.

Myocarditis is an inflammatory cardiac disorder and the primary cause of heart failure in young adults. Its origins can be attributed to various factors, including bacterial or viral infections, exposure to toxins or drugs, endocrine disruptors (EDs), and autoimmune processes. Tebuconazole (TEB), which is a member of the triazole fungicide family, is utilized to safeguard agricultural crop plants against fungal pathogens. Although TEB poses serious threats to mammal health, the information about how it induces toxic effects through various pathways, particularly in autoimmune diseases, are still limited. Thus, the aim of this paper was to evaluate the effect of TEB exposure in autoimmune myocarditis (AM). To induce AM, rats were immunized with porcine cardiac myosin and exposed to TEB for 21 days. Thereafter, animals were sacrificed, and histological, biochemical, and molecular analyses were performed. TEB exposure increased heart weight, systolic blood pressure and heart rate already augmented by AM. Additionally, it significantly increased creatine phosphokinase heart (CK-MB), creatine phosphokinase (CPK), cardiac troponin T (cTnT), and cardiac troponin I (cTnI), as compared to the control. From the histological perspective, TEB exacerbates the histological damage induced by AM (necrosis, inflammation and cell infiltration) and increased fibrosis and collagen deposition. TEB exposure strongly increased pro-inflammatory cytokines and prooxidant levels (O2-, H2O2, NO2-, lipid peroxidation) and reduced antioxidant enzyme levels, which were already dysregulated by AM. Additionally, TEB increased NOX-4 expression and the TGFß1-Smads pathway already activated by AM. Overall, our results showed that TEB exposure strongly aggravated the cardiotoxicity induced by AM.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA), medical treatment of severe systemic compromise: case report.

Case description: A 42-year-old woman with severe pulmonary and mediastinal inflammatory involvement, secondary to infiltration of a silicone-related allogenic material with systemic migration. Clinical findings: The patient developed esophageal and bronchial stenosis, recurrent infections, malnutrition, and respiratory deterioration, making surgical removal of the allogenic material impossible. Treatment and outcome: Clinical and radiological improvement was achieved after treatment with multiple intravenous and oral immunomodulators. Clinical relevance: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a heterogeneous disease resulting from exposure to allogenic substances in a susceptible subject. These substances cause autoimmune or autoinflammatory phenomena. Since ASIA was described ten years ago, its diagnostic criteria are still under discussion, with an uncertain prognosis. The ideal therapy is based on eliminating the causative substance, but this is not always possible. Therefore, it is necessary to start an immunomodulatory treatment, using it in this patient, a scheme that had not been previously reported in the literature.

Descripción del caso: Mujer de 42 años con compromiso inflamatorio pulmonar y mediastinal severo, secundario a infiltración de un material alogénico relacionado con la silicona con migración sistémica. Hallazgos clínicos: La paciente desarrolló estenosis esofágica y bronquial, infecciones recurrentes, desnutrición y deterioro respiratorio, imposibilitando la extracción quirúrgica del material alogénico. Tratamiento y resultado: Mejoría clínica y radiológica lograda tras un tratamiento con múltiples inmunomoduladores intravenosos y orales. Relevancia clínica: El síndrome autoinmune / inflamatorio inducido por adyuvantes (ASIA) es una enfermedad heterogénea que resulta de la exposición a sustancias alógenas en un sujeto con susceptibilidad genética. Estas sustancias inducen fenómenos autoinmunitarios o autoinflamatorios. Desde que ASIA fue descrito hace 10 años, sus criterios diagnósticos continúan en discusión, con un pronóstico incierto. El tratamiento idóneo se basa en eliminar la sustancia causante, pero no siempre es posible, por lo cual se hace necesario iniciar un tratamiento inmunomodulador, empleándose en esta paciente un esquema que no había sido reportado previamente en la literatura.