Epidemiology of Neuro-Behçet's Disease in Northern Spain 1999-2019: A Population-Based Study.

Background/Objectives: Neuro-Behçet's disease (NBD) is one of the most severe complications of Behçet's disease (BD). The incidence of NBD varies widely worldwide. This study aimed to estimate its current incidence in Northern Spain. Methods: This was a retrospective population-based cohort study of 120 patients in Northern Spain diagnosed with BD according to the 2013 International Criteria for BD (ICBD) between 1 January 1999 and 31 December 2019. NBD diagnoses were made according to International Consensus Recommendation (ICR) criteria. Overall, 96 patients were included, and their demographic and clinical data were collected. The incidence of NBD was estimated by age, gender, and year of diagnosis between 1999-2019. Results: NBD was diagnosed in 23 of 96 (24%) patients (15 women/8 men) (mean age: 44 ± 13.9 years). HLA-B51 was positive in 5 of 13 (38.4%) cases tested. A total of 10 (43.5%) patients had parenchymatous NBD, 10 (43.5%) had non-parenchymatous NBD, and 3 (13%) had mixed NBD. Incidence during the study period was 0.13 (95% CI, 0.11-0.26) per 100,000 people-years. There were no significant differences in gender in the incidence rate stratified by age (p > 0.05). Furthermore, there was a linear relationship with a mild decrease in age at diagnosis over time. Conclusions: Epidemiological characteristics of NBD in Northern Spain are similar to those of neighboring countries, except female gender predominance.

Clinical phenotypes of sarcoidosis using cluster analysis: a Spanish population-based cohort study.

OBJECTIVES: Sarcoidosis is a clinically heterogenous disease. The objective of this study is the identification of clinical phenotypes using cluster analysis. METHODS: A model-based clustering relaying on 19 clinical variables was performed in a retrospective cohort of 342 sarcoidosis patients, diagnosed and followed-up from 1999 to 2019 in a tertiary hospital at Northern Spain. Chi-square test and ANOVA were used to compare categorical and continuous variables among groups. Two-sample t-tests and the partition of Pearson's chi-square statistic were used in pairwise comparisons. The Wasfi severity score was calculated and compared among clusters. RESULTS: Cluster analysis identified five groups: C1 (16.1%), C2 (14.3%), C3 (24.3%), C4 (5.0%), and C5 (40.4%). Lung involvement was predominant, ranging from 55.1% (C2) to 100% (C1 and C4). Extrapulmonary involvement was significantly higher in C2 (96.4%) and C3 (98.0%). A significant lower FEV1 percent predicted was detected in C5 (90.5±21.8) versus C1 (102.0±22.9), C3 (102.3±17.6) and C4 (105.8±20.8). The cluster 5 had a lower FVC percent predicted (96.6±18.9) than others, ranging from 108.1±18.0 (C3) to 111.5±21.7 (C4). The prescription of systemic glucocorticoids and non-corticosteroid immunosuppressants was higher in the clusters 1, 3 and 5. Chronicity rates were higher in C3 (31.3%) and C5 (32.6%) compared to C1 (9.1%) and C4 (0%), as well as the Wasfi severity score values. CONCLUSIONS: Five phenotypes with different clinical and prognostic characteristics are proposed in our study. Cluster analysis can be a useful tool for identifying clinical patterns in a disease as heterogeneous as sarcoidosis and optimising its management.

Similarities and differences between systemic juvenile idiopathic arthritis and adult-onset Still's disease: a multicenter Spanish study.

To describe the characteristics of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), compare their presentation and evolution, and analyse possible complication predictors. Multicenter study. Data were retrieved from a hospital-based study of patients with a diagnosis or suspected diagnosis of sJIA or AOSD according to the responsible physician and followed-up for at least one year. Descriptive variables (classification criteria, clinical manifestations, complications, family, and personal history) were collected at disease onset and during follow-up. We present the clinical characteristics of 326 patients, 67% of whom had a diagnosis of sJIA and 33% of AOSD. Clinical manifestation frequencies were similar between the two groups, except for odynophagia, which was significantly more frequent in AOSD than in sJIA (78.4% vs. 25.5%; p < 0.0001). Among the complications, macrophage activation syndrome (MAS) was significantly more common in sJIA than in AOSD (24.4% vs. 9.5%; p = 0.002), to the extent that an sJIA diagnosis significantly increased the risk of MAS, together with serositis presence, and the need for biological therapy. Patients with sJIA and AOSD showed similar characteristics, supporting the idea that they are both part of Still's disease, but are expressed at different ages. Differences in manifestations and complications might be due to different management between diseases and immune response maturity.

Genetic Variants in RANK and OPG Could Influence Disease Severity and Bone Remodeling in Patients with Early Arthritis.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

PSGL-1, ADAM8, and selectins as potential biomarkers in the diagnostic process of systemic lupus erythematosus and systemic sclerosis: an observational study.

Background: Early diagnosis and treatment of Systemic lupus erythematosus (SLE) and Systemic sclerosis (SSc) present significant challenges for clinicians. Although various studies have observed changes in serum levels of selectins between healthy donors and patients with autoimmune diseases, including SLE and SSc, their potential as biomarkers has not been thoroughly explored. We aimed to investigate serum profiles of PSGL-1 (sPSGL-1), ADAM8 (sADAM8) and P-, E- and L-selectins (sP-, sE- and sL-selectins) in defined SLE and SSc patient cohorts to identify disease-associated molecular patterns. Methods: We collected blood samples from 64 SLE patients, 58 SSc patients, and 81 healthy donors (HD). Levels of sPSGL-1, sADAM8 and selectins were analyzed by ELISA and leukocyte membrane expression of L-selectin and ADAM8 by flow cytometry. Results: Compared to HD, SLE and SSc patients exhibited elevated sE-selectin and reduced sL-selectin levels. Additionally, SLE patients exhibited elevated sPSGL-1 and sADAM8 levels. Compared to SSc, SLE patients had decreased sL-selectin and increased sADAM8 levels. Furthermore, L-selectin membrane expression was lower in SLE and SSc leukocytes than in HD leukocytes, and ADAM8 membrane expression was lower in SLE neutrophils compared to SSc neutrophils. These alterations associated with some clinical characteristics of each disease. Using logistic regression analysis, the sL-selectin/sADAM8 ratio in SLE, and a combination of sL-selectin/sE-selectin and sE-selectin/sPSGL-1 ratios in SSc were identified and cross-validated as potential serum markers to discriminate these patients from HD. Compared to available diagnostic biomarkers for each disease, both sL-selectin/sADAM8 ratio for SLE and combined ratios for SSc provided higher sensitivity (98% SLE and and 67% SSc correctly classified patients). Importantly, the sADAM8/% ADAM8(+) neutrophils ratio discriminated between SSc and SLE patients with the same sensitivity and specificity than current disease-specific biomarkers. Conclusion: SLE and SSc present specific profiles of sPSGL-1, sE-, sL-selectins, sADAM8 and neutrophil membrane expression which are potentially relevant to their pathogenesis and might aid in their early diagnosis.

Role and potential of 18F-fluorodeoxyglucose-positron emission tomography-computed tomography in large-vessel vasculitis: a comprehensive review.

Large-vessel vasculitis (LVV) is a group of diseases characterized by inflammation of the aorta and its main branches, which includes giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and Takayasu's arteritis (TAK). These conditions pose significant diagnostic and management challenges due to their diverse clinical presentations and potential for serious complications. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET-CT) has emerged as a valuable imaging modality for the diagnosis and monitoring of LVV, offering insights into disease activity, extent, and response to treatment. 18F-FDG-PET-CT plays a crucial role in the diagnosis and management of LVV by allowing to visualize vessel involvement, assess disease activity, and guide treatment decisions. Studies have demonstrated the utility of 18F-FDG-PET-CT in distinguishing between LVV subtypes, evaluating disease distribution, and detecting extracranial involvement in patients with cranial GCA or PMR phenotypes. Additionally, 18F-FDG-PET-CT has shown promising utility in predicting clinical outcomes and assessing treatment response, based on the correlation between reductions in FDG uptake and improved disease control. Future research should focus on further refining PET-CT techniques, exploring their utility in monitoring treatment response, and investigating novel imaging modalities such as PET-MRI for enhanced diagnostic accuracy in LVV. Overall, 18F-FDG-PET-CT represents a valuable tool in the multidisciplinary management of LVV, facilitating timely diagnosis and personalized treatment strategies to improve patient outcomes.

Assessing the contribution of genes involved in monogenic bone disorders to the etiology of atypical femoral fractures.

BACKGROUND: Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture. RESULTS: Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria. CONCLUSIONS: Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

Regulation of monocyte apoptosis and DNA extrusion in monocyte extracellular traps by PSGL-1: Relevance in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by severe organ damage and lacking curative treatment. While various immune cell types, especially dysfunctional B and T cells and neutrophils, have been related with disease pathogenesis, limited research has focused on the role of monocytes in SLE. Increased DNA extracellular traps, apoptosis and necrosis have been related to lupus pathogenesis. Our goal is to analyze the contribution of P-selectin glycoprotein ligand 1 (PSGL-1) in SLE monocytes to disease pathogenesis by investigating the control exerted by PSGL-1 on monocyte apoptosis and DNA extrusion in extracellular traps (METs). Monocytes from active disease patients (aSLE) exhibited reduced levels of PSGL-1. Importantly, lower PSGL-1 levels in SLE monocytes associated with several clinical characteristics, including anti-dsDNA autoantibodies, lupus anticoagulant, clinical lung involvement, and anemia. Monocytes from SLE patients showed higher susceptibility to apoptosis than healthy donors (HD) monocytes and PSGL-1/P-selectin interaction decreased secondary necrosis in HD but not in aSLE monocytes. Regarding METs, aSLE monocytes exhibited higher susceptibility to generate METs than HD monocytes. The interaction of HD monocytes with P-selectin induced Syk activation and reduced the levels of DNA extruded in METs. However, in aSLE monocytes, PSGL-1/P-selectin interaction did not activate Syk or reduce the amount of extruded DNA. Our data suggest a dysfunctional PSGL-1/P-selectin axis in aSLE monocytes, unable to reduce secondary necrosis or the amount of DNA released into the extracellular medium in METs, potentially contributing to lupus pathogenesis.

Genetics of vasculitis.

Systemic vasculitis encompasses a wide range of conditions characterized by varying degrees of inflammation in blood vessels. Although the etiology of vasculitis remains unclear, accumulated data suggest that it is triggered in genetically predisposed individuals by the concurrence of certain environmental factors. The importance of the genetic component has been consistently supported by evidence of familial aggregation, differential prevalence by ethnicity, and multiple genetic associations with disease susceptibility and severity reported in recent years. The strongest association signals in most vasculitides correspond to genetic variants within the HLA region, suggesting an important role of the immune system in its pathophysiology. However, each type of vasculitis has distinct defining HLA association markers, likely due to disease-specific differences in antigenic drivers. Furthermore, other genetic polymorphisms located outside the HLA region play an important role in susceptibility to different vasculitides. More recent research has assessed the shared genetic susceptibility evident across different vasculitides. Future studies should focus on the identification of genetic markers that can serve as reliable biomarkers for early diagnosis, prognosis, and treatment response in systemic vasculitis.

Subcutaneous vs intravenous abatacept in rheumatoid arthritis-interstitial lung disease. National multicentre study of 397 patients.

BACKGROUND: Evidence on abatacept (ABA) utility for rheumatoid arthritis (RA) - associated interstitial lung disease (ILD) is growing. Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations. However, this has not been studied in respiratory outcomes. OBJECTIVE: To compare the effectiveness of ABA in RA-ILD patients according to the route of administration. METHODS: National retrospective multicentre study of RA-ILD patients on treatment with ABA. They were divided into 2 groups: a) IV, and b) SC. The following outcomes were analysed from baseline to final follow-up using linear mixed models: a) forced vital capacity (FVC), b) diffusing capacity of the lungs for carbon monoxide (DLCO), c) chest high resolution computed tomography (HRCT), d) dyspnoea, e) RA activity, and f) sparing corticosteroids effect. RESULTS: A total of 397 patients were included (94 IV-ABA and 303 SC-ABA), median follow-up of 24 [10-48] months. After adjustment for possible confounders, FVC and DLCO remained stable during the first 24 months without differences between IV-ABA and SC-ABA (p = 0.6304 and 0.5337). Improvement/ stability of lung lesions in HRCT was observed in 67 % of patients (75 % IV-ABA, 64 % SC-ABA; p = 0.07). Dyspnoea stabilized/ improved in 84 % of patients (90 % IV-ABA, 82 % SC-ABA; p = 0.09). RA - disease activity improved in both groups. No statistically significant differences regarding any of the variables studied between the two groups were found. ABA was withdrawn in 87 patients (21.9 %), 45 % IV-ABA and 37 % SC-ABA (p = 0.29). ILD worsening and articular inefficacy were the most common reasons for ABA discontinuation. CONCLUSION: In patients with RA-ILD, ABA seems to be equally effective regardless of the route of administration.

Diagnosis of giant cell arteritis by 18F-FDG PET/CT in patients on glucocorticoid therapy: importance of delayed imaging.

OBJECTIVES: The aim of this study is to analyse the diagnostic value of positron emission tomography (PET) in patients with giant cell arteritis (GCA) despite glucocorticoid (GC) therapy before PET acquisition. METHODS: Consecutive patients with strongly suspected GCA according to 2022 EULAR/ACR criteria were included. The physician diagnosis of GCA after 6 months of follow-up was the gold standard. PET was performed at baseline and 6 months later. In patients with negative results at 60 min, delayed imaging was performed at 180 min. RESULTS: Twenty-six patients were included with a median (IQR) age of 70.5 (57-88) years. Baseline PET was positive in all but one: 18 patients at 60 min and 7 patients after delayed imaging at 180 min. The median (IQR) GC dose at the time of baseline PET was 45 mg/d (26.2-45) of prednisone equivalent with a median exposure of 14 days (7-76.2). At 6 months of follow-up, PET was performed in 22 patients, with positive results in 16. Delayed imaging was performed in 6 patients due to negative PET at 60 min, with positive results in all cases, despite treatment with GC and/or biological therapy. CONCLUSIONS: In patients on GC therapy, delayed imaging protocols applying procedural recommendations for vascular quantification could improve diagnostic accuracy. Therefore, we suggest performing imaging only at 180 min in patients who have been on GCs for more than 3 days as well as in those with highly suspected GCA but negative findings in baseline PET at 60 min.

Positron Emission Tomography/Computed Tomography in Polymyalgia Rheumatica: When and for What-A Critical Review.

Polymyalgia rheumatica (PMR) is an inflammatory disease common in people aged 50 years and older. This condition is characterized by the presence of pain and stiffness involving mainly the shoulder and pelvic girdle. Besides the frequent association with giant cell arteritis (GCA), several conditions may mimic PMR or present with PMR features. Since the diagnosis is basically clinical, an adequate diagnosis of this condition is usually required. Positron emission tomography/computed tomography (PET-CT) has proved to be a useful tool for the diagnosis of PMR. The use of 18F-FDG-PET imaging appears promising as it provides detailed information on inflammatory activity that may not be evident with traditional methods. However, since PET-CT is not strictly necessary for the diagnosis of PMR, clinicians should consider several situations in which this imaging technique can be used in patients with suspected PMR.

Increased Risk of Herpes Zoster in Rheumatoid Arthritis Not Only Due to JAK Inhibitors-Study of 392 Patients from Single University Center.

Background/Objectives: Patients with rheumatoid arthritis (RA) have an increased risk of infection. Their risk of presenting herpes zoster (HZ) is 1.5-2 times higher than immunocompetent individuals and disseminated presentation is more frequent. Our aim was to analyze the prevalence and general features of HZ in RA patients. Methods: This was a prospective study of 392 RA patients included in the vaccination program of our hospital between 2011 and 2016, and follow-up continued until December 2020. A diagnosis of HZ was made according to clinical manifestations: skin rash, blisters, paresthesia, and local pain in one or more dermatomes. Results: We studied 392 participants (309 women/83 men), mean age 59 ± 13 years. Every patient was followed-up over a mean period of 137 ± 110 months (range: 42 months-42 years). HZ infection was observed in 30 of 392 (25 women/5 men) patients, age (mean ± SD) 64.7 ± 11.8 years. Prevalence was 7.65% in this period and the incidence rate was 13.22/1000 patients/year. Three patients had facial involvement, one had optic involvement, and one patient presented disseminated HZ. Seven patients presented post herpetic neuralgia treated with gabapentinoids. The main features of RA of these 30 patients were: positive RF (n = 17; 56.6%), positive anti-CCP (n = 13; 43.3%), and erosive disease (n = 10; 33.3%). At HZ infection, the treatments were glucocorticoids (n = 19; 63.3%), conventional DMARDs (n = 15; 50%), biological DMARDs (n = 15; 50%), tofacitinib (n = 2; 6.6%), and upadacitinib (n = 1; 3.3%). Conclusions: HZ is a relatively frequent viral complication in RA patients. In our series, one patient presented disseminated HZ and nearly 25% of patients had post-herpetic neuralgia. Including a HZ vaccine in our vaccination program for RA patients may be beneficial.

Sex-specific impact of inflammation on traditional cardiovascular risk factors and atherosclerosis in axial spondyloarthritis. A multicentre study of 913 patients.

INTRODUCTION: The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed. METHODS: Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment. RESULTS: After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (ß coefficient: -1.2 (95% CI: -0.3 to -0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (ß coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high-very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis. CONCLUSION: Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.

Effectiveness and Safety of the COVID-19 Vaccine in Patients with Rheumatoid Arthritis in a Real-World Setting.

Novel mechanisms of COVID-19 vaccines raised concern about their potential immunogenicity in patients with rheumatoid arthritis (RA) undergoing immunomodulatory treatments. We designed a retrospective single-center study to investigate their effectiveness and safety in this population, analyzing data from the first vaccination program (December 2020-October 2021). Inclusion criteria were availability of post-vaccination serology and a minimum subsequent follow-up of 6 months. Binding antibody units (BAU/mL) ≥ 7.1 defined an adequate serological response. Post-vaccine COVID-19 incidence and its timing since vaccination, adverse events (AEs), and RA flares were recorded. Adjusted logistic and linear multivariate regression analyses were carried out to identify factors associated with vaccine response. We included 118 patients (87.2% women, age 65.4 ± 11.6 years, evolution 12.0 ± 9.6 years), of whom 95.8% had a complete vaccination schedule. Adequate humoral immunogenicity was achieved in 88.1% of patients and was associated with previous COVID-19 and mRNA vaccines, whereas smoking, aCCP, age, and DMARDs exerted a negative impact. Post-vaccine COVID-19 occurred in 18.6% of patients, a median of 6.5 months after vaccination. Vaccine AE (19.5%) and RA flares (1.7%) were mostly mild and inversely associated with age. Our results suggest that COVID-19 vaccines induce adequate humoral immunogenicity, with an acceptable safety profile in RA patients.

Effectiveness Of Tocilizumab In Aortitis And Aneurysms Associated With Giant Cell Arteritis.

OBJECTIVE: Aortitis in Giant Cell Arteritis (GCA-aortitis) is a frequent complication that may lead to aneurysms. Tocilizumab (TCZ) was approved in GCA, but the efficacy in GCA-aortitis and aneurysms has not been analyzed to date. Our aim was to assess the effectiveness and safety of TCZ in a wide series of GCA-aortitis and aneurysms. METHODS: Multicentre observational study with GCA-aortitis treated with TCZ. GCA was diagnosed by: a) ACR criteria, b) temporal artery biopsy, and/or c) imaging techniques. Aortitis was diagnosed mainly by PET/CT. Main outcomes were EULAR and imaging remission. Others were clinical remission, analytical normalization, corticosteroid-sparing effect, and the prevention and improvement of aneurysms. RESULTS: 196 patients with GCA-aortitis treated with TCZ. After 6 months, 72.2% reached EULAR remission but only 12% an imaging remission; increasing up-to 81.4% and 31.8%, respectively, at 24 months. A rapid clinical remission, ESR and CRP normalization was observed in 47.4%, 84.3% and 55.6%, at 1 month, increasing to 89.6%, 85.3% and 80.3% at 24 months, respectively. Aneurysms were present in 10 (5%) patients. Five of them required early surgery, while 3 others enlarged. No patient on TCZ therapy developed aneurysms during follow-up. CONCLUSION: In patients with GCA-aortitis treated with TCZ, a rapid and maintained clinical and analytical improvement was observed. However, there was an uncoupling between clinical and EULAR remission with imaging remission.

Effectiveness of janus kinase inhibitors in relapsing giant cell arteritis in real-world clinical practice and review of the literature.

BACKGROUND: A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. METHODS: Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. RESULTS: Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. CONCLUSIONS: This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

Broadening the clinical spectrum of giant cell arteritis: from the classic cranial to the predominantly extracranial pattern of the disease.

INTRODUCTION: Giant cell arteritis (GCA) is a large vessel (LV) vasculitis that affects people aged 50 years and older. Classically, GCA was considered a disease that involved branches of the carotid artery. However, the advent of new imaging techniques has allowed us to reconsider the clinical spectrum of this vasculitis. AREASCOVERED: This review describes clinical differences between patients with the cranial GCA and those with a predominantly extracranial LV-GCA disease pattern. It highlights differences in the frequency of positive temporal artery biopsy depending on the predominant disease pattern and emphasizes the relevance of imaging techniques to identify patients with LV-GCA without cranial ischemic manifestations. The review shows that so far there are no well-established differences in genetic predisposition to GCA regardless of the predominant phenotype. EXPERT COMMENTARY: The large branches of the extracranial arteries are frequently affected in GCA. Imaging techniques are useful to identify the presence of 'silent' GCA in people presenting with polymyalgia rheumatica or with nonspecific manifestations. Whether these two different clinical presentations of GCA constitute a continuum in the clinical spectrum of the disease or whether they may be related but are definitely different conditions needs to be further investigated.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.