Abstract 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).
To evaluate the effect of potential confounders on the association between sex and disease impact in recent-onset psoriatic arthritis.
We performed a multicentre observational prospective study ...(2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset was generated using data for each patient at the 3 visits (baseline, first year, and second year of follow-up) matched with the PsAID values at each of the 3 visits. Once variables associated with both PsAID ≥4 and sex were selected, those that led to a difference of >10% between the adjusted and crude estimations were identified as potential confounders in the association between sex and PsAID. Lastly, the final multivariate logistic regression model estimating the association between sex and PsAID was defined.
The dataset contained 418 observations (158 at baseline, 135 at the first follow-up visit, and 125 at the second visit). The confounders identified in the multivariate model were HAQ, global pain, level of physical activity, and joint pattern at diagnosis. After adjustment for these variables, no statistically significant association was observed between female sex and PsAID ≥4.
The association between female sex and greater disease impact could be explained by the influence of other variables, specifically higher HAQ score, greater intensity of pain, differences in the level of physical activity and in the joint pattern at diagnosis (lower frequency of the spondylitis pattern in women).
Abstract
Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An ...influence of the
interleukin (IL)33- IL1 receptor like (IL1RL)1
signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the
IL33-IL1RL1
pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within
IL33
(rs3939286, rs7025417 and rs7044343) and three within
IL1RL1
(rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when
IL33
and
IL1RL1
variants were analysed independently. Likewise, no statistically significant differences were found in
IL33
or
IL1RL1
genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when
IL33
and
IL1RL1
haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the
IL33-IL1RL1
signalling pathway does not contribute to the genetic network underlying IgAV.
To evaluate which patient and disease characteristics are associated with the perception of high-impact disease (PsAID ≥4) in recent-onset psoriatic arthritis.
We performed a multicenter ...observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset was generated using data for each patient at the 3 visits (baseline, first year, and second year of follow-up) matched with the PsAID values at each of the 3 visits. PsAID was categorized into two groups (<4 and ≥4). We trained a logistic regression model and random forest–type and XGBoost machine learning algorithms to analyze the association between the outcome measure and the variables selected in the bivariate analysis. A k-fold cross-validation with k = 5 was performed.
The sample comprised 158 patients. Of the patients who attended the clinic, 45.8% scored PsAID ≥4 at baseline; 27.1%, at the first follow-up visit, and in 23.0%, at the second follow-up visit. The variables associated with PsAID ≥4 were, in decreasing order of importance: HAQ, pain, educational level, and physical activity. Higher HAQ (logistic regression coefficient 10.394; IC95% 7.777,13.011), higher pain (5.668; 4.016, 7.320), lower educational level (-2.064; -3.515, -0.613) and high level of physical activity (1.221; 0.158, 2.283) were associated with a higher frequency of PsAID ≥4. The mean values of the measures of validity of the algorithms were all ≥85%.
Despite the higher weight given to pain when scoring PsAID, we observed a greater influence of physical function on disease impact.
Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has ...shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA.
Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA.
No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls.
Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.
To determine the potential impact of extra-articular manifestations (EAMs) on disease characteristics and cardiovascular (CV) risk in patients with axial spondylarthritis (axSpA).
This is a ...cross-sectional study from the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Data on the history of CV events, subclinical carotid atherosclerosis, and disease-related features, including EAMs, were collected.
888 axSpA patients were recruited. Concomitant acute anterior uveitis (AAU), psoriasis (PSO), and inflammatory bowel disease (IBD) were present in 177 (19.9%), 96 (10.8%), and 57 (6.4%) patients, respectively. When compared with axSpA patients without EAMs, a significant increase in past CV events was observed in patients with PSO (9% versus 4%, p = 0.048) and in those with at least one EAM (7% versus 4%, p = 0.032) or with more than one EAM (11% versus 4%, p = 0.022). The frequency of carotid plaques and the values of cIMT were higher in patients with EAMs than in those without EAMs, although only the univariable analysis for carotid plaques in patients with PSO (39% versus 30%, p = 0.038) and for cIMT in patients with AAU (665 ± 156 µm versus 637 ± 139 µm, p = 0.042) and those with at least one EAM (661 ± 155 µm versus 637 ± 139 µm, p = 0.024) showed significant results. In addition, patients with PSO or IBD were found to have specific disease-related features, such as higher ESR at diagnosis, and more frequent use of glucocorticoids and TNF inhibitors than those without EAMs. Also, PSO patients had more commonly peripheral involvement and those with AAU more severe radiographic damage than those without EAMs. The frequency of HLA B27 was higher in patients with AAU and lower in those with PSO or IBD compared to those without EAMs.
Patients with axSpA and EAMs, in addition to displaying their own disease-related features, are likely to have an increased CV risk that appears proportional to the number of EAMs and could be related to proatherogenic factors other than traditional CV risk factors, such as the inflammatory load and the use of glucocorticoids.
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To determine the potential impact of sex-specific disease-related characteristics on cardiovascular (CV) disease in axial spondyloarthritis (axSpA).
Cross-sectional study of the Spanish AtheSpAin ...cohort to study CV disease in axSpA. Data on carotid ultrasound and CV disease and disease-related features were collected.
611 men and 301 women were recruited. Classic CV risk factors were significantly less prevalent in women, who also showed a lower frequency of carotid plaques (p = 0.001), lower carotid intima-media thickness (IMT) values (p<0.001) and CV events (p = 0.008). However, after adjustment for classic CV risk factors, only the differences with respect to carotid IMT remained statistically significant. Women showed higher ESR at diagnosis (p = 0.038), and more active disease (ASDAS, p = 0.012, and BASDAI, p<0.001). They had shorter disease duration (p<0.001), lower prevalence of psoriasis (p = 0.008), less structural damage (mSASSS, p<0.001), and less mobility limitation (BASMI, p = 0.033). To establish whether these findings could lead to sex differences in CV disease burden, we compared the prevalence of carotid plaques in men and women with the same level of CV risk stratified according to the Systematic Coronary Risk Evaluation (SCORE). Men included in the low-moderate CV risk SCORE category had more carotid plaques (p = 0.050), along with longer disease duration (p = 0.004), higher mSASSS (p = 0.001) and psoriasis (p = 0.023). In contrast, in the high-very high-risk SCORE category, carotid plaques were observed more frequently in women (p = 0.028), who were characterized as having worse BASFI (p = 0.011), BASDAI (p<0.001) and ASDAS (p = 0.027).
Disease-related features may influence the expression of atherosclerosis in patients with axSpA. This may be especially applicable to women at high CV risk, characterized by greater disease severity and more severe subclinical atherosclerosis than men, suggesting a stronger interaction between disease activity and atherosclerosis in women with axSpA.
•Identifying pro-atherogenic factors in rheumatic diseases can help prevent cardiovascular events.•Axial spondyloarthritis features associated with atherosclerosis remain unclear.•Inflammation and ...disease severity are associated with atherosclerosis in axial spondyloarthritis.
To identify disease-related factors associated with subclinical atherosclerosis and cardiovascular (CV) events in a large series of patients with axial spondyloarthritis (axSpA) and to identify possible differences in the effect of the potential pro-atherogenic factors between ankylosing spondylitis (AS) non-radiographic axSpA (nr-axSpA).
This is a cross-sectional observational study of the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Subclinical atherosclerosis determined by carotid ultrasound included assessment of carotid intima-media thickness (cIMT) and plaque detection.
639 AS and 167 nr-axSpA patients were recruited. CV risk factors (CRF) and several disease-related factors showed a statistically significant association with subclinical atherosclerosis in the crude analysis. After adjustment for age, sex, and smoking (model 1), associations remained statistically significant for spinal mobility, inflammatory bowel disease, use of prednisone, and Disease-modifying antirheumatic drugs (DMARD) when assessing carotid plaques and for acute phase reactants (APR) at diagnosis, use of prednisone, DMARD, and TNF-inhibitors when measuring cIMT. In model 2, which also included classic CRF as confounding factors to identify axSpA features with a potential independent pro-atherogenic effect, the functional status was the only variable significantly associated with plaques and the use of prednisone and APR at diagnosis with cIMT. No association differences were found between both subtypes of patients. Besides, APR at diagnosis were also associated with subsequent development of CV events that had occurred in 33 patients.
Apart from CRF, atherosclerotic disease in AxSpA is associated with disease-related factors such as inflammatory response and disease severity, with no differences between AS and nr-axSpA.
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To compare the atherosclerosis disease burden between ankylosing spondylitis (AS) and non-radiographic (nr) axial spondyloarthritis (axSpA) and establish a model that allows to identify ...high-cardiovascular (CV) risk in axial spondyloarthritis patients.
Cross-sectional study from the AtheSpAin cohort, a Spanish multicenter cohort aimed to study atherosclerosis in axSpA. Carotid ultrasound (US) was performed to determine the carotid intima-media wall thickness (cIMT) and detect the presence of carotid plaques. The European cardiovascular disease risk assessment model, the Systematic COronary Risk Evaluation (SCORE), was also applied.
A set of 639 patients with AS and 167 patients with nr-axSpA without history of CV events were recruited. AS patients were older showing more CV risk factors and higher values of C reactive protein and erythrocyte sedimentation rate (ESR) than those with nr-axSpA. However, no difference in the prevalence of carotid plaques or in the cIMT was found between both groups in the adjusted analysis. The percentage of patients reclassified from the low and moderate CV risk categories to the very high-risk category due to the presence of carotid plaques was comparable in AS and nr-axSpA (10.7% versus 10.1% and 40.5% versus 45.5%, respectively). A model containing age, BASFI and ESR applied to moderate risk axSpA patients identified 41% of these patients as having very high-risk patients with high specificity (88%).
The atherosclerosis burden is similar in nr-axSpA and AS. As occurred for AS, more than 40% of axSpA patients included in the category of moderate CV risk according to the SCORE are reclassified into very high risk after carotid US, and a clinically relevant proportion of them can be detected by applying a model containing age, BASFI and ESR.
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To determine whether giant cell arteritis (GCA) patients with the typical pattern of cranial ischemic manifestations and those with the extracranial large-vessel-vasculitis (LVV)-GCA phenotype ...exhibit different HLA-DRB1 association.
178 biopsy-proven GCA patients who had cranial ischemic features but no LVV manifestations, 100 patients with LVV-GCA without cranial ischemic manifestations and 486 ethnically matched healthy controls were recruited. All patients and controls were Spanish of European ancestry. We compared HLA-DRB1 phenotype frequencies between the three groups.
Both GCA subgroups had well-differentiated clinical features. Patients with LVV-GCA were younger (68.0 ± 10.0 years versus 74.0 ± 10.4 years; p < 0.01) and presented more commonly with polymyalgia rheumatica symptoms (81% versus 39.3%; p < 0.01) than those with the classic cranial GCA phenotype. HLA-DRB1*04 phenotype frequency was significantly increased in patients with classic cranial GCA compared to controls (42.1% versus 23.5%, respectively; p < 0.01; odds ratio-OR 95% confidence interval-CI = 2.38 1.62–3.47). This association was mainly due to the HLA-DRB1*04:01 allele (20.8% versus 5.3%, respectively; p < 0.01; OR 95% CI = 4.64 2.63–8.26). HLA-DRB1*04 association was also observed in LVV-GCA patients when compared to controls (46.0% versus 23.5%, respectively; p < 0.01; OR 95% CI = 2.78 1.73–4.44). Similar to cranial GCA, the association was also mainly due to the HLA-DRB1*04:01 allele (19.0% versus 5.3%, respectively; p < 0.01; OR 95% CI = 4.15 2.06–8.19). Cranial and LVV-GCA patients did not exhibit HLA-DRB1 allele differences.
Cranial and extracranial LVV-GCA share similar HLA-DRB1 association.
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