Select Minor Cannabinoids from Cannabis sativa are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between labs or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. Significance Statement Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study we evaluated 5 minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that 4 of the 5 minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.

Comparison of the effect of treatment with NSAIDs added to anti-TNF therapy versus anti-TNF therapy alone on the progression of structural damage in the spine over 2 years in patients with radiographic axial spondyloarthritis from the randomised-controlled CONSUL trial.

OBJECTIVES: The study aimed to evaluate the effect of adding a non-steroidal anti-inflammatory drug (NSAID), celecoxib (CEL), to a tumour necrosis factor inhibitor (TNFi), golimumab (GOL), compared with TNFi monotherapy on radiographic spinal progression in patients with radiographic axial spondyloarthritis (r-axSpA) over 2 years. METHODS: R-axSpA patients, having risk factors for radiographic progression (high disease activity plus C reactive protein >5 mg/L and/or ≥1 syndesmophyte(s)), underwent a 12-week run-in phase with GOL 50 mg every 4 weeks. In the core phase (96 weeks), only patients with a good clinical response at week 12 were randomised (1:1) to GOL+CEL 200 mg two times per day (combination therapy) or GOL monotherapy. The primary endpoint was radiographic progression assessed by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) change at week 108 in the intent-to-treat population. RESULTS: A total of 128 patients were enrolled in the run-in phase; and 109 patients were randomised at week 12 to monotherapy (n=55) or combination therapy (n=54). At week 108, 97 (52 vs 45) patients completed the study. The change in mSASSS at week 108 was 1.7 (95% CI 0.8 to 2.6) in the monotherapy vs 1.1 (95% CI 0.4 to 1.8) in the combination therapy groups (p=0.79). New syndesmophytes occurred in 25% of patients in the monotherapy vs 11% of patients in the combination therapy groups (p=0.12). During the study, no significant differences in adverse events and serious adverse events were observed between the groups. CONCLUSIONS: Combination therapy with GOL+CEL did not demonstrate statistically significant superiority over GOL monotherapy in retarding radiographic spinal progression over 2 years in r-axSpA.

Impact of body composition on clinical outcomes in patients with active radiographic axial spondyloarthritis under biological therapy.

OBJECTIVE: To assess the association of body composition, evaluated by bioimpedance analysis (BIA), with disease activity, physical function, and mobility in patients with axSpA undergoing bDMARD treatment for one year. METHODS: Patients with AS (radiographic axSpA) were enrolled in an extension of the German Spondyloarthritis Inception Cohort (GESPIC). Patients were required to be candidates for bDMARD therapy at baseline presenting high disease activity despite previous treatment with nonsteroidal anti-inflammatory drugs. Outcomes (disease activity, function, and mobility) and body composition parameters were assessed at baseline and every 6 months thereafter. Body composition was assessed by BIA. The association between body composition parameters and outcomes over 1 year was analyzed using longitudinal generalized estimating equations. RESULTS: Seventy-four patients with radiographic axSpA were included in current analysis with a mean age of 36.5 years, disease duration of 6.2 years and ASDAS-CRP score of 3.4 at baseline. Fat mass value and fat mass index were positively associated with disease activity (ASDAS: ß = 0.01, 95% CI [-0.01, 0.03] and ß = 0.04, 95% CI [-0.01, 0.08], respectively) and functional disability (BASFI). Visceral adipose tissue (VAT) was associated with reduced spine mobility (BASMI: ß = 0.20, 95% CI [0.07, 0.33]). Additionally, increase in VAT and fat mass parameters was linked to worse disease activity and functional disability in women, while they were strongly associated with reduced spinal mobility in men. CONCLUSIONS: Higher levels of body fat and VAT were positively associated with increased disease activity, functional disability, and reduced spinal mobility in patients with radiographic axSpA treated with bDMARDs.

Oatp (Organic Anion Transporting Polypeptide)-Mediated Transport: A Mechanism for Atorvastatin Neuroprotection in Stroke.

BACKGROUND: Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke. METHODS: Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride-stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. RESULTS: At 2-hour post-middle cerebral artery occlusion, [3H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post-middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor). CONCLUSIONS: Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents.

Anatomical variation of the sacroiliac joint carries an increased risk for erosion and bone marrow oedema in axial spondyloarthritis.

OBJECTIVES: To assess the impact of joint shape variations on inflammatory lesions on SI joint MRIs in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1194 patients from four different prospective cohorts were evaluated, with 684 (57.3%) having sufficient imaging data for inclusion (379 axSpA, 305 controls). All images were evaluated for joint form, erosion, sclerosis, fat metaplasia and bone marrow oedema (BMO) by two independent readers. Logistic regression analyses were used to assess the association of joint form and lesions on imaging for axSpA patients and controls. RESULTS: Atypical joint forms were common in both axSpA (43.5% [154/354]) and control patients (44.2% [134/303]); both intra-articular variants and a crescent joint shape were significantly more common in axSpA patients (18.4% vs 11.6% and 11.0% vs 5.3.%, respectively; P < 0.001). The axSpA patients with intra-articular joint form variants had 2-fold higher odds of exhibiting erosions [odds ratio (OR) 2.09 (95% CI 1.18, 3.69)] and BMO [OR 1.79 (95% CI 1.13, 2.82)]; this association was not observed in controls. Accessory joints increased the odds for sclerosis in axSpA patients [OR 2.54 (95% CI 1.10, 5.84)] and for sclerosis [OR 17.91 (95% CI 6.92, 46.37)] and BMO [OR 2.05 (95% CI 1.03, 4.07)] in controls. CONCLUSIONS: Joint form variations are associated with the presence of inflammatory lesions on SI joint MRIs of axSpA patients. This should be taken into consideration in future research on the interplay of mechanical strain and inflammation in axSpA.

Self-reported diagnostic confidence predicts diagnostic accuracy in axial spondyloarthritis imaging.

OBJECTIVES: Reporting diagnostic confidence (DC) in axial spondyloarthritis (axSpA) imaging is recommended by the ASAS guidelines. Our aim was to investigate whether self-reported DC predicts diagnostic accuracy in axSpA imaging using X-ray (XR), computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: We performed a post hoc analysis including 163 patients with low back pain (89 axSpA and 56 non-axSpA). Nine blinded readers with different experience levels (inexperienced (< 1 year), semi-experienced (3-8 years) and experienced (> 12 years)) scored the sacroiliac joint images for compatibility with axSpA. DC was reported on a scale from 1 (not sure) to 10 (very sure). Mean DC scores and standard deviations were calculated for correct and incorrect responses using XR, CT, MRI, XR+MRI and CT+MRI. Differences in DC were assessed using the Mann-Whitney U test. RESULTS: DC scores were higher for correct axSpA diagnoses and differed significantly between correct and incorrect responses for all modalities (p< 0.001), with a mean DC of 7.1 ± 2.1 and 6.3 ± 2.1 for XR, 8.3 ± 1.8 and 6.7 ± 2.0 for CT, 8.1 ± 1.9 and 6.2 ± 1.9 for MRI, 8.2 ± 1.8 and 6.7 ± 1.8 for XR+MRI and 8.4 ± 1.8 and 6.8 ± 1.8 for CT+MRI, respectively. This was also the case when looking at the results by experience group, except for XR in the inexperienced group. CONCLUSION: Providing self-reported DC in radiological reports is useful information to predict diagnostic reliability in axSpA imaging.

Deep Learning Detects Changes Indicative of Axial Spondyloarthritis at MRI of Sacroiliac Joints.

Background MRI is frequently used for early diagnosis of axial spondyloarthritis (axSpA). However, evaluation is time-consuming and requires profound expertise because noninflammatory degenerative changes can mimic axSpA, and early signs may therefore be missed. Deep neural networks could function as assistance for axSpA detection. Purpose To create a deep neural network to detect MRI changes in sacroiliac joints indicative of axSpA. Materials and Methods This retrospective multicenter study included MRI examinations of five cohorts of patients with clinical suspicion of axSpA collected at university and community hospitals between January 2006 and September 2020. Data from four cohorts were used as the training set, and data from one cohort as the external test set. Each MRI examination in the training and test sets was scored by six and seven raters, respectively, for inflammatory changes (bone marrow edema, enthesitis) and structural changes (erosions, sclerosis). A deep learning tool to detect changes indicative of axSpA was developed. First, a neural network to homogenize the images, then a classification network were trained. Performance was evaluated with use of area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. P < .05 was considered indicative of statistically significant difference. Results Overall, 593 patients (mean age, 37 years ± 11 [SD]; 302 women) were studied. Inflammatory and structural changes were found in 197 of 477 patients (41%) and 244 of 477 (51%), respectively, in the training set and 25 of 116 patients (22%) and 26 of 116 (22%) in the test set. The AUCs were 0.94 (95% CI: 0.84, 0.97) for all inflammatory changes, 0.88 (95% CI: 0.80, 0.95) for inflammatory changes fulfilling the Assessment of SpondyloArthritis international Society definition, and 0.89 (95% CI: 0.81, 0.96) for structural changes indicative of axSpA. Sensitivity and specificity on the external test set were 22 of 25 patients (88%) and 65 of 91 patients (71%), respectively, for inflammatory changes and 22 of 26 patients (85%) and 70 of 90 patients (78%) for structural changes. Conclusion Deep neural networks can detect inflammatory or structural changes to the sacroiliac joint indicative of axial spondyloarthritis at MRI. © RSNA, 2022 Online supplemental material is available for this article.

Treatment with tumour necrosis factor inhibitors is associated with a time-shifted retardation of radiographic spinal progression in patients with axial spondyloarthritis.

OBJECTIVE: The objective of the current study was to analyse the association between treatment with tumour necrosis factor inhibitors (TNFi) and radiographic spinal progression in patients with axial spondyloarthritis (axSpA) from a long-term inception cohort. METHODS: A total of 243 patients with axSpA from the German Spondyloarthritis Inception Cohort with at least two sets of spinal radiographs obtained at least 2 years apart during a 10-year follow-up were included. Spinal radiographs were evaluated by three trained and calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The association between the current TNFi, previous TNFi and radiographic spinal progression defined as the absolute mSASSS change score over 2 years was analysed using longitudinal generalised estimating equations analysis. RESULTS: TNFi treatment in the current 2-year interval was not associated with retardation of radiographic spinal progression (ß=-0.02 (95% CI -0.37 to 0.34) and -0.17 (95% CI -0.54 to 0.20) for any and ≥12 months treatment duration, respectively, adjusted for sex, the Ankylosing Spondylitis Disease Activity Score, smoking, presence of definite radiographic sacroiliitis, mSASSS at baseline and non-steroidal anti-inflammatory drug intake). TNFi treatment in the previous 2-year interval, was, however, significantly associated with reduction of mSASSS progression, which was especially evident in patients who received TNFi in the previous and in the current intervals: ß=-0.58 (95% CI -1.02 to -0.13), adjusted for the same variables. CONCLUSION: TNFi treatment was associated with a time-shifted effect on radiographic spinal progression in axSpA that became evident between years 2 and 4 after treatment initiation.

Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study.

OBJECTIVES: To evaluate a dermatologist-centred screening tool followed by a structured rheumatological examination including MRI of sacroiliac joints and spine for the recognition of psoriatic arthritis with axial involvement (axPsA). METHODS: This was a prospective multicentre study. Adult patients with a confirmed diagnosis of psoriasis who had chronic back pain (≥3 months), onset <45 years and had not been treated with any biologic or targeted synthetic disease-modifying antirheumatic drug in the 12 weeks before screening were referred to a specialised rheumatology clinic. A rheumatological investigation including clinical, laboratory and genetic assessments as well as imaging with conventional radiography and MRI of sacroiliac joints and spine was performed. The primary outcome of the study was the proportion of patients diagnosed with axPsA among all referred patients with PsO. RESULTS: Rheumatologists examined 100 patients of those who qualified for referral. 14 patients (including 3 with both axial and peripheral involvement) were diagnosed with axPsA and 5 were diagnosed with peripheral PsA solely. All patients diagnosed with axPsA had active inflammatory and/or structural (post)inflammatory changes in the sacroiliac joints and/or spine on imaging. In five patients, MRI changes indicative of axial involvement were found only in the spine. All but one patient with PsA (13/14 with axPsA and 5/5 with pPsA) fulfilled the Classification Criteria for Psoriatic Arthritis criteria for PsA. The Assessment of SpondyloArthritis International Society criteria for axSpA were fulfilled in 9 (64.3%) patients diagnosed with axPsA. CONCLUSIONS: Applying a dermatologist-centred screening tool may be useful for the early detection of axPsA in at-risk patients with psoriasis .

Antigen-specific immune reactions by expanded CD8+ T cell clones from HLA-B*27-positive patients with spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disease that is tightly linked to HLA-B*27 but the pathophysiological basis of this link is still unknown. It is discussed whether either the instability of HLA-B*27 molecules triggers predominantly innate immune reactions or yet unknown antigenic peptides presented by HLA-B*27 induce adaptive autoimmune reactions by CD8+ T cells. To analyze the pathogenesis of SpA, we here investigated the T cell receptor (TCR) usage and whole transcriptomes of CD8+ single cells from synovial fluid of HLA-B*27-positive SpA patients and HLA-B*27-negative controls. In HLA-B*27-positive patients, we confirmed preferential expression of several TCR ß-chain families, found even more restricted usage of particular TCR α-chains, assigned matching TCR αß-chain pairs with homologous CDR3-sequences, and detected identical TCR-chains in different patients. Gene expression analyses by single cell mRNAseq revealed that genes specific for the tissue resident memory phenotype, exhaustion, and apoptosis were particularly highly expressed in expanded clonotypes from HLA-B*27-positive SpA patients. Together, several independent lines of evidence argue in favor of an (auto)antigenic peptide related pathogenesis.

The impact of psoriasis on the clinical characteristics, disease burden and treatment patterns of peripheral spondyloarthritis.

OBJECTIVES: To evaluate the clinical characteristics, disease burden, and treatment patterns of peripheral spondyloarthritis (pSpA) patients with and without psoriasis using data from the ASAS-perSpA study. METHODS: We included 433 patients who had a diagnosis of pSpA according to the rheumatologist's diagnosis from the ASAS-PerSpA study. The presence of a personal history of psoriasis was defined as the presence of signs of psoriasis at physical examination or the presence of psoriatic nail dystrophy, including onycholysis, pitting and hyperkeratosis, or a history of psoriasis diagnosed by a physician. Clinical characteristics, patient-reported outcomes and treatment pattern were compared between subgroups with and without psoriasis. RESULTS: A total of 83 patients (19.2%) had a personal history of psoriasis. Patients with psoriasis were older (48.4 vs 43.2 years) and had a longer diagnostic delay (7.4 vs 3.5 years), a higher frequency of dactylitis (36.1 vs 20.0%) and enthesitis (65.1 vs 55.4%) than patients without psoriasis. A longer diagnostic delay (odds ratio [OR] = 1.06 [95% CI 1.01, 1.11]), lower odds for HLA-B27 positivity (OR = 0.31 [95% CI 0.15, 0.65]) and higher odds for enthesitis (OR = 2.39 [95% CI 1.16, 4.93]) were associated with the presence of psoriasis in a multivariable regression analysis. While patient-reported outcomes were comparable between groups, a higher use of biologic DMARDs was observed in patients with vs without psoriasis. CONCLUSION: The presence of psoriasis has an impact on clinical characteristics of pSpA. pSpA patients without psoriasis were less frequently treated with biologic DMARDs despite similar disease burden as compared with patients with psoriasis.

Elucidating the role of a positive family history in differentiating between axial and peripheral spondyloarthritis: an ancillary analysis of the ASAS-PerSpA study.

OBJECTIVES: Positive family history (PFH) of spondyloarthritis (SpA) is important in the diagnosis of SpA. However, the contribution of a PFH in differentiating the two SpA subtypes (axial and peripheral spondyloarthritis (pSpA)), in particular the importance of second-degree relative (SDR) has not been well-studied. We aimed to investigate whether PFH of radiographic axial spondyloarthritis (r-axSpA), psoriasis, uveitis, reactive arthritis and inflammatory bowel disease in first-degree relative (FDR) and second-degree relative (SDR) contributes to differentiation between axSpA and pSpA using the data from a multinational cohort study. METHODS: The ASAS-PerSpA study dataset was used to assess the effects of a PFH on differentiating between axSpA and pSpA via generalised structural equation modelling. Model building using backward selection was performed to obtain a final model. Direct, indirect and total effects of the path analysis were calculated. RESULTS: A total of 3803 patients were included: 2458 axSpA and 1345 pSpA patients. FDR (OR: 3.75, 95% CI: 2.86-4.91, p<0.001) and SDR (OR: 4.58, 95% CI: 3.19-6.59, p<0.001) with r-axSpA were positively associated while FDR (OR: 0.262, 95% CI: 0.207-0.331, p<0.001) and SDR (OR: 0.305, 95% CI: 0.221-0.420, p<0.001) with psoriasis were negatively associated with differentiating patients with axSpA from pSpA. CONCLUSIONS: The presence of r-axSpA and psoriasis in FDR or SDR are useful in differentiating axSpA from pSpA. SDR with r-axSpA may contribute greater towards the differentiation than FDR. Clinicians should consider taking an extensive family history of SpA and their subtypes to better differentiate the subtypes within the SpA spectrum.

Clinical characteristics of patients with spondyloarthritis and inflammatory bowel disease versus inflammatory bowel disease-related arthritis.

The purpose of this study was to clarify the clinical characteristics of spondyloarthritis (SpA) patients with inflammatory bowel disease (IBD) compared to those without IBD. Furthermore, among patients with SpA and IBD, we aimed to clarify what clinical characteristics lead rheumatologists to diagnose "IBD-related arthritis." Utilizing SpA and psoriatic arthritis (PsA) patients' data from an international, cross-sectional, observational study, we analyzed information on demographics and disease characteristics, dichotomizing patients by IBD status. The presence or absence of IBD was determined based on data collection of treating rheumatologists. Patients with SpA (including PsA) and IBD were also categorized based on treating rheumatologists' definitive diagnosis in regard to SpA type, and compared by whether the patients had IBD-related arthritis or not. Among 4465 SpA patients, 287 (6.4%, 95%CI 5.7-7.2%) were identified with IBD. Compared to SpA patients without IBD, patients with SpA and IBD had a longer diagnostic delay (5.1 vs. 2.9 years, p < 0.001). In patients with SpA and IBD, 111 (38.7%, 95%CI 33.0-44.6%) were diagnosed with IBD-related arthritis. Multivariable analyses showed that HLA-B27 positivity [OR = 0.35, (95%CI 0.15-0.80)], psoriasis [OR = 0.14, (95%CI 0.04-0.50)], IBD as first symptom of SpA [OR = 3.32, (95%CI 1.84-6.01)], and need for IBD-specific treatment [OR = 5.41, (95%CI 2.02-14.50)] were independently associated with the definitive diagnosis of IBD-related arthritis. Collaboration with gastroenterologists is needed to shorten the diagnostic delay in patients with SpA and IBD. The recognition of the factors for the diagnosis of "IBD-related arthritis" may lead to the elucidation of the pathogenesis.

Assessment of radiographic sacroiliitis in anteroposterior lumbar vs conventional pelvic radiographs in axial spondyloarthritis.

OBJECTIVE: The aim was to investigate the reliability and validity of radiographic sacroiliitis assessment in anteroposterior (AP) lumbar radiographs compared with conventional pelvic radiographs in patients with axial spondyloarthritis (axSpA). METHODS: Patients from the German Spondyloarthritis Inception Cohort were selected based on the availability of pelvic and AP lumbar radiographs with visible SI joints at baseline and year 2. Two readers scored the images independently in a random order according to the modified New York criteria. The sacroiliitis sum score was calculated as the mean of both readers. Patients were classified as radiographic (r-)axSpA if radiographic sacroiliitis of grade ≥2 bilaterally or grade ≥3 unilaterally was present in the opinion of both readers and as non-radiographic (nr-)axSpA otherwise. The reliability and validity of sacroiliitis assessment in AP lumbar radiographs was assessed using intraclass correlation coefficients (ICCs), absolute agreement and κ statistics. RESULTS: A total of 226 sets of radiographs were scored from 113 patients included in the study. The ICC for the sacroiliitis sum score was 0.91 at both baseline and year 2. A total of 62 (54.9%) and 55 (48.7%) patients were classified as r-axSpA at baseline and 65 (57.5%) and 60 (53.1%) patients at year 2 based on evaluation of pelvic and AP lumbar radiographs, respectively. The absolute agreement between the methods on the classification was 84.9 and 85.0% at baseline and year 2, respectively, with the κ of 0.70 at both time points. CONCLUSION: Radiographic sacroiliitis can be assessed in AP lumbar radiographs with a similar reliability to conventional pelvic radiographs.

Diagnosing axial spondyloarthritis: estimation of the disease probability in patients with a priori different likelihoods of the diagnosis.

OBJECTIVE: To evaluate the diagnostic value of SpA parameters and their combination for the diagnosis of axial SpA in patients with an a priori different probability of the diagnosis. METHODS: A total of 361 patients with chronic back pain and suspicion of axial SpA (181 referred by primary care physicians or orthopaedists, 180 recruited via an online screening tool) received a structured rheumatologic examination, which resulted into a diagnosis or exclusion of axial SpA. The prevalence of axial SpA indicating the pre-test probability was 40% in the physician-referred subgroup and 20% in the online screening subgroup. Sensitivities, specificities and likelihood ratios for SpA features were determined in both subgroups and the respective post-test probabilities of axial SpA were calculated. RESULTS: The relative diagnostic value of single SpA features varied substantially between the groups with different referral pathways. For instance, HLA-B27 positivity increased the probability of the presence of axial SpA by 35% to 55% in online-screened patients and by 22% to 62% in physician-referred patients. The absence of HLA-B27 resulted in a sharp decrease in the probability of the presence of axial SpA in physician-referred patients (from 40% to 6%). This decrease was less sharp in the online screening group (from 20% to 10%). These differences were especially relevant in patients with a small number (one to two) of positive SpA features. CONCLUSION: The diagnostic value of SpA features varies in different patient populations, which should be considered in the diagnostic approach.

Role of mitochondria in the differential action of sodium deoxycholate and ursodeoxycholic acid on rat duodenum.

Sodium deoxycholate (NaDOC) inhibits the intestinal Ca2+ absorption and ursodeoxycholic acid (UDCA) stimulates it. The aim of this study was to determine whether NaDOC and UDCA produce differential effects on the redox state of duodenal mitochondria altering the Krebs cycle and the electron transport chain (ETC) functioning, which could lead to perturbations in the mitochondrial dynamics and biogenesis. Rat intestinal mitochondria were isolated from untreated and treated animals with either NaDOC, UDCA, or both. Krebs cycle enzymes, ETC components, ATP synthase, and mitochondrial dynamics and biogenesis markers were determined. NaDOC decreased isocitrate dehydrogenase (ICDH) and malate dehydrogenase activities affecting the ETC and ATP synthesis. NaDOC also induced oxidative stress and increased the superoxide dismutase activity and impaired the mitochondrial biogenesis and functionality. UDCA increased the activities of ICDH and complex II of ETC. The combination of both bile acids conserved the functional activities of Krebs cycle enzymes, ETC components, oxidative phosphorylation, and mitochondrial biogenesis. In conclusion, the inhibitory effect of NaDOC on intestinal Ca2+ absorption is mediated by mitochondrial dysfunction, which is avoided by UDCA. The stimulatory effect of UDCA alone is associated with amelioration of mitochondrial functioning. This knowledge could improve treatment of diseases that affect the intestinal Ca2+ absorption.

Prediction of acute neurovascular syndromes with prehospital clinical features witnessed by bystanders.

BACKGROUND: The prompt recognition of an acute neurovascular syndrome by the patient or a bystander witnessing the event can directly influence outcome. We aimed to study the predictive value of the medical history and clinical features recognized by the patients' bystanders to preclassify acute stroke syndromes in prehospital settings. METHODS: We analyzed 369 patients: 209 (56.6%) with acute ischemic stroke (AIS), 107 (29.0%) with intracerebral hemorrhage (ICH), and 53 (14.4%) with subarachnoid hemorrhage (SAH). All patients had neuroimaging as diagnostic gold standard. We constructed clinical prediction rules (CPRs) with features recognized by the bystanders witnessing the stroke onset to classify the acute neurovascular syndromes before final arrival to the emergency room (ER). RESULTS: In all, 83.2% cases were referred from other centers, and only 16.8% (17.2% in AIS, 15% in ICH, and 18.9% in SAH) had direct ER arrival. The time to first assessment in ≤ 3 h occurred in 72.4% (73.7%, 73.8%, and 64.2%, respectively), and final ER arrival in ≤ 3 h occurred in 26.8% (32.1%, 15.9%, and 28.3%, respectively). Clinical features referred by witnesses had low positive predictive values (PPVs) for stroke type prediction. Language or speech disorder + focal motor deficit showed 63.3% PPV, and 77.0% negative predictive value (NPV) for predicting AIS. Focal motor deficit + history of hypertension had 35.9% PPV and 78.8% NPV for ICH. Headache alone had 27.9% PPV and 95.3% NPV for SAH. In multivariate analyses, seizures, focal motor deficit, and hypertension increased the probability of a time to first assessment in ≤ 3 h, while obesity was inversely associated. Final ER arrival was determined by age and a direct ER arrival without previous referrals. CONCLUSION: CPRs constructed with the witnesses' narrative had only adequate NPVs in the prehospital classification of acute neurovascular syndromes, before neuroimaging confirmation.

Clinical and imaging characteristics of osteitis condensans ilii as compared with axial spondyloarthritis.

OBJECTIVES: Osteitis condensans ilii (OCI) has become an important differential diagnosis for axial spondyloarthritis (axSpA). The objective of this matched case-control study was to investigate demographic, clinical, laboratory and MRI characteristics of OCI as compared with axial spondyloarthritis (axSpA). METHODS: A total of 60 patients diagnosed with OCI were included in the final analysis. From 27 of these patients, MRIs of the sacroiliac joints were available. OCI patients were matched with a 1:1 ratio by back pain duration to patients with definite axSpA in order to compare clinical, laboratory and MRI characteristics. RESULTS: The OCI patients were nearly all females (96.7 vs 46.7%), had a significantly lower prevalence of inflammatory back pain (39.5 vs 88.9%), a significantly lower percentage of HLA-B27 positives (35.2 vs 80.0%) and a lower prevalence of the majority of other SpA features as compared with axSpA patients. Interestingly, there was no difference in the prevalence of osteitis in the sacroiliac joints (92.6 vs 85.2% in OCI and axSpA, respectively, P = 0.44), but there was a difference in the prevalence of erosions (7.4 vs 66.7%, respectively, P = 0.0001). In addition, in OCI nearly all lesions were localized in the anterior part of the sacroiliac joints while in axSpA lesions were localized predominantly in the middle part of the joint (for osteitis: 96 vs 4% in OCI and 28.6 vs 71.4% in axSpA; P = 0.0002 for the inter-group difference). CONCLUSION: Clinical and imaging features of OCI compared with axSpA are described that should help in differential diagnosis.

Combined treatment of menadione and calcitriol increases the antiproliferative effect by promoting oxidative/nitrosative stress, mitochondrial dysfunction, and autophagy in breast cancer MCF-7 cells.

The aim of this study was to determine new insights into the molecular mechanisms involved in the antiproliferative action of menadione + calcitriol (MEN+D) on MCF-7 cells. After 24 h, MEN+D inhibited the cell growth but was not observed with each single treatment. The combined drugs reduced the mitochondrial respiration at that time, as judged by an increase in the proton leak and a decrease in the ATP generation and coupling efficiency. At longer times, 48 or 96 h, either D or MEN reduced the proliferation, but the effect was higher when both drugs were used together. The combined treatment increased the superoxide anion ([Formula: see text]) and nitric oxide (NO•) contents as well as acidic vesicular organelles (AVOs) formation. The percentage of cells showing the lower mitochondrial membrane potential (ΔΨm) was highly increased by the combined therapy. LC3-II protein expression was enhanced by any treatment. In conclusion, the antiproliferative action of MEN+D involves oxidative/nitrosative stress, mitochondrial alteration, and autophagy. This combined therapy could be useful to treat breast cancer cells because it inhibits multiple oncogenic pathways more effectively than each single agent.

Relation of α2-Antiplasmin Genotype and Genetic Determinants of Fibrinogen Synthesis and Fibrin Clot Formation with Vascular Endothelial Growth Factor Level in Axial Spondyloarthritis.

OBJECTIVE: Coagulation and fibrinolysis are interrelated with the expression of vascular endothelial growth factor (VEGF), which frequently is increased in axial spondyloarthritis (axSpA). We tested whether (i) α2-antiplasmin (A2AP) Arg6Trp, (ii) fibrinogen, factor XIII A-subunit or B-subunit genotypes are associated with VEGF levels and assessed whether the known association between elevated VEGF and radiographic spinal progression in axSpA depends on genetic background. METHODS: One hundred and eighty-six axSpA patients from the German Spondyloarthritis Inception Cohort were genotyped, characterized for VEGF levels, and statistically analyzed. The association between VEGF and radiographic spinal progression was assessed in dependence on genetic background in stratified analyses. RESULTS: A2AP 6Trp carriage was associated with VEGF elevation (OR: 2.37, 95% CI: 1.06-5.29) and VEGF levels (6Trp, 455 ± 334 pg/mL; 6Arg/Arg, 373 ± 293 pg/mL; p < 0.008). Association between elevated VEGF and radiographic spinal progression in axSpA (OR: 3.11, 95% CI: 1.02-8.82) depended remarkably on the fibrinogen (FGA) genotype. When considering axSpA patients with elevated VEGF, in FGA rs6050A>G wild types, 42.1% of patients (8 of 19) progressed, while in G-allele carriers, no radiographic progression happened (0 of 13) (p < 0.04). CONCLUSIONS: The A2AP Arg6Trp genotype seems to influence VEGF levels in axSpA. The predictive value of VEGF elevations in respect of radiographic spinal progression in axSpA depends on FGA genotypes.