Integrating Spatial and Morphological Characteristics into Melanoma Prognosis: A Computational Approach.

In this study, the prognostic value of cellular morphology and spatial configurations in melanoma has been examined, aiming to complement traditional prognostic indicators like mitotic activity and tumor thickness. Through a computational pipeline using machine learning and deep learning methods, we quantified nuclei sizes within different spatial regions and analyzed their prognostic significance using univariate and multivariate Cox models. Nuclei sizes in the invasive band demonstrated a significant hazard ratio (HR) of 1.1 (95% CI: 1.03, 1.18). Similarly, the nuclei sizes of tumor cells and Ki67 S100 co-positive cells in the invasive band achieved HRs of 1.07 (95% CI: 1.02, 1.13) and 1.09 (95% CI: 1.04, 1.16), respectively. Our findings reveal that nuclei sizes, particularly in the invasive band, are potentially prognostic factors. Correlation analyses further demonstrated a meaningful relationship between cellular morphology and tumor progression, notably showing that nuclei size within the invasive band correlates substantially with tumor thickness. These results suggest the potential of integrating spatial and morphological analyses into melanoma prognostication.

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.

Exploring complement biomarkers in suspected axial spondyloarthritis.

OBJECTIVES: To investigate lectin pathway proteins (LPPs) as biomarkers for axial spondyloarthritis (axSpA) in a cross-sectional cohort with a suspicion of axSpA, comprising newly diagnosed axSpA and chronic low back pain (cLBP) individuals. METHODS: Serum samples from 515 participants within the OptiRef cohort, including 151 axSpA patients and 364 cLBP patients, were measured using immunoassays for LPPs (mannan-binding lectin (MBL), collectin liver-1 (CL-L1), M-ficolin, H-ficolin and L-ficolin, MBL-associated serine proteases (MASP)-1, -2 and -3, MBL-associated proteins (MAp19 and MAp44) and the complement activation product C3dg). RESULTS: Serum levels of L-ficolin, MASP-2 and C3dg were elevated in axSpA patients, whereas levels of MASP-3 and CL-L1 were decreased, and this remained significant for C3dg and MASP-3 after adjustment for C reactive protein (CRP). A univariate regression analysis showed serum levels of CL-L1, MASP-2, MASP-3 and C3dg to predict the diagnosis of axSpA, and MASP-3 and C3dg remained significant in a multivariate logistic regression analysis. Assessment of the diagnostic potential showed that a combination of human leukocyte antigen B27 (HLA-B27) and measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, however, with a concomitant loss of sensitivity. CONCLUSIONS: Serum levels of complement activation, that is, C3dg, and MASP-3 differed significantly between axSpA and cLBP patients after adjustment for CRP. Although combining HLA-B27 with measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, this seems unjustified due to the concomitant loss of sensitivity. However, both C3dg and MASP-3 were associated with axSpA diagnosis in multivariate logistic regression, suggesting an involvement of complement in the inflammatory processes and possibly pathogenesis in axSpA.

Comparing clinical profiles in spondyloarthritis with Crohn's disease or ulcerative colitis: insights from the ASAS-PerSpA study.

Objectives: Assuming SpA manifestations may vary among patients with different inflammatory bowel disease (IBD) subtypes, we explored the clinical characteristics associated with the presence of Crohn's disease (CD) or ulcerative colitis (UC) in patients with spondyloarthritis (SpA). Methods: We included 3152 patients of ASAS-PerSpA study diagnosed with either axial SpA or peripheral SpA, according to their treating rheumatologist. Of these, 146 (4.6%) had confirmed IBD by endoscopy and were categorized into CD or UC groups. Demographics, clinical characteristics, treatments and patient-reported outcomes were compared between the two subgroups. Results: From 146 patients included in the current analysis, 87 (59.6%) had CD [75 (86.2%) axial SpA and 12 (13.8%) peripheral SpA], and 39 (26.7%) had UC [34 (87.2%) axial SpA and 5 (12.8%) peripheral SpA]. CD and UC groups had similar age with average of 44.9 (13.5) vs 44.0 (13.0) years, respectively, and a slight male predominance in CD (63.2%) compared with UC (51.3%). Diagnostic delay for SpA was 7.0 (6.9) years for CD and 8.8 (8.1) years for UC. Chronic back pain was the most reported symptom present in 95.4% of CD patients and 89.7% of UC patients. Both groups had similar musculoskeletal phenotyping, with higher frequency of psoriasis (15.4%) and uveitis 28.2% in UC; and higher tendency to be HLA-B27 positive in CD (51.9% in CD vs.s 39.4% in UC). Conclusion: In our analysis patients with SpA and concurrent CD or UC had mainly similar musculoskeletal phenotypes. However, they differ slightly in extra-musculoskeletal manifestations and HLA-B27 prevalence.

Diagnostic accuracy in axial spondyloarthritis: a systematic evaluation of the role of clinical information in the interpretation of sacroiliac joint imaging.

OBJECTIVES: Radiography and MRI of the sacroiliac joints (SIJ) are relevant for the diagnosis and classification of patients with axial spondyloarthritis (axSpA). This study aimed to evaluate the impact of clinical information (CI) on the accuracy of imaging interpretation. METHODS: Out of 109 patients referred because of suspicion of axSpA with complete imaging sets (radiographs and MRI of SIJ), 61 were diagnosed with axSpA (56%). Images were independently evaluated by three radiologists in four consecutive reading campaigns: radiographs and radiographs+MRI without and with CI including demographic data, SpA features, physical activity and pregnancy. Radiographs were scored according to the modified New York criteria, and MRIs for inflammatory and structural changes compatible with axSpA (yes/no). The clinical diagnosis was taken as reference standard. The compatibility of imaging findings with a diagnosis of axSpA (precision) before and after the provision of CI and radiologists' confidence with their findings (0-10) were evaluated. RESULTS: The precision of radiographs evaluation without versus with CI increased from 70% to 78% (p=0.008), and for radiographs+MRI from 81% to 82% (p=1.0), respectively. For CR alone, the sensitivity and specificity of radiologic findings were 51% and 94% without and 60% and 100% with CI, while, for radiographs+MRI, they were 74% and 90% vs 71% and 98%, respectively. The diagnostic confidence of radiologists increased from 5.2±1.9 to 6.0±1.7 with CI for radiographs, and from 6.7±1.6 to 7.2±1.6 for radiographs+MRI, respectively. CONCLUSION: The precision, specificity and diagnostic confidence of radiologic evaluation increased when CI was provided.

Learning imaging in axial spondyloarthritis: more than just a matter of experience.

OBJECTIVE: Reliable interpretation of imaging findings is essential for the diagnosis of axial spondyloarthritis (axSpA) and requires a high level of experience. We investigated experience-dependent differences in diagnostic accuracies using X-ray (XR), MRI and CT. METHODS: This post hoc analysis included 163 subjects with low back pain. Eighty-nine patients had axSpA, and 74 patients had other conditions (mechanical, degenerative or non-specific low back pain). Final diagnoses were established by an experienced rheumatologist before the reading sessions. Nine blinded readers (divided into three groups with different levels of experience) scored the XR, CT and MRI of the sacroiliac joints for the presence versus absence of axSpA. Parameters for diagnostic performance were calculated using contingency tables. Differences in diagnostic performance between the reader groups were assessed using the McNemar test. Inter-rater reliability was assessed using Fleiss kappa. RESULTS: Diagnostic performance was highest for the most experienced reader group, except for XR. In the inexperienced and semi-experienced group, diagnostic performance was highest for CT&MRI (78.5% and 85.3%, respectively). In the experienced group, MRI showed the highest performance (85.9%). The greatest difference in diagnostic performance was found for MRI between the inexperienced and experienced group (76.1% vs 85.9%, p=0.001). Inter-rater agreement was best for CT in the experienced group with κ=0.87. CONCLUSION: Differences exist in the learnability of the imaging modalities for axSpA diagnosis. MRI requires more experience, while CT is more suitable for inexperienced radiologists. However, diagnosis relies on both clinical and imaging information.

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.

Association of nociplastic and neuropathic pain components with the presence of residual symptoms in patients with axial spondyloarthritis receiving biological disease-modifying antirheumatic drugs.

OBJECTIVE: To evaluate the association of nociplastic (NoP) and neuropathic pain (NP) components with residual symptoms in patients with radiographic axial spondyloarthritis (r-axSpA) receiving biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: 78 patients with r-axSpA from the GErman SPondyloarthritis Inception Cohort receiving a bDMARD for at least 3 months were included in this analysis. The Widespread Pain Index (WPI) and the PainDETECT (PD) questionnaire were used to quantify the NoP and the NP components, respectively. Axial Spondyloarthritis Disease Activity Score (ASDAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were used as measures of residual symptoms. C reactive protein (CRP) was used as a measure of systemic inflammatory activity. Univariable and multivariable regression analyses of disease activity were performed. The regions of the WPI score and items of the PD score were used for cluster analyses. RESULTS: Linear multivariable regression analysis showed that WPI and PD were independently associated with ASDAS (b=0.1, 95% CI 0.04 to 0.17, and b=0.05, 95% CI 0.02 to 0.08, respectively) and BASDAI (b=0.24, 95% CI 0.08 to 0.39, and b=0.17, 95% CI 0.1 to 0.25, respectively) in r-axSpA patients receiving stable treatment with bDMARDs. Furthermore, WPI and PD were found to be significantly associated with the presence of relevant residual symptoms as defined by BASDAI ≥4 (OR 1.93, 95% CI 1.09 to 4.15, and OR 1.32, 95% CI 1.04 to 1.85, respectively). The effects were present also in patients with normal level of CRP. Cluster analysis revealed three distinct pain distribution profiles and four specific sensory symptom constellations allowing differentiation of different pain subtypes. CONCLUSION: Both NoP and NP components seem to be associated with residual symptoms in patients with r-axSpA receiving treatment with bDMARDs.

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.

Shared and Distinct Gut Microbiota in Spondyloarthritis, Acute Anterior Uveitis, and Crohn's Disease.

OBJECTIVE: Spondyloarthritis (SpA) is a group of immune-mediated diseases highly concomitant with nonmusculoskeletal inflammatory disorders, such as acute anterior uveitis (AAU) and Crohn's disease (CD). The gut microbiome represents a promising avenue to elucidate shared and distinct underlying pathophysiology. METHODS: We performed 16S ribosomal RNA sequencing on stool samples of 277 patients (72 CD, 103 AAU, and 102 SpA) included in the German Spondyloarthritis Inception Cohort and 62 back pain controls without any inflammatory disorder. Discriminatory statistical methods were used to disentangle microbial disease signals from one another and a wide range of potential confounders. Patients were naive to or had not received treatment with biological disease-modifying antirheumatic drugs (DMARDs) for >3 months before enrollment, providing a better approximation of a true baseline disease signal. RESULTS: We identified a shared, immune-mediated disease signal represented by low abundances of Lachnospiraceae taxa relative to controls, most notably Fusicatenibacter, which was most abundant in controls receiving nonsteroidal antiinflammatory drug monotherapy and implied to partially mediate higher serum C-reactive protein. Patients with SpA showed an enrichment of Collinsella, whereas human leukocyte antigen (HLA)-B27+ individuals displayed enriched Faecalibacterium. CD patients had higher abundances of a Ruminococcus taxon, and previous conventional/synthetic DMARD therapy was associated with increased Akkermansia. CONCLUSION: Our work supports the existence of a common gut dysbiosis in SpA and related inflammatory pathologies. We reveal shared and disease-specific microbial associations and suggest potential mediators of disease activity. Validation studies are needed to clarify the role of Fusicatenibacter in gut-joint inflammation, and metagenomic resolution is needed to understand the relationship between Faecalibacterium commensals and HLA-B27.

The combined treatment of insulin and naringin improves bone properties in rats with type 1 diabetes mellitus.

We have studied the effects of individual and combined treatment of insulin (I) and naringin (NAR) on the bone structure and biomechanical properties of femurs from streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups: (1) controls, (2) STZ-induced diabetic rats, (3) STZ-induced diabetic rats treated with I, (4) STZ-induced diabetic rats treated with NAR, and (5) STZ-induced diabetic rats treated with I + NAR. Bone mineral density (BMD), bone histomorphometry, biomechanical testing, and bone biomarker expressions were accomplished in femur of all animals, as well as serum biochemical analyses. The combined treatment of I + NAR increased the body weight and the femur BMD from STZ-induced diabetic rats. The bone biomechanical properties and the bone morphology of the femurs from STZ-induced diabetic rats were also improved by the combined treatment. The increased number of osteoclasts in STZ-induced diabetic rats was partially prevented by I, NAR, or I + NAR. NAR or I + NAR completely blocked the decrease in the number of osteocalcin (+) cells in the femur from STZ-induced diabetic rats. RUNX family transcription factor 2 immunostaining was much lower in STZ-induced diabetic rats than in control animals; the combination of I + NAR totally blocked this effect. The combined treatment not only ameliorated bone quality and function, but also normalized the variables related to glucose metabolism. Therefore, the combination of I + NAR might be a better therapeutic strategy than the individual I or NAR administration to reduce bone complications in diabetic patients.

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.

HLA-B27 status and inflammatory MRI lesions of the sacroiliac joints: a post hoc analysis in patients without axial spondyloarthritis.

OBJECTIVE: The assessment of inflammatory and structural lesions in the sacroiliac joint (SIJ) is crucial in axial spondyloarthritis (axSpA). HLA-B27 status plays an important role in axSpA diagnosis and has been linked to MRI lesion burden in the general population. We aimed to investigate the sex-specific influence of HLA-B27 status on inflammatory and structural MRI findings in patients with low back pain of non-inflammatory origin. METHODS: This post hoc analysis included 139 non-axSpA patients (90 women) with chronic low back pain. Two readers scored MRIs of the SIJ for the presence of sclerosis, erosion, fat metaplasia, bone marrow oedema (BMO) and ankylosis. Frequencies and extent of lesions were compared regarding the HLA-B27 status using χ2 tests and t-tests. Regression models to assess the sex-dependent influence of HLA-B27 on lesion burden were computed. RESULTS: HLA-B27 was positive in 33 women (36.7%) and 23 men (46.9%). The overall occurrence of all SIJ lesions did not differ in HLA-B27 negative and positive individuals. There were no significant differences in the extent of lesions considering the HLA-B27 positivity, for erosion (mean sum score (MSS) of 0.91 vs 0.48; p=0.144), sclerosis (MSS 1.65 vs 1.88; p=0.576), fat metaplasia (MSS 0.56 vs 0.27; p=0.425), BMO (MSS 0.75 vs 0.59; p=0.460) and ankylosis (MSS 0.06 vs 0.04; p=0.659). CONCLUSION: HLA-B27 status has no significant influence on the occurrence and extent of SIJ lesions in patients with low back pain of non-inflammatory origin in either men or women.

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.

Papel de la plasticidad celular en la regeneración intestinalinducida por lesiones / Role of cell plasticity in injury-induced intestinal regeneration

El sistema intestinal posee una capacidad regenerativa intrínseca y fisiológica que tiene lugar a partir de las células madreLgr5+ ubicadas en el fondo de las criptas intestinales, las cuales se diferencian hacia las células progenitoras secretoras y absortivas con sus respectivas células especializadas mediante la activación de señalizaciones intracelulares como Wnt, Hippo y Notch. Condiciones adversas como lesiones e infecciones tisulares inducen esta actividad regenerativa promovida por variados mecanismos que influyen en el microambiente celular. El sistema inmunológico detecta alteraciones en el tejido intestinal y, a través de la activación de células inmunocompetentes y la secreción de citoquinas proinflamatorias, favorece la desdiferenciación de células especializadas hacia células madre para desencadenar la respuesta regenerativa. En cuanto al sistema nervioso entérico, su influencia está sujeta a modificaciones en la microbiota y los hábitos alimenticios, y se encuentra determinada en gran parte, por las células gliales entéricas y la expresión de distintos marcadores de plasticidad, que permiten limitar la lesión y reparar el tejido. Por su parte, la epigenéticamodifica la expresión genética y consecuentemente, la capacidadregenerativa intestinal, variando de acuerdo a cada paciente porla influencia de factores externos como la dieta o el estadopsicobiológico. De esta forma, la respuesta regenerativa intestinalinducida por lesiones, integra múltiples mecanismos y poseeimportantes repercusiones clínicas en cuanto a EII, disbiosise incluso tumorogénesis; conocer los mecanismos que regulanesta actividad puede sentar las bases para la creación de terapias innovadoras en el mismo ámbito(AU)

The intestinal system has an intrinsic and physiological regenerative capacity that takes place from the Lgr5+ stem cells located at the bottom of the intestinal crypts, which differentiate into secretory and absorptive progenitor cells with their specialized cells by activating intracellular signalslike Wnt, Hippo and Notch. Adverse conditions such asinjuries and tissue infections induce this regenerative activity promoted by various mechanisms that influence the cellular microenvironment. The immune system senses disturbances in the intestinal tissue and, through the activation of immunocompetent cells and the secretion of proinflammatorycytokines, favors the dedifferentiation of specialized cells intostem cells to trigger the regenerative response. Regarding theenteric nervous system, its influence is subject to modificationsin the microbiota and dietary habits, and is largely determinedby enteric glial cells and the expression of different plasticitymarkers, which enable to limit injuries and repair tissue. On the other hand, epigenetics modifies genetic expressionand, consequently, intestinal regenerative capacity, varying according to each patient due to the influence of external factors such as diet or psychobiological status. There fore, the intestinal regenerative response induced by lesions integrates multiple mechanisms and has important clinical repercussions in terms of IBD, dysbiosis, and even tumorigenesis; knowing themechanisms that regulate this activity can lay the foundations for the creation of innovative therapies in the same field (AU)

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.

Keep an Eye on the Back: Spondyloarthritis in Patients With Acute Anterior Uveitis.

OBJECTIVES: This study was undertaken to analyze the prevalence of spondyloarthritis (SpA) in patients with acute anterior uveitis (AAU), to identify parameters associated with the presence of SpA, and to evaluate the performance of referral algorithms for identifying patients with a high probability of having SpA. METHODS: Prospectively recruited consecutive patients with noninfectious AAU underwent structured rheumatologic assessment including magnetic resonance imaging of the sacroiliac joints, allowing a definitive diagnosis/exclusion of concomitant SpA. Fisher's exact test and Mann-Whitney U test were used to compare AAU patients with SpA and AAU patients without SpA. Furthermore, logistic regression analyses were performed. The predictive performance of SpA referral strategies was analyzed by calculating the sensitivity, specificity, positive predictive value, and positive and negative likelihood ratios. RESULTS: Among the 189 AAU patients evaluated, 106 (56%) were diagnosed as having SpA. The majority of SpA patients (93%) had predominantly axial SpA and 7 patients had peripheral SpA. In 74 patients (70%), the SpA diagnosis was established for the first time. In multivariable logistic regression analysis, psoriasis (odds ratio [OR] 12.5 [95% confidence interval (95% CI) 1.3-120.2]), HLA-B27 positivity (OR 6.3 [95% CI 2.4-16.4]), elevated C-reactive protein level (OR 4.8 [95% CI 1.9-12.4]), and male sex (OR 2.1 [95% CI 1.1-4.2]) were associated with the presence of SpA. None of the ophthalmologic parameters were found to be predictive of SpA. The Dublin Uveitis Evaluation Tool (DUET) showed higher specificity for SpA recognition than the Assessment of SpondyloArthritis international Society (ASAS) tool for the early referral of patients with a suspected diagnosis of axial SpA (specificity for SpA 42% versus 28%), whereas the sensitivity of the ASAS tool was slightly higher than the DUET tool (sensitivity for SpA 80% versus 78%). However, more than 20% of the AAU patients in this study who were diagnosed as having SpA would have been missed by both referral strategies. CONCLUSION: Our study revealed a high prevalence of SpA in AAU patients overall, as well as a high prevalence of previously undiagnosed SpA in AAU patients. Therefore, we propose rheumatologic evaluation for all AAU patients with musculoskeletal symptoms.

Evaluation of the Disease Activity index for PSoriatic Arthritis (DAPSA) with a quick quantitative C reactive protein assay (Q-DAPSA) in patients with psoriatic arthritis: a prospective multicentre cross-sectional study.

OBJECTIVES: This study aimed to evaluate the Disease Activity index for PSoriatic Arthritis (DAPSA) based on a quick quantitative C reactive protein (qCRP) assay (Q-DAPSA) in a multicentre, prospective, cross-sectional study in patients with psoriatic arthritis (PsA). METHODS: The assessment of prospectively recruited study patients included joint examination and patient reported outcome (PRO) measures (patient global assessment, patient pain assessment). Following, the DAPSA based on a routine laboratory CRP measurement, Q-DAPSA and clinical DAPSA (cDAPSA) were calculated. Cross-tabulations and weighted Cohen's kappa were performed to analyse the agreement of disease activity categories. Bland-Altman plots and intraclass correlation coefficients were used to determine the agreement of numerical values regarding CRP and qCRP as well as different disease activity scores. RESULTS: Altogether, 104 patients with PsA could be included in the statistical analysis. With Q-DAPSA, 102 of 104 (98.1%) patients achieved identical disease activity categories in comparison to DAPSA with a weighted Cohen's kappa of 0.980 (95% CI: 0.952 to 1.000). The agreement between DAPSA and cDAPSA was slightly lower with identical disease activity categories seen in 97 of 104 (93.3%) of patients and with a weighted Cohen's kappa of 0.932 (95% CI 0.885 to 0.980). CONCLUSIONS: The Q-DAPSA showed an almost perfect agreement with the conventional DAPSA regarding identical disease activity categories. Thus, the Q-DAPSA can be used as a timely available disease activity score in patients with PsA with the additional benefit of CRP involvement. Consequently, the Q-DAPSA could facilitate the implementation of the treat-to-target concept in clinical routine and clinical trials.

Giant Koenen Tumors as the Presenting and Only Clinical Sign of Tuberous Sclerosis Complex in a 56-Year-Old Man and Its Surgical Management.

Introduction: Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement. Multiple ungual fibromas, also known as Koenen tumors (KTs), are one of the major diagnostic criteria and occur approximately in 50% of patients with TSC. They are disfiguring, painful, and challenging to treat as they frequently recur. There are 2 previous cases in the literature of KTs as the only clinical sign of TSC. Case Presentation: A 56-year-old male patient with intellectual disability presented with a history of ungual growths that had gradually increased in size and number for 20 years. The diagnosis of KTs was established on clinical grounds, without the requirement of histological confirmation. No additional clinical evidence of TSC was found. Complete surgical excision of the tumors located in the proximal nail matrix, periungual folds, and nail bed of each toe was successfully performed. Discussion: The association between KTs and intellectual disability with TSC supported the clinical diagnosis. To date, there is no standard first-line treatment for KTs. Complete surgical excision up to the proximal base of the tumor offers satisfactory results in terms of functionally and esthetic appearance and could be considered the preferred therapeutic modality for patients with severe functional and cosmetic impairment. Prompt recognition of the many signs and symptoms associated with TSC is important to achieve early diagnosis, preventing further complications.