Effect of osteoprotegerin and Dickkopf-related protein 1 on radiological progression in tightly controlled rheumatoid arthritis.

OBJECTIVE: To analyze the association between circulating osteoprotegerin (OPG) and Dickkopf-related protein 1 (DKK-1) and radiological progression in patients with tightly controlled rheumatoid arthritis (RA). METHODS: Serum levels of OPG and DKK-1 were measured in 97 RA patients who were treated according to a treat-to-target strategy (T2T) aimed at remission (DAS28<2.6). Radiologic joint damage progression was assessed by changes in the total Sharp-van der Heijde score (SHS) on serial radiographs of the hands and feet. The independent association between these biomarker levels and the structural damage endpoint was examined using regression analysis. RESULTS: The mean age of the 97 RA patients (68 women) at the time of the study was 54 ± 14 years, and the median disease duration was 1.6 ± 1.5 years. Most patients were seropositive for either RF or ACPA, and the large majority (76%) were in remission or had low disease activity. After a median follow-up time of 3.3 ± 1.5 years (range, 1-7.5 yrs.), the mean total SHS annual progression was 0.88 ± 2.20 units. Fifty-two percent of the patients had no progression (defined as a total SHS of zero). The mean serum OPG level did not change significantly over the study period (from 3.9 ± 1.8 to 4.07 ± 2.23 pmol/L), whereas the mean serum DKK-1 level decreased, although not significantly (from 29.9 ± 10.9 to 23.6 ± 18.8 pmol/L). In the multivariate analysis, the predictive factors increasing the likelihood of total SHS progression were age (OR per year = 1.10; p = 0.003) and a high mean C-reactive protein level over the study period (OR = 1.29; p = 0.005). Circulating OPG showed a protective effect reducing the likelihood of joint space narrowing by 60% (95% CI: 0.38-0.94) and the total SHS progression by 48% (95% CI: 0.28-0.83). The DKK-1 levels were not associated with radiological progression. CONCLUSION: In patients with tightly controlled RA, serum OPG was inversely associated with progression of joint destruction. This biomarker may be useful in combination with other risk factors to improve prediction in patients in clinical remission or low disease activity state

Mucocutaneous Response to New Therapeutic Strategies in Behçet’s Disease: A Retrospective Cohort Study

Mucocutaneous lesions are the most frequent symptoms of Behcet's disease (BD). Recently, new therapies are being used to treat refractory cases, but the effect of these treatments on mucocutaneous manifestations has been scarcely reported. Our objective was to describe the mucocutaneous response to the different therapies used to treat BD in routine clinical practice. We retrospectively reviewed the clinical records of all patients diagnosed with BD seen at our institution between January 2010 and January 2022. Patients with BD without mucocutaneous manifestations were excluded. We included 109 patients diagnosed with BD: 51 males (46.8%) and 58 females (53.2%). The mean age at diagnosis was 31.58 years (standard deviation (SD) 12.110) and the mean time of disease evolution was 14.94 years (SD 11.094). Oral ulcers were the most frequent symptom present in 100% of patients, followed by genital ulcers (GU) in 76.1% of patients. Twenty-four patients (22%) had severe mucocutaneous symptoms (> 12 lesions/year) before treatment. We found that among patients with GU there was a higher prevalence of episodes of posterior uveitis and venous thrombosis (p=0.011 and p=0.045, respectively). In our series, we observed a lower complete cutaneous response to colchicine in patients with GU, pathergy or severe mucocutaneous symptoms (p < 0.05). Regarding the choice of a TNF-alpha inhibitor, we observed a lower prevalence of complete cutaneous response to adalimumab among patients with GU (53.3% complete response in patients with GU vs. 100% in patients without GU, p=0.022), whereas no differences were found between clinical characteristics in the response to infliximab

Assessment of inflammation in patients with rheumatoid arthritis using thermography and machine learning: a fast and automated technique

Objectives Sensitive detection of joint inflammation in rheumatoid arthritis (RA) is crucial to the success of the treat-to-target strategy. In this study, we characterise a novel machine learning-based computational method to automatically assess joint inflammation in RA using thermography of the hands, a fast and non-invasive imaging technique. Methods We recruited 595 patients with arthritis and osteoarthritis, as well as healthy subjects at two hospitals over 4 years. Machine learning was used to assess joint inflammation from the thermal images of the hands using ultrasound as the reference standard, obtaining a Thermographic Joint Inflammation Score (ThermoJIS). The machine learning model was trained and tuned using data from 449 participants with different types of arthritis, osteoarthritis or without rheumatic disease (development set). The performance of the method was evaluated based on 146 patients with RA (validation set) using Spearman's rank correlation coefficient, area under the receiver-operating curve (AUROC), average precision, sensitivity, specificity, positive and negative predictive value and F1-score. Results ThermoJIS correlated moderately with ultrasound scores (grey-scale synovial hypertrophy=0.49, p<0.001; and power Doppler=0.51, p<0.001). The AUROC for ThermoJIS for detecting active synovitis was 0.78 (95% CI, 0.71 to 0.86; p<0.001). In patients with RA in clinical remission, ThermoJIS values were significantly higher when active synovitis was detected by ultrasound. Conclusions ThermoJIS was able to detect joint inflammation in patients with RA, even in those in clinical remission. These results open an opportunity to develop new tools for routine detection of joint inflammation

Cardiovascular Events in Systemic Lupus Erythematosus: A Nationwide Study in Spain From the RELESSER Registry

This article estimates the frequency of cardiovascular (CV) events that occurred after diagnosis in a large Spanish cohort of patients with systemic lupus erythematosus (SLE) and investigates the main risk factors for atherosclerosis. RELESSER is a nationwide multicenter, hospital-based registry of SLE patients. This is a cross-sectional study. Demographic and clinical variables, the presence of traditional risk factors, and CV events were collected. A CV event was defined as a myocardial infarction, angina, stroke, and/or peripheral artery disease. Multiple logistic regression analysis was performed to investigate the possible risk factors for atherosclerosis. From 2011 to 2012, 3658 SLE patients were enrolled. Of these, 374 (10.9%) patients suffered at least a CV event. In 269 (7.4%) patients, the CV events occurred after SLE diagnosis (86.2% women, median [interquartile range] age 54.9 years [43.2-66.1], and SLE duration of 212.0 months [120.8-289.0]). Strokes (5.7%) were the most frequent CV event, followed by ischemic heart disease (3.8%) and peripheral artery disease (2.2%). Multivariate analysis identified age (odds ratio [95% confidence interval], 1.03 [1.02-1.04]), hypertension (1.71 [1.20-2.44]), smoking (1.48 [1.06-2.07]), diabetes (2.2 [1.32-3.74]), dyslipidemia (2.18 [1.54-3.09]), neurolupus (2.42 [1.56-3.75]), valvulopathy (2.44 [1.34-4.26]), serositis (1.54 [1.09-2.18]), antiphospholipid antibodies (1.57 [1.13-2.17]), low complement (1.81 [1.12-2.93]), and azathioprine (1.47 [1.04-2.07]) as risk factors for CV events. We have confirmed that SLE patients suffer a high prevalence of premature CV disease. Both traditional and nontraditional risk factors contribute to this higher prevalence. Although it needs to be verified with future studies, our study also shows-for the first time-an association between diabetes and CV events in SLE patients

Comprehensive description of clinical characteristics of a large systemic lupus erythematosus cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries.RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions.A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis-adjusted by gender, age at diagnosis, and disease duration-revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08-1.20 (P < 0.001); 1.29; 95% CI: 1.15-1.44 (P < 0.001); and 2.10; 95% CI: 1.83-2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0-4)], damage [median SLICC/ACR/DI: 1 (IQ: 0-2)], and severity [median KATZ index: 2 (IQ: 1-3)] scores were low, 1 of every 4 deaths was due to SLE activity.RELESSER represents the largest European SLE registry established to dat

Adult-onset Still's disease with atypical cutaneous manifestations

The diagnosis of adult-onset Still's disease (AOSD) can be very difficult. There are no specific tests available, and diagnosis is usually based on a symptom complex and the well-described typical evanescent rash seen in the majority of patients. However, in recent years, other atypical cutaneous manifestations of AOSD have been reported. These atypical skin eruptions often present in addition to the typical evanescent rash but may also be the only skin manifestation, resulting in delayed diagnosis because of under-recognition. In this study, we present 3 new cases of AOSD with atypical cutaneous manifestations diagnosed during a 30-year period in our department and review 78 additional cases previously reported (PubMed 1990-2016). These 81 patients form the basis of the present analysis. The overall prevalence of atypical cutaneous manifestations in our AOSD population was 14%. These manifestations may appear at any time over the course of the disease, and usually occur in patients who have persistent and severe disease, with a considerable frequency of clinical complications (23%), including serositis, myopericarditis, lung involvement, abdominal pain, neurologic involvement, and reactive hemophagocytic syndrome. The most representative and frequent lesion among the nonclassical skin rashes is the development of persistent pruritic papules and/or plaques. Interestingly, these lesions show a distinctive histological pattern. Other, less frequently observed lesions include urticaria and urticaria-like eruptions, generalized or widespread non-pruritic persistent erythema, vesiculopustular eruptions, a widespread peau d'orange appearance of the skin, and edema of the eyelids mimicking dermatomyositis without any accompanying skin lesion. The great majority of these patients required medium or high doses of glucocorticoids (including intravenous methylprednisolone pulse therapy in some cases) and, in nearly 40%, a more potent or maintenance immunotherapy with immunosuppressant drugs and/or biologic agents (mainly anakinra or tocilizumab) to control or manage symptoms because of a polycyclic or chronic course. The development of atypical cutaneous manifestations seems to be associated with a potentially worse prognosis, with a mortality rate reaching 8% primarily because of infectious complications related to immunosuppressive therapy. In conclusion, the appearance of atypical cutaneous manifestations is not uncommon in AOSD. Recognition of this clinical variant is crucial for the early diagnosis of AOSD, as it might imply persistent disease activity and the need for more aggressive treatment

Efficacy of bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): A case series and review of the literature

The cornerstone of therapy in thromboangiitis obliterans (TAO) is complete abstinence from tobacco. In addition to discontinuation of cigarette smoking, very few pharmacological and surgical options of controversial efficacy are available to date. New therapeutic options with greater efficacy are clearly needed to properly manage these patients. In this preliminary study, we assessed the effectiveness and safety of bosentan in a case series of 8 adults with TAO and severe ischemic ulceronecrotic lesions who were treated with bosentan after inadequate response to platelet inhibitors, vasodilators, and intravenous alprostadil. Additionally, we reviewed 18 well-documented patients with refractory TAO treated with bosentan, which was previously reported (PubMed 1965-2015). These 26 patients formed the basis of our present analysis. All were current smokers. The median duration of bosentan treatment (SD) was 4.5 +/- 4 months (range 3-16). Eleven patients (42%) were unable to completely abstain from smoking during their follow-up. With bosentan treatment, no new ischemic lesions were observed in the target extremities. A complete therapeutic response was achieved in 80% of patients, whereas a partial response was observed in 12%. Two patients (8%) ultimately required amputation despite treatment. After discontinuation of bosentan, patients were followed for a median of 20 +/- 14 months (range 3-60). Two patients whose trophic lesions had healed relapsed. When comparing patients who gave up smoking with those who were unable to completely abstain from smoking during follow-up, no significant differences were found in efficacy outcomes. Four patients (15%) developed adverse events, requiring bosentan discontinuation in 1 case. These preliminary data suggest that bosentan may be considered a therapeutic option for treatment of cases of severe TAO refractory to conventional treatment, and merit further evaluation in larger controlled, randomized clinical studies

Galanin (1-15) enhances the behavioural effects of escitalopram in the forced swimming test in rats

The selective serotonergic reuptake inhibitors (SSRIs) are the most commonly used for the treatment of major depression. Recently, we observed that the Galanin N-terminal fragment (1-15) [GAL(1-15)] enhances the antidepressant-like effects induced by Fluoxetine (FLX) in the forced swimming test (FST) (Flores-Burgess et al, 2017). Therefore, we have analyzed the ability of GAL(1-15) to enhance the behavioural effects of Escitalopram (ESC), other SSRIs, in the FST and the tail suspension test (TST). In the first set of experiments, groups of rats received three injections (23, 5 and 1 hour) before FST of two different doses of ESC (5mg/Kg or 7,5mg/Kg) or vehicle to perform a dose-response curve in the FST. Secondly, different groups of rats received three injections of ESC (7,5mg/Kg) and a single injection of a threshold dose of GAL(1-15) (1nmol) or aCSF 15 minutes before the FST and TST. In the dose-response curve, ESC 5 mg/kg and 7,5 mg/kg significantly increase the swimming time (p<0.05), while lacking effects over immobility time. The threshold dose of GAL(1-15) 1nmol enhanced the antidepressant-like effects mediated by ESC 7,5mg/Kg, decreasing the immobility (p<0.05) and increasing the swimming time (p<0.05) in the FST. In TST, no differences were found between the treatments. Our results indicate an interaction between GAL(1-15) and ESC in the FST and open up the possibility to use GAL(1-15) for a combination therapy with SSRIs as a depression treatment.This study was supported by Spanish SAF2016-79008-P, PI-0083-2019 and UMA18-FEDERJA-008 Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Galanin (1-15) potentiates the antidepres-sant-like effects induced by Escitalopram in a rat model of depression

Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1–15) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1–15) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD

Galanin(1-15) reverses the impaired long-term memory effect of fluoxetine in the novel object recognition test. Role of 5-HT1A receptor in medial prefrontal cortex

In this work, we have studied the effects of GAL(1-15) on FLX- mediated effects on the NOR and the OLM, two tasks where FLX treatment impaired long-term memories 24h post-training. Since the mPFC is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have also analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in rats. A discrimination index (DI) was calculated as: DI=(N-F)/(N+F), and represent the difference in exploration time expressed as a proportion of the total time spent exploring the two objects. To analyze the binding characteristics and mRNA levels of 5-HT1AR, group of animals (n=6) were injected with FLX(10mg/kg) and GAL(1-15)(1nmol) alone or in combination and coronal sections of the mPFC were obtained to perform a quantitative autoradiography and in situ hybridization experiments In the NOR task, GAL(1-15)+FLX reversed the impairment memory effect induced by FLX(10mg/Kg) (p<0.05). This effect was blocked by the GALR2 antagonist M871. On the contrary, GAL(1-15) did not reverse the effect of FLX in the OLM task. In the autoradiographic experiments, GAL(1-15)+FLX increased the Kd (p<0.01) and the Bmax (p<0.05) values of the agonist radioligand [3H]-8-OH-DPAT compared with FLX in the mPFC. The coadministration also increased the 5-HT1AR mRNA levels (p<0.01) compared with the FLX group. Our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be used to reverse some of the adverse effects of FLX on memory processes.Financiado por proyectos de MINECO: SAF2016-79008-P; PSI2017-82604-R y BES-2014-068426 Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech