Epidemiology and clinical domains of Behçet's disease in the Cantabria region, Northern Spain.

OBJECTIVES: The prevalence of Behçet's disease (BD) has a considerable geographical and temporal variability. Data regarding epidemiology in Spain are limited. Our study aimed to assess the epidemiology and clinical domains of BD in a population-based cohort from Northern Spain and to compare the results with other geographical areas of other countries. METHODS: We conducted a cross-sectional study of a well-defined population in Northern Spain. Cases of suspected BD between January 1980 and December 2018 were identified. The diagnosis of BD was established according to the International Study Group (ISG) for Behçet's Disease. The incidence of BD between 1999 and 2018 was estimated by sex, age, and year of diagnosis. RESULTS: Of 120 patients with probable BD, 59 patients met ISG criteria and were finally included in the study, with a male/female ratio of 0.97; mean age 49.7±14.7 years. Incidence during the period of study was 0.492 per 100,000 people, observing an increase from January 1999 to December 2018. Prevalence was 10.14 per 100,000 inhabitants in 2018. Clinical manifestations were relapsing aphthous stomatitis (100%), genital ulcers (78%), skin involvement (84.7%), joint involvement (64.4%), uveitis (55.9%), central nervous system (16.9%), vascular (10.2%), and gastrointestinal manifestations (6.8%). CONCLUSIONS: The prevalence of BD in Cantabria is higher than in other Southern European countries. This difference may reflect a combination of geographic, genetic, or methodological variations, as well as the free accessibility to the Spanish Public Health System for the entire population. Clinical phenotypes observed are similar to those described in other world regions.

Long-term survival of renal transplantation in patients with lupus nephritis: experience from a single university centre.

OBJECTIVES: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). Unfortunately, 10-20% of patients with LN develop end-stage renal disease (ESRD), and renal transplantation may be a therapeutic option. However, concerns about LN recurrence after transplant have been reported. We aimed to assess long-term post-transplant graft and patient survival in LN compared to patients with non-autoimmune nephropathy (polycystic kidney disease - PCKD). METHODS: We carried out a single-centre retrospective study of all patients who underwent renal transplantation due to LN in a referral unit between 1980 and 2018. This cohort was compared with a group of PCKD patients. The main outcome variables were graft and patient survival for up to 20 years, and the time-course of serum creatinine and proteinuria in the first 5 years after transplantation. Cumulative survival rates were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: We included 53 patients: LN group (n=21) and PCKD group (n=32). Baseline clinical characteristics were similar in both groups, except age at transplantation (39.8±11.3 years in the LN group and 46.6±5.0 years in the PCKD group; p=0.004). No significant differences were found regarding graft (p=0.59) or patient survival (p=0.087) at 20 years of follow-up. CONCLUSIONS: Despite concerns about LN recurrence after renal transplantation, this study shows that this procedure might be a safe alternative therapy for ESRD related to SLE and may provide long-term survival.

π-Bridge Substitution in DASAs: The Subtle Equilibrium between Photochemical Improvements and Thermal Control*.

Donor-acceptor Stenhouse adducts (DASAs) are playing an outstanding role as innovative and versatile photoswitches. Until now, all the efforts have been spent on modifying the donor and acceptor moieties to modulate the absorption energy and improve the cyclization and reversion kinetics. However, there is a strong dependence on specific structural modifications and a lack of predictive behavior, mostly owing to the complex photoswitching mechanism. Here, by means of a combined experimental and theoretical study, the effect of chemical modification of the π-bridge linking the donor and acceptor moieties is systematically explored, revealing the significant impact on the absorption, photocyclization, and relative stability of the open form. In particular, a position along the π-bridge is found to be the most suited to redshift the absorption while preserving the cyclization. However, thermal back-reaction to the initial isomer is blocked. These effects are explained in terms of an increased acceptor capability offered by the π-bridge substituent that can be modulated. This strategy opens the path toward derivatives with infra-red absorption and a potential anchoring point for further functionalization.

Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study.

OBJECTIVES: The impact of inflammatory rheumatic diseases on COVID-19 severity is poorly known. Here, we compare the outcomes of a cohort of patients with rheumatic diseases with a matched control cohort to identify potential risk factors for severe illness. METHODS: In this comparative cohort study, we identified hospital PCR+COVID-19 rheumatic patients with chronic inflammatory arthritis (IA) or connective tissue diseases (CTDs). Non-rheumatic controls were randomly sampled 1:1 and matched by age, sex and PCR date. The main outcome was severe COVID-19, defined as death, invasive ventilation, intensive care unit admission or serious complications. We assessed the association between the outcome and the potential prognostic variables, adjusted by COVID-19 treatment, using logistic regression. RESULTS: The cohorts were composed of 456 rheumatic and non-rheumatic patients, in equal numbers. Mean age was 63 (IQR 53-78) years and male sex 41% in both cohorts. Rheumatic diseases were IA (60%) and CTD (40%). Most patients (74%) had been hospitalised, and the risk of severe COVID-19 was 31.6% in the rheumatic and 28.1% in the non-rheumatic cohort. Ageing, male sex and previous comorbidity (obesity, diabetes, hypertension, cardiovascular or lung disease) increased the risk in the rheumatic cohort by bivariate analysis. In logistic regression analysis, independent factors associated with severe COVID-19 were increased age (OR 4.83; 95% CI 2.78 to 8.36), male sex (1.93; CI 1.21 to 3.07) and having a CTD (OR 1.82; CI 1.00 to 3.30). CONCLUSION: In hospitalised patients with chronic inflammatory rheumatic diseases, having a CTD but not IA nor previous immunosuppressive therapies was associated with severe COVID-19.

The Number of Traditional Cardiovascular Risk Factors Is Independently Correlated with Disease Activity in Patients with Psoriatic Arthritis.

Background and objectives: Psoriatic arthritis (PsA) is associated with several comorbidities, including among others an increased risk of cardiovascular (CV) disease, atherosclerosis, metabolic syndrome, hypertension dyslipidemia, and diabetes. The purpose of the present study was to determine how the number of CV risk factors correlates with disease related data such as disease activity. Materials and Methods: Cross-sectional study that encompassed 305 patients who fulfilled the CASPAR criteria for PsA were assessed for lipid profile, disease activity measurements, and the presence of six traditional CV risk factors (diabetes mellitus, dyslipidemia, hypertension, obesity, chronic kidney disease, and smoking status). A multivariable regression analysis, adjusted for age, sex, and disease duration, was performed to evaluate if the number of classic CV risk factors was independently related with specific features of the disease, including disease activity. Results: Disease duration was found to be higher, after adjustment for age and sex, in patients with 1 or 2, and 3 or higher CV factors, compared to those patients without CV risk factors. Similarly, DAPSA (Disease Activity in PSoriatic Arthritis score) was found to be independently upregulated in patients with a higher number of CV risk factors. In this sense, as DAPSA score increases the odds ratio (OR) of having 1 or 2 (OR 1.12 (95% confidence interval (CI) 1.03-1.21), p = 0.010), and 3 or higher (OR 1.15 (95% CI 1.04-1.26), p = 0.004) CV factors was significantly higher compared to no CV risk factors category. This was independently found after adjustment for age, sex, and disease duration. Conclusions: PsA patients with a higher number of CV risk factors exhibit an upregulated disease activity compared to those without them. This is independent of disease duration and other demographics factors.

Synthesis and characterization of bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives.

Aminoazobenzene derivatives with four ortho substituents with respect to the N-N double bond are a relatively unexplored class of azo compounds that show promise for use as photoswitches in biology. Tetra-ortho-methoxy-substituted aminoazobenzene compounds in particular can form azonium ions under physiological conditions and exhibit red-light photoswitching. Here, we report the synthesis and characterization of two bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives. These compounds form red-light-absorbing azonium ions, but only under very acidic conditions (pH < 1). While the low pK a makes the azonium form unsuitable, the neutral versions of these compounds undergo trans-to-cis photoisomerization with blue-green light and exhibit slow (τ1/2 ≈ 10 min) thermal reversion and so may find applications under physiological conditions.

A biomimetic molecular switch at work: coupling photoisomerization dynamics to peptide structural rearrangement.

In spite of considerable interest in the design of molecular switches towards photo-controllable (bio)materials, few studies focused on the major influence of the surrounding environment on the switch photoreactivities. We present a combined experimental and computational study of a retinal-like molecular switch linked to a peptide, elucidating the effects on the photoreactivity and on the α-helix secondary structure. Temperature-dependent, femtosecond UV-vis transient absorption spectroscopy and high-level hybrid quantum mechanics/molecular mechanics methods were applied to describe the photoisomerization process and the subsequent peptide rearrangement. It was found that the conformational heterogeneity of the ground state peptide controls the excited state potential energy surface and the thermally activated population decay. Still, a reversible α-helix to α-hairpin conformational change is predicted, paving the way for a fine photocontrol of different secondary structure elements, hence (bio)molecular functions, using retinal-inspired molecular switches.

Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring.

The synthesis and photophysical behavior of an unexplored family of green fluorescent protein (GFP)-like chromophore analogues is reported. The compound (Z)-4-(4-hydroxybenzylidene)-1-propyl-2-(propylamino)-1H-imidazol-5(4 H)-one (p-HBDNI, 2 a) exhibits significantly enhanced fluorescence properties relative to the parent compound (Z)-5-(4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H-imidazol-4-one (p-HBDI, 1). p-HBDNI was considered as a model system and the photophysical properties of other novel 2-amino-3,5-dihydro-4H-imidazol-4-one derivatives were evaluated. Time-dependent DFT calculations were carried out to rationalize the results. The analogue AIDNI (2 c), in which the 4-hydroxybenzyl group of p-HBDNI was replaced by an azaindole group, showed improved photophysical properties and potential for cell staining. The uptake and intracellular distribution of 2 c in living cells was investigated by confocal microscopy imaging.

Hydantoin-based molecular photoswitches.

A new family of molecular photoswitches based on arylidenehydantoins is described together with their synthesis and photochemical and photophysical studies. A series of hydantoin derivatives have been prepared as single isomers using simple and versatile chemistry in good yields. Our studies show that the photostationary states of these compounds can be easily controlled by means of external factors, such as the light source or filters. Moreover, the detailed investigations proved that these switches are efficient (i.e., they make efficient use of the light energy, are high fatigue resistant, and are very photostable). In some cases, the switches can be completely turned on/off, a desirable feature for specific applications. A series of theoretical calculations have also been carried out to understand the photoisomerization mechanism at the molecular level.

Uveitis in psoriatic arthritis: study of 406 patients in a single university center and literature review.

BACKGROUND/PURPOSE: The manifestations of uveitis are well established in axial spondyloarthritis (ax-SpA), but not in psoriatic arthritis (PsA). We aimed to assess, in a large unselected series of PsA: (A) the frequency and clinical features of uveitis; (B) its association with PsA activity, the impact of disease and functional disability, and (C) its relationship with the biological treatment. In addition, a literature review was performed. METHODS: Retrospective longitudinal study of PsA patients from a single referral hospital. PsA was classified according to the CASPAR criteria, and uveitis was diagnosed by experienced ophthalmologists. RESULTS: We studied 406 patients with PsA (46.3±12.3 years). Uveitis was observed in 20 (4.9%). Uveitis was acute in all cases, anterior (80%), unilateral (80%) and recurrent (50%). Patients with uveitis had a higher prevalence of HLA-B27 (45% vs 7.5%, p<0.0001), sacroiliitis on MRI (25% vs 8.3% p=0.027), ocular surface pathology (10% vs 0.8%, p=0.021), and median PsA impact of Disease Score (5.9 (2.1-6.8) vs 1.25 (0.0-3.0), p=0.001) and Bath Ankylosing Spondylitis Functional Index (4 (1.6-5) vs 1.0 (0.0-3.5), p=0.01) than patients without uveitis.The exposure adjusted incidence rate (episodes/100 patients-year) of uveitis before versus after biological treatment decreased with anti-TNFα monoclonal antibodies (56.3 vs 9.4) and increased with etanercept (ETN) (6.03 vs 24.2) and secukinumab (SECU) (0 vs 50) (including only one patient treated in the last two cases). CONCLUSION: The prevalence of uveitis in patients with PsA was about 5%. The pattern was similar to that observed in ax-SpA. Uveitis was associated with a worse quality of life and greater functional disability. The uveitis exposure adjusted incidence rate decreased with anti-TNFα monoclonal antibodies and increased with ETN and SECU.

Systemic treatment in sarcoidosis: Experience over two decades.

OBJECTIVE: The aim of this study was to evaluate the frequency of systemic treatment in a cohort of sarcoidosis patients and identify presenting clinical features as predictive factors of the need for systemic immunosuppressive therapy. METHODS: Retrospective study of 342 patients diagnosed and followed-up from January 1999 to December 2019 in a University Hospital in Northern Spain. The diagnosis of sarcoidosis was established according to ATS/ERS/WASOG criteria. A comparative analysis was performed between treated and untreated patients. Predictive factors of treatment prescription according to initial clinical manifestations were identified (multivariate analysis). RESULTS: Mean age at diagnosis was 47.7±15.1 years, with a slight female predominance (51.8%) and Caucasian majority (94.2%). The main clinical manifestation was thoracic involvement (88.3%). Extrathoracic manifestations were detected in 68.4% cases, mainly cutaneous (34.2%), articular (27.8%) and ocular (17.8%). A total of 207 (60.5%) patients required systemic treatment. Glucocorticoid therapy was the most widely used (60.5%). Conventional immunosuppressive therapy in 25.4%, more frequently MTX (21.9%). Biologic therapy was prescribed in 12.9%, especially adalimumab (9.1%). Male gender (OR: 1.65; 95%CI: 1.06-2.56), intrathoracic (OR: 2.41; 95%CI: 1.22-4.76), ocular (OR: 4.14; 95%CI: 2.01-8.52), parotid (OR: 1.60; 95%CI: 1.39-1.94), neurological (OR: 5.00; 95%CI: 1.68-14.84), and renal (OR: 1.59; 95%CI: 1.38-1.94) involvement were identified as risk factors associated with the need of systemic treatment. CONCLUSION: Most patients (60.5%) of sarcoidosis in our series required systemic therapy. An association between certain characteristics at initial presentation (male gender, lung, ocular, parotid, neurological and renal involvement) and the need of systemic treatment was identified.

Coronavirus disease 2019 in patients with rheumatic immune-mediated diseases in a single University Hospital, matched case-control study and literature review.

Background: COVID-19 may present different degrees of severity. Viral infections in patients with rheumatic inflammatory diseases (R-IMID) trend to present more severe disease. However, data comparing the severity of the disease between R-IMID and the general population are scarce. Objectives: To compare predisposing factors, clinical, serological features, and severity of COVID-19 infection in patients with and without R-IMID. Methods: Case-control study in a single University Hospital. We included all consecutive patients with a diagnosis of an R-IMID and COVID-19 infection up to March 31st, 2021. This cohort was compared to patients without R-IMID and not receiving immunosuppressive therapy, matched for sex and age (±5 years). Confirmed infection was defined if a patient had a positive nasopharyngeal swab for SARS-CoV-2. Severity was divided into mild, moderate, severe and critical according to the United States National Institute of Health (NIH) guidelines. Results: We included 274 R-IMID patients (185 women/89 men), mean age 59.1 ± 18 years. More frequent R-IMID were: Rheumatoid arthritis (28.8%), Psoriatic Arthritis (20.1%), axial Spondyloarthritis (12.4%), Polymyalgia Rheumatica (8%) and Systemic Lupus Erythematosus (8%). Hypertension and dyslipidemia were more frequent in patients with R-IMID. Although most of the cases were mild, critical cases and deaths were more frequent in R-IMID. When adjusted by comorbidities, no statistical differences were observed. Conclusion: R-IMID have a very similar clinical presentation when compared to the general population. There is a trend to an increased severity of the disease in patients with R-IMID.

Epidemiology of sarcoidosis in northern Spain, 1999-2019: A population-based study.

BACKGROUND: The incidence of sarcoidosis varies widely worldwide. The aim of this study was to estimate the incidence of sarcoidosis in a population-based cohort from northern Spain. METHODS: Patients diagnosed with sarcoidosis at Marqués de Valdecilla University Hospital, corresponding to the central Cantabria that encompasses Santander city and the surroundings, between January 1999 and December 2019were assessed. The diagnosis of sarcoidosis was established according to ATS/ERS/WASOG criteria as follows: compatible clinical and radiological presentation, histopathologic confirmation, and exclusion of other granulomatous diseases. Demographic and clinical data were collected. The incidence of sarcoidosis between 1999-2019 was estimated by sex, age, and year of diagnosis. RESULTS: A total of 234 patients were included, with a male/female ratio of 0.81. The mean age of the cohort at diagnosis was 48.43 ± 14.83 years and 129 (55.1%) were women. Incidence during the period of study was 3.58 per 100,000 populations (95% confidence interval: 3.13 - 4.07). No gender predominance was observed. An increase in age at diagnosis over time was found in the linear regression analysis. Thoracic affection was found in 180 patients (76.9%). Most common extra-thoracic areas affected were skin (34.2%), joints (30.8%) and eyes (15.4%). CONCLUSIONS: The incidence of sarcoidosis estimated in this study was similar to that of other Mediterranean countries. No gender predominance was observed. Consistent with previous studies, male presented an incidence peak 10 years earlier than female. A second peak between ages 60-69 years was identified in both sexes.

Disease Activity Influences Cardiovascular Risk Reclassification Based on Carotid Ultrasound in Patients with Psoriatic Arthritis.

OBJECTIVE: Because the addition of carotid ultrasound (US) into composite cardiovascular (CV) risk scores has been found effective for identifying patients with inflammatory arthritis and high CV risk, we aimed to determine whether its use would facilitate the reclassification of patients with psoriatic arthritis (PsA) into the very high Systematic Coronary Risk Evaluation (SCORE) risk category and whether this might be related to disease features. METHODS: This was a cross-sectional study involving 206 patients who fulfilled ClASsification for Psoriatic ARthritis criteria for PsA, and 179 controls. We assessed lipid profile, SCORE, disease activity measurements, and the presence of carotid plaques and carotid intima-media thickness by ultrasonography. A multivariable regression analysis, adjusted for classic CV risk factors, was performed to evaluate whether the risk of reclassification could be explained by disease-related features and to assess the most parsimonious combination of risk reclassification predictors. RESULTS: Forty-seven percent of patients were reclassified into a very high SCORE risk category after carotid US compared to 26% of controls (p < 0.001). Patients included in the low SCORE risk category were those who were more commonly reclassified (30% vs 14%, p = 0.002). The Disease Activity Index for PsA (DAPSA) score was associated with reclassification (ß 1.10, 95% CI 1.02-1.19; p = 0.019) after adjusting for age and traditional CV risk factors. A model containing SCORE plus age, statin use, and DAPSA score yielded the highest discriminatory accuracy compared to the SCORE-alone model (area under the receiver-operating characteristic curve 0.863, 95% CI 0.789-0.936 vs 0.716, 95% CI 0.668-0.764; p < 0.001). CONCLUSION: Patients with PsA are more frequently reclassified into the very high SCORE risk category following carotid US assessment than controls. This was independently explained by the disease activity.

Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune-Mediated Inflammatory Diseases. A Multicenter Study.

We aimed to assess the efficacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 ± 13.9 years). The underlying diseases were Bechet's disease (n = 5), neuromyelitis optica (n = 3), systemic lupus erythematosus (n = 2), sarcoidosis (n = 1), relapsing polychondritis (n = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis (n = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab (n = 6), rituximab (n = 6), infliximab (n = 5) and tocilizumab (n = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate (n = 11), azathioprine (n = 2), mycophenolate mofetil (n = 1) and hydroxychloroquine (n = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean ± SD BCVA (0.8 ± 0.3 LogMAR vs. 0.6 ± 0.3 LogMAR; p = 0.03), mean ± SD RNFL (190.5 ± 175.4 µm vs. 183.4 ± 139.5 µm; p = 0.02), mean ± SD MT (270.7 ± 23.2 µm vs. 369.6 ± 137.4 µm; p = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10-61.5) mg/day at baseline to. 2.5 (0-5) mg/day after one year of follow-up; p = 0.001. After a mean ± SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is effective in patients with refractory non-MS ON.

Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients.

Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Our aim was to assess the efficacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves' Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age ± standard deviation 51 ± 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 ± 0.25 vs. 0.9 ± 0.16; p = 0.0001), CAS (4.64 ± 1.5 vs. 1.05 ± 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 ± 4.1 vs. 16.73 ± 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 ± 2.1 months, low disease activity (CAS ≤ 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or inefficacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.