Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases.

Autoinflammatory diseases include disorders with a genetic cause and also complex syndromes associated to polygenic or multifactorial factors. Eye involvement is present in many of them, with different extent and severity. The present review covers ophthalmological lesions in the most prevalent monogenic autoinflammatory diseases, including FMF (familial Mediterranean fever), TRAPS (TNF receptor-associated periodic syndrome), CAPS (cryopyrin-associated periodic syndromes), Blau syndrome, DADA2 (deficiency of adenosine deaminase 2), DITRA (deficiency of the interleukin-36 receptor antagonist), other monogenic disorders, including several ubiquitinopathies, interferonopathies, and the recently described ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Among polygenic autoinflammatory diseases, ocular manifestations have been reviewed in Behçet's disease, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome, Still's disease and autoinflammatory bone diseases, which encompass CRMO (chronic recurrent multifocal osteomyelitis) and SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome.

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Maternal and fetal outcomes of pregnancy in women with primary systemic vasculitis: A single-center cohort study of 20 patients and 30 pregnancies.

OBJECTIVES: To analyze pregnancy outcomes of patients with primary systemic vasculitis followed in a third-level referral center. METHODS: Retrospective cohort study of all pregnant women with systemic vasculitis followed between 2009 and 2022 at the High-Risk Pregnancy Clinic of the Department of Systemic Autoimmune Diseases of the Hospital Clínic, Barcelona. RESULTS: Twenty women with primary vasculitis were identified, with a total of 30 pregnancies. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (n = 7) and Behçet disease (n = 4) were the most frequent types of vasculitis. All women had the diagnosis of vasculitis before pregnancy, with a median time between disease diagnosis and pregnancy of 5.8 years (range: 2 months-29 years). Most were in remission at conception (76.7 %). During pregnancy, a vasculitis flare occurred in 4 (13.3 %) patients (one each with Takayasu arteritis, eosinophilic granulomatosis with polyangiitis [EGPA], IgA vasculitis [IgAV], and Behçet disease [BD]). Four (16.7 %) of the successful pregnancies had post-partum relapses (one each with EGPA, granulomatosis with polyangiitis, IgAV, and BD). Eighty percent of pregnancies resulted in live babies. In four cases (13.3 %), medical termination of pregnancy was decided, considering the mother or baby health risk. There were two spontaneous miscarriages, and no stillbirths or neonatal deaths. Preeclampsia was the most frequent maternal complication (25 %). Newborns were preterm in 24 % and low birthweight in 20 % of cases. No maternal deaths occurred. CONCLUSIONS: This cohort study shows that vasculitis relapses during pregnancy and post-partum, together with other pregnancy complications, occur in a considerable number of patients with systemic vasculitides, although a final good pregnancy outcome can be expected in most cases. These findings emphasize the convenience of managing these special situations in expert reference centers.

Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry.

INTRODUCTION: Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). METHODS: Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). RESULTS: Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38-5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4-14.9, p = 0.0003). Three minor AEs were reported. CONCLUSIONS: TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05200715.

Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

OBJECTIVES: Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. METHODS: Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. RESULTS: Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. CONCLUSIONS: Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism.

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.

Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs).

Beckground: Despite the recent advances in the field of autoinflammatory diseases, most patients with recurrent fever episodes do not have any defined diagnosis. The present study aims at describing a cohort of patients suffering from apparently unexplained recurrent fever, in whom non-radiographic axial spondylarthritis (SpA) represented the unique diagnosis identified after a complete clinical and radiologic assessment. Materials and methods: Patients' data were obtained from the international registry on Undifferentiated Systemic AutoInflammatory Diseases (USAIDs) developed by the AutoInflammatory Disease Alliance (AIDA) network. Results: A total of 54 patients with recurrent fever episodes were also affected by non-radiographic axial SpA according to the international classification criteria. SpA was diagnosed after the start of fever episodes in all cases; the mean age at the diagnosis of axial SpA was 39.9 ± 14.8 years with a diagnostic delay of 9.3 years. The highest body temperature reached during flares was 42°C, with a mean temperature of 38.8 ± 1.1°C. The most frequent manifestations associated to fever were: arthralgia in 33 (61.1%) cases, myalgia in 24 (44.4%) cases, arthritis in 22 (40.7%) cases, headache in 15 (27.8%) cases, diarrhea in 14 (25.9%) cases, abdominal pain in 13 (24.1%) cases, and skin rash in 12 (22.1%) cases. Twenty-four (44.4%) patients have taken daily or on-demand non-steroidal anti-inflammatory drugs (NSAIDs) and 31 (57.4%) patients have been treated with daily or on demand oral glucocorticoids. Colchicine was used in 28 (51.8%) patients, while other conventional disease modifying anti-rheumatic drugs (cDMARDs) were employed in 28 (51.8%) patients. Forty (74.1%) patients underwent anti-tumor necrosis factor (TNF) agents and 11 (20.4%) were treated with interleukin (IL)-1 inhibitors. The response to TNF inhibitors on recurrent fever episodes appeared more effective than that observed with anti-IL-1 agents; colchicine and other cDMARDs were more useful when combined with biotechnological agents. Conclusion: Signs and symptoms referring to axial SpA should be inquired in patients with apparently unexplained recurrent fever episodes. The specific treatment for axial SpA may lead to a remarkable improvement in the severity and/or frequency of fever episodes in patients with unexplained fevers and concomitant axial SpA.

Papel de la neuropatía diabética en la aparición y desarrollo del síndrome del pie diabético / Role of Diabetic Neuropathy in the Onset and Development of Diabetic Foot Syndrome

Introducción: La neuropatía diabética es la complicación más frecuente de la diabetes mellitus y una de sus posibles consecuencias es el síndrome del pie diabético. Los médicos del primer nivel de atención deben conocer el comportamiento clínico de la neuropatía diabética y, sobre todo, como influye en la aparición y desarrollo del síndrome del pie diabético. Objetivo: Describir el papel de la neuropatía diabética en la aparición y desarrollo del síndrome del pie diabético. Métodos: Para la obtención de la información se utilizaron como motores de búsqueda de información científica los correspondientes a Scielo, Pubmed, y Google Académico. Se usaron como palabras clave: diabetes mellitus; neuropatía diabética; pie diabético; síndrome de pie diabético; úlcera de pie diabético; ataque de pie diabético. Se evaluaron diferentes trabajos de revisión, investigación y páginas web, y se excluyeron los artículos que tuvieran más de 10 años de publicados, en idiomas diferentes al español, portugués e inglés y que no se refirieran al tema de estudio a través del título. Esto permitió la cita de 45 referencias bibliográficas. Conclusiones: La neuropatía diabética constituye el principal factor de riesgo en la aparición y desarrollo del síndrome del pie diabético, sobre todo cuando se asocia a artropatía (defectos podálicos), enfermedad vascular periférica y/o sepsis. El control de la glucemia, la detección temprana del pie de riesgo y el cuidado preventivo de los miembros inferiores, repercutirá favorablemente en la salud y bienestar del paciente(AU)

Introduction: Diabetic neuropathy is the most frequent complication of diabetes mellitus and one of its possible consequences is diabetic foot syndrome. First level of care physicians should know the clinical behavior of diabetic neuropathy and, above all, how it influences the appearance and development of diabetic foot syndrome. Objective: To describe the role of diabetic neuropathy in the appearance and development of diabetic foot syndrome. Methods: To obtain the information, SciELO, PubMed and Google Scholar were used as search engines for scientific information. The keywords used were: diabetes mellitus; diabetic neuropathy; diabetic foot; diabetic foot syndrome; diabetic foot ulcer; diabetic foot attack. Different review papers, research papers and web pages were evaluated and articles that were more than 10 years old and published in languages other than Spanish, Portuguese and English and that did not refer to the subject of the study through the title were excluded. This allowed the citation of 45 bibliographic references. Conclusions: Diabetic neuropathy constitutes the main risk factor in the appearance and development of diabetic foot syndrome, especially when associated with arthropathy (foot defects), peripheral vascular disease and/or sepsis. Glycemic control, early detection of the foot at risk and preventive care of the lower limbs will have a favorable impact on the patient's health and well-being(AU)

Efficacy and Safety of Adalimumab in Pediatric Non-infectious Non-anterior Uveitis: Real-life Experience From the International AIDA Network Uveitis Registry.

INTRODUCTION: Scientific evidence of the effectiveness of the tumor necrosis factor inhibitor adalimumab (ADA) in pediatric patients with non-infectious non-anterior uveitis is still limited. The aim of this study is to investigate the therapeutic role of ADA in a cohort of pediatric patients with non-anterior uveitis. METHODS: This is an international multicenter study analyzing real-life data referred to pediatric patients treated with ADA for intermediate uveitis/pars planitis, posterior uveitis and panuveitis. Data were drawn from the AutoInflammatory Disease Alliance (AIDA) registry for patients with uveitis. RESULTS: Twenty-one patients (36 affected eyes) were enrolled, and all patients benefited from ADA administration. In detail, 11 patients (19 affected eyes) did not experience further ocular inflammation after ADA introduction; 10 cases (17 affected eyes) showed a significant clinical improvement consisting of a decrease in severity and/or frequency of ocular relapses. The number of ocular flares dropped from 3.91 to 1.1 events/patient/year after ADA introduction (p = 0.0009); macular edema and retinal vasculitis were respectively observed in 18 eyes and 20 eyes at the start of ADA and in 4 eyes and 2 eyes at the last assessment. The mean daily glucocorticoid dosage significantly decreased from 26.8 ± 16.8 mg/day at the start of ADA to 6.25 ± 6.35 mg/day at the last assessment (p = 0.002). Intermediate uveitis/pars planitis (p = 0.01) and posterior uveitis (p = 0.03) were more frequently observed in patients with full response to ADA; panuveitis (p = 0.001) was significantly more frequent among patients continuing to experience uveitic flares. This could be related to a higher use of systemic glucocorticoids (p = 0.002) and conventional immunosuppressants (p = 0.007) at the start of ADA when treating intermediate uveitis/pars planitis. Regarding the safety profile, only one adverse event was reported during ADA treatment, consisting of the development of generalized adenopathy. CONCLUSIONS: ADA proved to have an effective therapeutic role in all pediatric patients with non-anterior uveitis enrolled in the study. An overall glucocorticoid-sparing effect was observed despite the severity of cases enrolled. A more aggressive treatment of panuveitis and posterior uveitis at start of ADA could increase the likelihood of full response to therapy.

Embolización de la arteria gástrica izquierda: un novedoso procedimiento para el tratamiento de la obesidad / Left gastric artery embolization: a novel procedure for the treatment of obesity

Introducción: La embolización de la arteria gástrica izquierda, es una técnica novedosa, mínimamente invasiva que se investiga como un método alternativo, a menudo complementario, para controlar el apetito y el peso corporal a través de la reducción de la secreción de la hormona grelina. Objetivo: Describir la seguridad y la eficacia de la embolización de la arteria gástrica izquierda, como procedimiento terapéutico para el tratamiento de la obesidad. Método: Se realizó una búsqueda de literatura relevante sobre el tema en el segundo semestre de 2019. Se utilizaron como buscadores de información científica a Pubmed y a Google Académico; se revisaron 54 artículos, de los cuales 36 fueron referenciados. Conclusiones: La seguridad y la eficacia de la embolización de la arteria gástrica izquierda como proceder terapéutico para el tratamiento de la obesidad fue aceptable en la mayoría de los estudios revisados; la escasez de la evidencia (pocos casos) y la falta de protocolos estandarizados para esta intervención, requieren de ensayos clínicos aleatorizados, con una muestra mayor de casos y a más largo plazo.

Introduction: left gastric artery embolization is a novel, minimally invasive technique that is being investigated as an alternative method, often complementary, to control appetite and body weight by means of reducing the secretion of the ghrelin hormone. Objective: to describe the safety and efficacy of left gastric artery embolization as a therapeutic procedure for the treatment of obesity. Methods: a review of the relevant literature on the subject was carried out in the second semester of 2019. Pubmed and Google Scholar were used as scientific information search engines; 54 articles were reviewed, of which 36 were referenced. Conclusions: the safety and efficacy of left gastric artery embolization as a therapeutic procedure for the treatment of obesity was acceptable in most of the reviewed studies; the lack of evidence (few cases) and standardized protocols for this intervention require randomized clinical trials, with a larger sample of cases and over a longer period of time.

Efficacy of canakinumab in a patient with adult-onset glucocorticoid-resistant periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, a polygenic or multifactorial condition, is the most frequent autoinflammatory disease in children. There is increasing evidence that some patients may have a disease onset during adulthood. With regard to PFAPA syndrome treatment, single medium-to-high doses of glucocorticoids during flares constitute the therapy of choice in children and adults, colchicine may be useful in some patients, and tonsillectomy has been reported of utility mainly in paediatric patients. Interleukin-1 (IL-1) blockers have been sporadically used with good response in glucocorticoid-resistant cases. We report a patient with an adult onset of glucocorticoid-resistant PFAPA syndrome and inconsistent response to colchicine and anakinra, who later achieved a complete and sustained response to canakinumab. Although canakinumab seems to be a good therapeutic option in paediatric and adult patients with refractory PFAPA syndrome, the best anti-IL-1 agent and the sequence of administration have to be still determined in well-designed clinical trials.

Elementos básicos para el diagnóstico y manejo terapéutico del hipotiroidismo primario en el paciente adulto / Basic Elements for the Diagnosis and Treatment of Primary Hypothyroidism in the Adult Patient

Introducción: El hipotiroidismo primario, con frecuencia, es diagnosticado de forma tardía y no siempre las dosis indicadas de levotiroxina son las más convenientes. Urge llamar la atención sobre estos aspectos y actualizar el conocimiento sobre este tema. Objetivo: Describir los elementos básicos para el diagnóstico y manejo terapéutico del hipotiroidismo primario en el paciente adulto, en el primer nivel de atención. Métodos: Se realizó una búsqueda de literatura relevante sobre el tema. Se utilizaron como buscadores de información científica a Pubmed y a Google Académico. La estrategia de búsqueda incluyó los siguientes términos como palabras claves: hipotiroidismo primario; hipotiroidismo subclínico; diagnóstico y tratamiento. Fueron evaluados artículos que, en general, tenían menos de 10 años de publicados, en idioma español e inglés, que hicieran referencia específicamente al tema de estudio a través del título. Fueron excluidos los artículos que no cumplieron con estas condiciones. Esto permitió que 72 fueran referenciados. Conclusiones: Para realizar el diagnóstico del hipotiroidismo primario, es fundamental conocer los factores de riesgo y el cuadro clínico correspondiente. La elevación de la tirotropina en suero es la mejor prueba diagnóstica y casi siempre indica la presencia de hipotiroidismo primario. Se debe tener presente al inicio del tratamiento, la edad del paciente, el tiempo de evolución de la enfermedad, la intensidad del hipotiroidismo, el momento fisiológico y la presencia de enfermedades asociadas. Todos los pacientes con hipotiroidismo primario manifiesto deben ser tratados con levotiroxina sódica, pero aquellos con hipotiroidismo subclínico no siempre se benefician con este tratamiento(AU)

Introduction: Primary hypothyroidism is often diagnosed lately and not always are the indicated doses of levothyroxine the most convenient. It is urgent to draw attention towards these aspects and to update knowledge on this subject. Objective: To describe the basic elements for the diagnosis and therapeutic management of primary hypothyroidism in adult patients at the first level of care. Methods: A search for relevant literature on the subject was carried out. Pubmed and Google Scholar were used as search engines for retrieving scientific information. The search strategy included the following terms as keywords: hipotiroidismo primario [primary hypothyroidism], hipotiroidismo subclínico [subclinical hypothyroidism], diagnóstico y tratamiento [diagnosis and treatment]. Generally speaking, articles within ten years of having been published were assessed, written in Spanish and English and making a specific reference to the subject of the study in their respective titles. Articles not meeting these conditions were excluded. This allowed for 72 articles be referenced. Conclusions: To make the diagnosis of primary hypothyroidism, it is essential to know the risk factors and the corresponding clinical picture. Serum thyrotropin elevation is the best diagnostic test and almost always indicates the presence of primary hypothyroidism. The patient's age, the time of evolution of the disease, the intensity of the hypothyroidism, the physiologic time and the presence of associated diseases should be taken into account at the beginning of treatment. All patients with overt primary hypothyroidism should be treated with levothyroxine sodium, but those with subclinical hypothyroidism do not always benefit from this treatment(AU)

Algunas características del tratamiento con insulina en el paciente con diabetes mellitus tipo 2 / Some Characteristics of Insulin Treatment in Patients with Type 2 Diabetes Mellitus

Introducción: La insulina es un importante fármaco que puede ser empleado en el tratamiento del paciente diabetes mellitus tipo 2. Objetivo: Describir algunas de las características del tratamiento con insulina en el paciente con diabetes mellitus tipo 2. Métodos: La información necesaria para redactar el presente artículo se obtuvo en el trimestre octubre-diciembre de 2020. Se utilizó como motores de búsqueda de información científica a Google Académico, Pubmed y Scielo. Se evaluaron diferentes trabajos de revisión, de investigación y páginas web, que en general tenían menos de 10 años de publicados, en idioma español, portugués o inglés. Fueron utilizadas como palabras clave: tratamiento; insulina; análogos de insulina; diabetes mellitus. Fueron excluidos los artículos que no reunían las condiciones señaladas. Esto permitió el estudio de 80 artículos, de los cuales 43 fueron referenciados. Conclusiones: La insulina es una hormona polipeptídica sintetizada por las células β de los islotes de Langerhans del páncreas. Su efecto es ejercido fundamentalmente a nivel del hígado, tejido adiposo y músculo, y es una opción terapéutica en cualquier fase evolutiva de la diabetes mellitus tipo 2, cuando los agentes orales no logran las metas o si se presentan ciertas complicaciones. Se dispone de una amplia gama de tipos de insulina con distintos perfiles de acción y concentración, lo que permite clasificarlas de diferentes maneras. Se han establecido diferentes criterios sobre cuándo se debe comenzar y cómo orientar el tratamiento con insulina en la persona con diabetes mellitus tipo 2, lo que hacen posible un mejor control glucémico(AU)

Introduction: Insulin is an important drug that can be used for providing treatment to the patient with type 2 diabetes mellitus. Objective: To describe some of the characteristics of insulin treatment in patients with type 2 diabetes mellitus. Methods: The necessary information for writing this article was obtained in the trimester October-December 2020. As search engines for scientific information, Google Scholar, Pubmed and SciELO were used. Different review papers, research papers and web pages were assessed, generally less than ten years old and published in Spanish, Portuguese or English. The following keywords were used: tratamiento [treatment], insulina [insulin]; análogos de insulina [insulin analogues], diabetes mellitus. The articles not meet the above conditions were excluded. This allowed the study of eighty articles, of which 43 were referenced. Conclusions: Insulin is a polypeptide hormone synthesized by the β cells of the islets of Langerhans of the pancreas. Its effect is produced primarily at the liver, adipose tissue and muscle levels. It is a therapeutic option in any evolutionary phase of type 2 diabetes mellitus, when oral agents fail to achieve goals or if certain complications occur. A wide range of insulin types with different action and concentration profiles are available, allowing them to be classified in different ways. Different criteria have been established about when to start and how to guide insulin treatment in the person with type 2 diabetes mellitus, making better glycemic control possible(AU)

Reacciones adversas de los inhibidores del cotransportador sodio-glucosa tipo 2 en personas con diabetes mellitus

Introducción: Las bondades que ofrece el uso de los inhibidores del cotransportador sodio-glucosa tipo 2 en el tratamiento de la diabetes mellitus, se reportan preocupantes eventos y reacciones adversas por el empleo de este grupo de medicamentos. De ahí, la necesidad de su conocimiento por parte de los facultativos. Objetivo: Mencionar las reacciones adversas a medicamentos más frecuentes de los inhibidores del cotransportador sodio-glucosa tipo 2 en personas con diabetes mellitus. y describir aquellas de mayor interés clínico por su gravedad. Métodos: La información se obtuvo en el trimestre octubre-diciembre de 2020. Se evaluaron diferentes artículos de revisión, de investigación y páginas Web, en general tenían menos de 10 años de publicados, en idioma español, portugués o inglés. Se utilizó como motores de búsqueda de información científica a Google Académico, Pubmed y SciElo. Fueron utilizadas como palabras claves: inhibidores del cotransportador sodio-glucosa tipo 2; tratamiento; reacciones adversas; y diabetes mellitus. Fueron excluidos los artículos que no reunían las condiciones señaladas. Esto permitió el estudio de 88 artículos, de los cuales 50 fueron referenciados. Conclusiones: Los inhibidores del cotransportador sodio-glucosa tipo 2, pueden producir variadas reacciones adversas -descritas en el texto-, que de manera potencial pueden aumentar la morbilidad y mortalidad. Su uso ofrece la posibilidad de reacciones adversas graves de interés clínico, entre las que se describen: cetoacidosis diabética euglucémica, insuficiencia renal aguda, riesgo de amputaciones de los pies y fascitis necrosante del perineo.

Introduction: The benefits offered by the use of sodium-glucose cotransporter type 2 inhibitors in the treatment of diabetes mellitus, worrisome adverse events and reactions are reported for the use of this group of drugs. Hence, the need for physicians to be aware of them. Objective: To describe the most frequent adverse drug reactions of sodium-glucose cotransporter type 2 inhibitors in people with diabetes mellitus and those of greatest clinical interest due to their severity. Methods: The information was obtained in the October-December 2020 quarter. Different review articles, research articles and Web pages were evaluated, generally less than 10 years old, in Spanish, Portuguese or English. Google Scholar, Pubmed and SciElo were used as search engines for scientific information. The following keywords were used: sodium-glucose cotransporter type 2 inhibitors; treatment; adverse reactions; and diabetes mellitus. Articles that did not meet the indicated conditions were excluded. This allowed the study of 88 articles, of which 50 were referenced. Conclusions: Type 2 sodium-glucose cotransporter inhibitors can produce various adverse reactions -described in the text-, which can potentially increase morbidity and mortality. Their use offers the possibility of serious adverse reactions of clinical interest, among which the following are described: euglycemic diabetic ketoacidosis, acute renal failure, risk of foot amputations and necrotizing fasciitis of the perineum.

Skin Manifestations in Patients with Selective Immunoglobulin E Deficiency.

Selective immunoglobulin E deficiency (SIgED) is still an unrecognised primary immunodeficiency despite several observations supporting its existence. This study aimed to describe the skin manifestations associated with SIgED. We retrospectively assessed medical records of patients with SIgED, the diagnosis being based on serum IgE levels ≤2 Uk/L associated with normal serum levels of immunoglobulins G, M, and A. A total of 25 patients (24 female) with SIgED were included in the study. Eleven patients (44%) presented chronic spontaneous urticaria (CSU), five (20%) angioedema always associated with CSU, five erythema (20%), and six eczema (24%). Other, less frequent manifestations were lichen planus, anaphylactoid purpura, thrombocytopenic purpura, bullous pemphigoid, bullous pyoderma gangrenosum, and atypical skin lymphoproliferative infiltrate associated with reactive lymphadenopathy, chronic cholestasis, arthritis, and fibrosing mediastinitis. Fifteen patients (60%) had different types of associated autoimmune diseases, Hashimoto's thyroiditis being the most frequent (n = 5, 20%), followed by arthritis (n = 4, 16%), autoimmune hepatitis, neutropenia, vitiligo, and Sjögren's syndrome (n = 2, 8% each). Five malignancies were diagnosed in four patients (16%). An ultralow IgE serum level may be the only biomarker that reveals the presence of a dysregulated immune system in patients with a broad spectrum of skin manifestations.

Paradigm shift in monogenic autoinflammatory diseases and systemic vasculitis: The VEXAS syndrome. / Cambio de paradigma en las enfermedades autoinflamatorias monogénicas y las vasculitis sistémicas: el síndrome VEXAS.

VEXAS syndrome was described by the end of 2020 as an autoinflammatory disease caused by post-zygotic variants in the UBA1 gene. VEXAS syndrome occurs in adult males with recurrent fever, arthralgia/arthritis, ear/nose chondritis, neutrophilic dermatosis, lung inflammation, venous thrombosis, and different types of vasculitis. Common laboratory changes include raised acute phase reactants and macrocytic anemia. The coexistence of myelodysplasia is frequent, and bone marrow vacuolization of myeloid and erythroid precursors is characteristic. Glucocorticoids are effective at medium-high doses, but the remaining immunosuppressive drugs, either conventional or biological, have showed limited or absent efficacy. Azacitidine has been associated with a good response, especially in patients with accompanying myelodysplastic syndrome. Allogeneic hematopoietic stem cell transplantation appears to be the only curative therapy by now. VEXAS syndrome has become a paradigm shift in the diagnosis and treatment of autoinflammatory diseases and systemic vasculitis.

Algunos elementos de interés acerca del diagnóstico y tratamiento de la tormenta tirotóxica / Some elements of interest about the diagnosis and treatment of thyrotoxic storm

Introducción: La tormenta tirotóxica se produce por la liberación repentina y rápida de hormonas tiroideas al torrente sanguíneo. Constituye la complicación más peligrosa de la tirotoxicosis. Objetivo: Describir los principales elementos de interés acerca del diagnóstico y del tratamiento de la tormenta tirotóxica. Métodos: Se utilizaron como motores de búsqueda los correspondientes a las bases de datos Google Académico, Pubmed y SciELO. Las palabras clave utilizadas fueron: tormenta tirotóxica, tormenta tiroidea, tirotoxicosis, hipertiroidismo, diagnóstico y tratamiento. Se evaluaron y se incluyeron los trabajos de revisión, de investigación y las páginas web que tuvieran menos de 10 años de publicados y que por el título trataban el tema de estudio. Fueron excluidos los artículos que no estuvieran en idioma español, portugués o inglés. En total 34 artículos fueran referenciados. Conclusiones: El diagnóstico es eminentemente clínico y se realiza por la detección de factores desencadenantes. Se suma la exacerbación del cuadro clínico de tirotoxicosis previamente existente, el cual afecta a varios sistemas del organismo como consecuencia del aumento de las hormonas tiroideas circulantes. Lo ideal es prevenir la tormenta tirotóxica, aunque ya establecido el tratamiento no se debe retrasar la terapia de la causa desencadenante y de la causa específica. Deberá estar encaminada a reducir la síntesis y la secreción de las hormonas tiroideas y a minimizar las acciones periféricas de estas. Deberán emplearse diferentes fármacos y otras medidas terapéuticas para tratar las complicaciones sistémicas para complementar el tratamiento(AU)

Introduction: Thyrotoxic storm is caused by the sudden and rapid release of thyroid hormones into the bloodstream. It is the most dangerous complication of thyrotoxicosis. Objective: Describe some elements of interest about the diagnosis and treatment of thyrotoxic storm. Methods: Search engines corresponding to Google Scholar, Pubmed and SciELO databases were used. The keywords used were: thyrotoxic storm; thyroid storm; thyrotoxicosis; hyperthyroidism; diagnosis and treatment. The review papers, research papers and web pages, which in general, had less than 10 years of publication and that by the title dealt with the subject of study were evaluated and included. Articles that were not in Spanish, Portuguese or English were excluded. A total of 34 articles were referenced. Conclusions: The diagnosis is eminently clinical and is made by the detection of triggers, to which is added the exacerbation of the clinical picture of thyrotoxicosis previously existing, which affects several systems of the body as a result of the circulating thyroid hormones increase. The ideal is to prevent the thyrotoxic storm; although if the treatment is already established, the therapy of the triggering cause and the specific cause should not be delayed. It should be aimed at reducing the synthesis and secretion of thyroid hormones and minimizing their peripheral actions. Different drugs and other therapeutic measures should be used to treat systemic complications to complement treatment(AU)