Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Diffuse alveolar hemorrhage in patients with systemic lupus erythematosus: data from the Spanish society of rheumathology Lupus Register (RELESSER).

INTRODUCTION:  Diffuse alveolar hemorrhage (DAH) is a rare complication with high mortality in patients with systemic lupus erythematosus (SLE). Early diagnosis and treatment are essential to improve patient prognosis. To determine the characteristics of patients with DAH and their mortality in a Spanish cohort of patients with SLE. METHODS:  Patients from the RELESSER (Spanish Society of Rheumatology Lupus Register) who had had at least one confirmed episode of DAH were included. Epidemiological, clinical, and laboratory characteristics were analyzed. RESULTS:  4024 patients were included in the RELESSER register, 37 (0.9%), had at least one recorded episode of DAH. Only further data for 14 patients could be analyzed. In total, 92.9% were women, and for 4 (28.6%) DAH coincided with the debut of SLE. More than 80% of patients had renal involvement and thrombocytopenia. The most frequent manifestations were dyspnea (85.7%) and hypoxemia (100%), with the classic triad of hemoptysis, anemia and pulmonary infiltrates, appearing in 6 (46.2%) patients. The most frequently used treatments were glucocorticoids (85.7%) and cyclophosphamide (69.2%); plasmapheresis was utilized in 5 patients (35.7%) and 8, (57.1%) received intravenous immunoglobulins; 12 (85.7%) patients required admission to the ICU and 5 (35.7%) died. Tobacco use, history of lupus nephritis (LN), concomitant infection, and treatment with cyclophosphamide were more frequent in patients who died. CONCLUSIONS:  DAH is rare in patients with SLE; in up to one-third of patients, it may appear at the onset of the disease. Some factors, such as smoking, a history of LN, treatment with cyclophosphamide, or concomitant infection, are more prevalent in patients with an unfavorable outcome.

Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry.

OBJECTIVES: This article estimates the frequency of polyautoimmunity and associated factors in a large retrospective cohort of patients with SLE. METHODS: RELESSER (Spanish Society of Rheumatology Lupus Registry) is a nationwide multicentre, hospital-based registry of SLE patients. This is a cross-sectional study. The main variable was polyautoimmunity, which was defined as the co-occurrence of SLE and another autoimmune disease, such as autoimmune thyroiditis, RA, scleroderma, inflammatory myopathy and MCTD. We also recorded the presence of multiple autoimmune syndrome, secondary SS, secondary APS and a family history of autoimmune disease. Multiple logistic regression analysis was performed to investigate possible risk factors for polyautoimmunity. RESULTS: Of the 3679 patients who fulfilled the criteria for SLE, 502 (13.6%) had polyautoimmunity. The most frequent types were autoimmune thyroiditis (7.9%), other systemic autoimmune diseases (6.2%), secondary SS (14.1%) and secondary APS (13.7%). Multiple autoimmune syndrome accounted for 10.2% of all cases of polyautoimmunity. A family history was recorded in 11.8%. According to the multivariate analysis, the factors associated with polyautoimmunity were female sex [odds ratio (95% CI), 1.72 (1.07, 2.72)], RP [1.63 (1.29, 2.05)], interstitial lung disease [3.35 (1.84, 6.01)], Jaccoud arthropathy [1.92 (1.40, 2.63)], anti-Ro/SSA and/or anti-La/SSB autoantibodies [2.03 (1.55, 2.67)], anti-RNP antibodies [1.48 (1.16, 1.90)], MTX [1.67 (1.26, 2.18)] and antimalarial drugs [0.50 (0.38, 0.67)]. CONCLUSION: Patients with SLE frequently present polyautoimmunity. We observed clinical and analytical characteristics associated with polyautoimmunity. Our finding that antimalarial drugs protected against polyautoimmunity should be verified in future studies.

Analysis of two autoimmunity genes, IRAK1 and MECP2, in giant cell arteritis.

OBJECTIVES: The Xq28 region, containing IRAK and MECP2, represent a common susceptibility locus for a high number of autoimmune diseases. Our aim in the present study was to evaluate the influence of the IRAK1 and MECP2 autoimmunity-associated genetic variants in the giant cell arteritis (GCA) susceptibility and its clinical subphenotypes. METHODS: We analysed a total of 627 female biopsy-proven GCA patients and 1,520 female healthy controls of Spanish Caucasian origin. Two polymorphisms, rs1059702 and rs17345, located at IRAK1 and MECP2, respectively, were genotyped using TaqMan® allelic discrimination assays. RESULTS: No association with any of the analysed polymorphisms was evident when genotype and allele frequencies were compared between GCA patients and controls (rs1059702: allelic p-value=0.699, OR=0.96, CI 95% 0.80-1.17; rs17435: allelic p-value=0.994, OR=1.00, CI 95% 0.84-1.19). Likewise, the subphenotype analysis yield similar negative results. CONCLUSIONS: We have assessed for the first time the possible role of IRAK1 and MECP2 autoimmune disease-associated polymorphisms in GCA. Our data suggest that IRAK1 rs1059702 and MECP2 rs17435 genetic variants do not play a significant role in GCA susceptibility or severity.

Damage in a large systemic lupus erythematosus cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER) with emphasis on the cardiovascular system: a longitudinal analysis.

OBJECTIVE: To assess organ damage, with emphasis on the cardiovascular system, over the different stages of the disease in a large SLE cohort. METHODS: Multicentre, longitudinal study of a cohort of 4219 patients with SLE enrolled in the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We longitudinally analysed SDI (globally and for each domain) over time only in the 1274 patients whose dates of damage events had been recorded. RESULTS: During the first year after diagnosis of SLE, 20% of the 1274 patients presented with new damage manifestations. At years 2 and 3, new damage was recorded in 11% and 9% of patients. The annual percentage of patients with new damage after year 5 decreased to 5%. In the first year with the disease, most damage was accumulated in the musculoskeletal, neuropsychiatric and renal systems; in later stages, most damage was in the musculoskeletal, ocular and cardiovascular systems. Considering 'cerebrovascular accident' and 'claudication for 6 months' as cardiovascular items, the cardiovascular system was the second most affected system during the early stages of SLE, with 19% of the patients who presented with damage affected at first year after diagnosis. During the late stages, 20-25% of the patients presenting with new damage did so in this modified cardiovascular domain of the SDI. CONCLUSIONS: New damage occurs mainly during the first year following diagnosis of SLE. Cardiovascular damage is relevant in both the early and the late stages of the disease. Strategies to prevent cardiovascular damage should be implemented early after diagnosis of SLE.

SLESIS-R: an improved score for prediction of serious infection in patients with systemic lupus erythematosus based on the RELESSER prospective cohort.

OBJECTIVE: To develop an improved score for prediction of severe infection in patients with systemic lupus erythematosus (SLE), namely, the SLE Severe Infection Score-Revised (SLESIS-R) and to validate it in a large multicentre lupus cohort. METHODS: We used data from the prospective phase of RELESSER (RELESSER-PROS), the SLE register of the Spanish Society of Rheumatology. A multivariable logistic model was constructed taking into account the variables already forming the SLESIS score, plus all other potential predictors identified in a literature review. Performance was analysed using the C-statistic and the area under the receiver operating characteristic curve (AUROC). Internal validation was carried out using a 100-sample bootstrapping procedure. ORs were transformed into score items, and the AUROC was used to determine performance. RESULTS: A total of 1459 patients who had completed 1 year of follow-up were included in the development cohort (mean age, 49±13 years; 90% women). Twenty-five (1.7%) had experienced ≥1 severe infection. According to the adjusted multivariate model, severe infection could be predicted from four variables: age (years) ≥60, previous SLE-related hospitalisation, previous serious infection and glucocorticoid dose. A score was built from the best model, taking values from 0 to 17. The AUROC was 0.861 (0.777-0.946). The cut-off chosen was ≥6, which exhibited an accuracy of 85.9% and a positive likelihood ratio of 5.48. CONCLUSIONS: SLESIS-R is an accurate and feasible instrument for predicting infections in patients with SLE. SLESIS-R could help to make informed decisions on the use of immunosuppressants and the implementation of preventive measures.

Serological short-chain fatty acid and trimethylamine N-oxide microbial metabolite imbalances in young adults with acute myocardial infarction.

Acute myocardial infarction (AMI) is associated with systemic inflammatory processes and metabolic alterations. Microbial-derived metabolites, such as short-chain fatty acids and trimethylamine N-oxide (TMAO), have emerged in recent years as key players in the modulation of inflammation, with potential implications for cardiovascular diseases. We performed a prospective observational study that monitored the serological concentration of bacterial metabolites in 45 young patients (<55 years) without cardiovascular risk factors but with AMI, at hospital admission and at 3 months of follow-up, and compared them with a control group. TMAO and acetate levels were significantly higher in AMI, whereas butyrate and propionate were significantly lower. The acetate/propionate ratio showed the most discrimination between AMI and controls by receiver operating characteristic analysis (area under the curve 0.769, P < 0.0001). A multivariate logistic regression model revealed that this ratio was independently associated with AMI. Short-chain fatty acid concentrations, but not TMAO, exhibited significant correlations with inflammatory and coagulation parameters. Three months after the acute AMI event, all metabolite levels returned to those observed in healthy controls except butyrate. In conclusion, our study reveals disturbances of the serological concentration of microbiota-derived metabolites in AMI that are also related to inflammatory and coagulation parameters. These findings highlight an interesting field of study in the potential role of microbial metabolites from gut in cardiovascular disease.

Evaluating remission and low disease activity from the perspective of the patient with axial spondyloarthritis: The cross-sectional ConREspAx study.

OBJECTIVES: To evaluate the properties of a single question to determine patient perception of remission and disease activity; to compare this with existing definitions for remission and low disease activity (LDA). METHODS: Single-center, cross-sectional study in a tertiary care hospital. Patients with axSpA (fulfilling ASAS criteria) were consecutively included. Both the patient's perception of remission and LDA and that of the physician were evaluated with a single question. Agreement between the patients' perception and other current definitions was tested using the prevalence-adjusted and bias-adjusted kappa (PABAK). The sensitivity (S) and specificity (Sp) of current definitions of disease states were tested against the patient's perception as the gold standard. RESULTS: The study population included 105 axSpA patients (63.8% males; 67.6% with radiographic sacroiliitis). Patients considered themselves to be in remission in 21% of cases and in LDA in 51.4%; physicians considered patients to be in remission in 45.7% of cases and in LDA in 35.2%. The poorest agreement was recorded for the patient's and the physician's perception of remission. The best agreement for patients' perception of remission was for a BASDAI < 2 and normal C-reactive protein values. This definition was also the most sensitive (S=72.7%) and specific (Sp=83.1%) when the patient's perception was taken as the gold standard. CONCLUSION: In a real-life setting, the evaluation of remission by the patient through a single question was the hardest criterion to achieve, although it did prove to be a feasible, valid, and specific way to assess remission.

Central nervous system involvement in systemic lupus erythematosus: Data from the Spanish Society of Rheumatology Lupus Register (RELESSER).

OBJECTIVES: To analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). METHODS: Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cerebrovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. RESULTS: A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29-2.67) and more specifically CVD (HR 2.17, 1.41-3.33) and organic brain syndrome (HR 2.11, 1.19-3.74) accounted as independent prognostic factors for poor survival. CONCLUSION: The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.

Influence of the EULAR recommendations for the use of imaging in large vessel vasculitis in the diagnosis of giant cell arteritis: results of the ARTESER register.

OBJECTIVE: The main study objective was to determine how giant cell arteritis (GCA) is diagnosed in our clinical practice and whether the EULAR recommendations have influenced the diagnostic procedures used. METHODS: ARTEritis of the Rheumatology Spanish Society -Sociedad Española de Reumatología (ARTESER) is a multicentre observational retrospective study conducted in 26 hospitals with support from the Spanish Society of Rheumatology. All patients diagnosed with GCA between 1 June 2013 and 29 March 2019 were included. The gold standard for the diagnosis of GCA was the judgement of the physician in charge, according to clinical criteria, supported by data available from laboratory tests, imaging studies (ultrasound, positron emission tomography (PET) and MRI/CT angiography) and temporal artery biopsy (TAB) when available. RESULTS: We included 1675 patients with GCA (mean age±SD (76.9±8.1) years, 1178 women (70.3%)). Of these, 776 patients had a positive TAB (46.3%), 503 (30.0%) positive ultrasound, 245 positive PET (14.6%) and 64 positive MRI/CT angiography (3.8%). These percentages changed substantially over the study. From 2013 to 2019, the use of ultrasound in diagnosis grew from 25.8% to 52.9% and PET from 12.3% to 19.6%, while use of TAB decreased from 50.3% to 33.3%. CONCLUSIONS: Biopsy was the most widely used diagnostic test for confirming GCA, but use of imaging as a diagnostic tool has grown in recent years. Following publication of the 2018 EULAR recommendations, ultrasound has displaced biopsy as the first-line diagnostic test; TAB was performed in a third and PET in a fifth of cases.

Risk of Severe COVID-19 Infection in Patients With Inflammatory Rheumatic Diseases.

OBJECTIVE: To describe the cohort of patients with inflammatory rheumatic diseases (IRD) hospitalized due to SARS-CoV-2 infection in the Ramón y Cajal Hospital, and to determine the increased risk of severe coronavirus disease 2019 (COVID-19) in patients with no IRD. METHODS: This is a retrospective single-center observational study of patients with IRD actively monitored in the Department of Rheumatology who were hospitalized due to COVID-19. RESULTS: Forty-one (1.8%) out of 2315 patients admitted due to severe SARS-CoV-2 pneumonia suffered from an IRD. The admission OR for patients with IRD was 1.91 against the general population, and it was considerably higher in patients with Sjögren syndrome, vasculitis, and systemic lupus erythematosus. Twenty-seven patients were receiving treatment for IRD with corticosteroids, 23 with conventional DMARDs, 12 with biologics (7 rituximab [RTX], 4 anti-tumor necrosis factor [anti-TNF], and 1 abatacept), and 1 with Janus kinase inhibitors. Ten deaths were registered among patients with IRD. A higher hospitalization rate and a higher number of deaths were observed in patients treated with RTX (OR 12.9) but not in patients treated with anti-TNF (OR 0.9). CONCLUSION: Patients with IRD, especially autoimmune diseases and patients treated with RTX, may be at higher risk of severe pneumonia due to SARS-CoV-2 compared to the general population. More studies are needed to analyze this association further in order to help manage these patients during the pandemic.

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: results from the COVIDSER study.

OBJECTIVES: To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. METHODS: The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. RESULTS: A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients' hospitalisation. CONCLUSIONS: The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.

Surgical considerations about amyloid goiter.

Amyloidosis is an uncommon syndrome consisting of a number of disorders having in common an extracellular deposit of fibrillary proteins. This results in functional and structural changes in the affected organs, depending on deposit location and severity. Amyloid infiltration of the thyroid gland may occur in 50% and up to 80% of patients with primary and secondary amyloidosis respectively. Amyloid goiter (AG) is a true rarity, usually found associated to secondary amyloidosis. AG may require surgical excision, usually because of compressive symptoms. We report the case of a patient with a big AG occurring in the course of a secondary amyloidosis associated to polyarticular onset juvenile idiopathic arthritis who underwent total thyroidectomy. Current literature is reviewed, an attempt is made to provide action guidelines, and some surgical considerations on this rare condition are given.

Spontaneous pneumomediastinum complicating interstitial lung disease, associated with clinically amyopathic dermatomyositis and positive anti-MDA5 antibodies / Neumomediastino espontáneo como complicación de enfermedad pulmonar intersticial, asociada con dermatomiositis clínicamente amiopática y anticuerpos anti-MDA5 positivos

Abstract Clinically amyopathic dermatomyositis comprises a special group of patients within the spectrum of dermatomyositis characterized by the presence of typical skin lesions, minimal or absent muscle involvement, and increased risk of interstitial lung disease. The antibodies directed against the protein encoded by melanoma differentiation-associated gene 5 (MDA5) are present in a significant proportion of patients with clinically amyopathic dermatomyositis, who develop rapidly progressive interstitial lung disease, with high mortality and frequently complicated by the onset of spontaneous pneumomediastinum. A case is presented of an African patient with anti-MDA5 positive clinically amyopathic dermatomyositis and interstitial lung disease with tomography pattern of organizing pneumonia who developed spontaneous pneumomediastinum during its clinical course.

Resumen La dermatomiositis clínicamente amiopática comprende un grupo especial de pacientes dentro del espectro de la dermatomiositis, caracterizados por la presencia de lesiones cutáneas típicas, compromiso muscular mínimo o ausente y riesgo aumentado de enfermedad pulmonar intersticial. Los anticuerpos dirigidos contra la proteína codificada por el gen asociado con la diferenciación del melanoma 5 (MDA5), están presentes en una proporción importante de pacientes con dermatomiositis clínicamente amiopática, los cuales desarrollan enfermedad pulmonar intersticial rápidamente progresiva, con elevada mortalidad y que se complica frecuentemente con la aparición de neumomediastino espontáneo. Presentamos el caso de una paciente de origen africano con dermatomiositis clínicamente amiopática anti-MDA5 positiva y enfermedad pulmonar intersticial con patrón tomográfico de neumonía organizada, que desarrolló neumomediastino espontáneo durante su evolución.

Chilblain lupus induced by TNF-α antagonists: a case report and literature review.

We report the case of a 72-year-old man with history of ankylosing spondylitis, who, during the treatment with infliximab, developed painful, erythematous-violaceous plaques with later development of ulcers on his feet associated with cold exposure. Concomitantly with the appearance of these lesions, he presented increased antinuclear antibodies (ANA) titers, positivity for anti-DNA and IgM anticardiolipin antibodies, low complement levels, polyclonal hypergammaglobulinemia, and lymphopenia. He was diagnosed of chilblain lupus induced by infliximab, this agent was withdrawn and initiated treatment for chilblains with improvement of lesions. On reviewing of the literature, we found seven reported cases of tumor necrosis factor α (TNF-α) antagonists-induced chilblain lupus, all in rheumatoid arthritis patients and four of them with clinical and immunological characteristics available are presented and compared with our case. Although it is infrequent, chilblain lupus forms part of the spectrum of TNF-α antagonists-induced lupus erythematosus; usually is limited to skin without progression to systemic lupus erythematosus; presents ANA, anti-DNA, and antinucleosome antibodies positivity as more frequent immunological alterations; and responds appropriately to the specific treatment, TNF-α antagonists withdrawal being not necessary in almost all cases.