Factors associated with discontinuation of biologics in patients with inflammatory arthritis in remission: data from the BIOBADASER registry.

BACKGROUND: The objectives of this study were to assess the discontinuation of biologic therapy in patients who achieve remission and identify predictors of discontinuation of biologics in patients with inflammatory arthritis in remission. METHODS: An observational retrospective study from the BIOBADASER registry comprising adult patients diagnosed with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA) and receiving 1 or 2 biological disease-modifying drugs (bDMARDs) between October 1999 and April 2021. Patients were followed yearly after initiation of therapy or until discontinuation of treatment. Reasons for discontinuation were collected. Patients who discontinued bDMARDs because of remission as defined by the attending clinician were studied. Predictors of discontinuation were explored using multivariable regression models. RESULTS: The study population comprised 3,366 patients taking 1 or 2 bDMARDs. Biologics were discontinued owing to remission by 80 patients (2.4%): 30 with RA (1.7%), 18 with AS (2.4%), and 32 with PsA (3.9%). The factors associated with a higher probability of discontinuation on remission were shorter disease duration (OR: 0.95; 95% CI: 0.91-0.99), no concomitant use of classic DMARDs (OR: 0.56; 95% CI: 0.34-0.92), and shorter usage of the previous bDMARD (before the decision to discontinue biological therapy) (OR: 1.01; 95% CI: 1.01-1.02); in contrast, smoking status (OR: 2.48; 95% CI: 1.21-5.08) was associated with a lower probability. In patients with RA, positive ACPA was associated with a lower probability of discontinuation (OR: 0.11; 95% CI: 0.02-0.53). CONCLUSIONS: Discontinuation of bDMARDs in patients who achieve remission is uncommon in routine clinical care. Smoking and positive ACPA in RA patients were associated with a lower probability of treatment discontinuation because of clinical remission.

Female Sex, Age, and Unfavorable Response to Tumor Necrosis Factor Inhibitors in Patients With Axial Spondyloarthritis: Results of Statistical and Artificial Intelligence-Based Data Analyses of a National Multicenter Prospective Registry.

OBJECTIVE: Real-world studies are needed to identify factors associated with response to biologic therapies in patients with axial spondyloarthritis (SpA). The objective was to assess sex differences in response to tumor necrosis factor inhibitors (TNFi) and to explore possible risk factors associated with TNFi efficacy. METHODS: A total of 969 patients with axial SpA (315 females, 654 males) enrolled in the BIOBADASER registry (2000-2019) who initiated a TNFi (first, second, or further lines) were studied. Statistical and artificial intelligence (AI)-based data analyses were used to explore the association of sex differences and other factors to TNFi response, using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), to calculate the BASDAI50, with an improvement of at least 50% of the BASDAI score, and using the Ankylosing Spondylitis Disease Activity Score, calculated using the C-reactive protein level (ASDAS-CRP). RESULTS: Females had a lower probability of reaching a BASDAI50 response with a first line TNFi treatment at the second year of follow-up (P = 0.018) and a lesser reduction of the ASDAS-CRP at this time point. The logistic regression model showed lower BASDAI50 responses to TNFi in females (P = 0.05). Other factors, such as older age (P = 0.004), were associated with unfavorable responses. The AI data analyses reinforced the idea that age at the beginning of the treatment was the main factor associated with an unfavorable response. The combination of age with other clinical characteristics (female sex or cardiovascular risk factors and events) potentially contributed to an unfavorable response to TNFi. CONCLUSION: In this national multicenter registry, female sex was associated with less response to a first-line TNFi by the second year of follow-up. A higher age at the start of the TNFi was the main factor associated with an unfavorable response to TNFi.

Clinical characteristics and risk factors associated with lymphoma in patients with systemic lupus erythematosus: a nationwide cohort study.

OBJECTIVES: To assess the characteristics and risk of lymphoma in a large cohort of patients with SLE. METHODS: A case-cohort analysis was performed within a dynamic cohort of SLE patients from the Spanish Society of Rheumatology Lupus Registry (RELESSER). Clinical and analytical features were compared between the lymphoma SLE group and the control SLE group using an independent-sample Student's t-test or Mann-Whitney test for continuous variables and the χ2 test for categorical variables with Fisher's exact test if necessary. The multivariate analysis was based on a generalized linear model. RESULTS: Twenty-one patients with SLE and lymphoma and 3965 non-lymphoma controls with SLE were studied. Most lymphomas were of B cell origin (n = 15/21), with diffuse large B cell lymphoma being the most frequent histological type (8/21, 38.1%). As in the general population, the risk of lymphoma in SLE was higher in male than in female patients and increased with age. In the lymphoma SLE group, bivariate analysis showed a significantly higher percentage of pericarditis, organic brain syndrome, seizures, vasculitis, haemolytic anaemia, splenomegaly, venous thrombosis and mean modified (excluding lymphoma) SLICC/ACR damage index. In contrast, renal involvement, positive anti-dsDNA, and antimalarials ever were less frequent. CONCLUSIONS: In this large multicentre Spanish cohort, we identified characteristics of SLE that are associated with a higher risk of lymphoma. Antimalarials were significantly negatively associated with risk of lymphoma in SLE patients. Nevertheless, further prospective studies are needed to clarify these findings.

Real-World Effectiveness and Treatment Retention of Secukinumab in Patients with Psoriatic Arthritis and Axial Spondyloarthritis: A Descriptive Observational Analysis of the Spanish BIOBADASER Registry.

Rheumatic diseases are extensively managed with biological disease-modifying antirheumatic drugs (bDMARDs), but a notable proportion of patients withdraw in the long term because of lack of effectiveness, adverse events, or the patient's decision. The present real-world analysis showed the effectiveness, retention, and safety data collected in the Spanish BIOBADASER registry for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA, including ankylosing spondylitis (AS) and non-radiographic axSpA) treated with secukinumab, a human antibody against interleukin-17A (IL-17A), for more than 12 months. Six hundred and thirty-nine patients were analysed (350, 262, and 27 PsA, AS, and nr-axSpA patients, respectively). The results showed an improvement in the disease activity after 1 year of treatment, in terms of decreases of the mean Disease Activity Score 28 using C-reactive protein (DAS28-CRP), the mean Disease Activity Psoriatic Arthritis (DAPSA) score, swollen joint counts (SJC), and tender joint counts (TJC) in PsA patients and decreases in the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the mean Ankylosing Spondylitis Disease Activity Score (ASDAS) in axSpA patients. This improvement was maintained or increased after 2 and 3 years of treatment, indicating that secukinumab is effective in both naïve and non-responder patients. Retention rates were higher when secukinumab was used as the first-line biological treatment, although they were also adequate in the second and third lines of treatment. Collected safety data were consistent with previous reports.

Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment: data from the BIOBADASER III register.

OBJECTIVES: To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). METHODS: All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young (< 25 years old), adult (25-64 years old), elderly (65-75 years old) or very elderly (> 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. RESULTS: 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13-1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01-2.24)] and female gender [HR 1.42 (1.22-1.64)]. CONCLUSION: Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics.

Hormonal Dependence and Cancer in Systemic Lupus Erythematosus.

OBJECTIVE: To estimate the incidence and analyze any cancer-associated factors in patients with systemic lupus erythematosus (SLE), differentiating between hormone-sensitive (HS) and non-HS cancers. METHODS: This was a retrospective multicenter study of a patient cohort from the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology. Included were the first cancer post-SLE diagnosis, clinical and sociodemographic information, cumulative damage, severity, comorbidities, treatments, and refractoriness. Cancers were classified as HS (prostate, breast, endometrium, and ovarian) and non-HS (the remainder). The standardized incidence ratio (SIR) was calculated and logistic regression models were built. RESULTS: A total of 3,539 patients (90.4% women) were included, 154 of whom had cancer (91% female), and 44 had HS cancer (100% female). The cancer SIR was 1.37 (95% confidence interval [95% CI] 1.15-1.59), with higher values in women age <65 years (SIR 2.38 [95% CI 1.84-2.91]). The SIR in women with HS versus non-HS cancer was 1.02 (95% CI 0.13-1.91) and 1.93 (95% CI 0.98-2.89). In HS versus non-HS cancers, SLE diagnostic age (odds ratio [OR] 1.04 [P = 0.002] versus 1.04 [P = 0.019]), and period of disease evolution (OR 1.01 [P < 0.001] versus 1.00 [P = 0.029]) were associated with cancer. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (OR 1.27 [P = 0.022]) and angiotensin-converting enzyme (ACE) inhibitor prescriptions (OR 2.87 [P = 0.048]) were associated with non-HS cancers. CONCLUSION: Cancer incidence in patients with SLE was higher than in the Spanish population, particularly among young women. This increase might be due to non-HS cancers, which would be associated with SLE involving greater cumulative damage where more ACE inhibitors are prescribed.

Bacteremia in Systemic Lupus Erythematosus in Patients from a Spanish Registry: Risk Factors, Clinical and Microbiological Characteristics, and Outcomes.

OBJECTIVE: To describe the incidence of bacteremia in a large multicentric cohort of patients with systemic lupus erythematosus (SLE) and their clinical characteristics and to identify risk factors. METHODS: All bacteremic episodes from the Spanish RELESSER registry were included. Clinical and laboratory characteristics concerning bacteremia and SLE status, as well as comorbidities at the time of infection, were retrospectively collected. A comparison with sex- and age-matched SLE controls without bacteremia was made. A logistic regression was conducted. RESULTS: The study included 114 episodes of bacteremia in 83 patients. The incidence rate was 2.7/1000 patient-years. At the time of bacteremia, the median age was 40.5 (range: 8-90) years, and 88.6% of patients were female. The Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index was 4 [interquartile range (IQR) 8]; 41% had an SLE flare (66% severe); Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was 3 (IQR 4). A comorbidity was recorded in 64% of cases. At the time of bacteremia, 88.6% received corticosteroids (68.6% > 10 mg/day) and 57% immunosuppressors. Gram-negative bacilli, most frequently Escherichia coli (29.8%), caused 52.6% of the episodes. The bacteremia-related mortality was 14% and bacteremia was recurrent in 27.2% of cases. A dose-response relationship was found between corticosteroids and bacteremia risk. In the multivariate analysis, these factors were associated with bacteremia: elevated creatinine (OR 1.31, 95% CI 1.01-1.70; p = 0.045), diabetes (OR 6.01, 95% CI 2.26-15.95; p < 0.001), cancer (OR 5.32, 95% CI 2.23-12.70; p < 0.001), immunosuppressors (OR 6.35, 95% CI 3.42-11.77; p < 0.001), and damage (OR 1.65, 95% CI 1.31-2.09; p < 0.001). CONCLUSION: Bacteremia occurred mostly in patients with active SLE and was frequently associated with severe flares and corticosteroid use. Recurrence and mortality were high. Immunosuppressors, comorbidities, and disease-related damage were associated with bacteremia.

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. METHODS: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. RESULTS: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. CONCLUSIONS: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus.

OBJECTIVES: To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort. METHODS: All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. RESULTS: A total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999). CONCLUSIONS: Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.

Comorbidities in Patients With Primary Sjögren's Syndrome and Systemic Lupus Erythematosus: A Comparative Registries-Based Study.

OBJECTIVE: To compare the prevalence of the main comorbidities in 2 large cohorts of patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), with a focus on cardiovascular (CV) diseases. METHODS: This was a cross-sectional multicenter study where the prevalence of more relevant comorbidities in 2 cohorts was compared. Patients under followup from SJOGRENSER (Spanish Rheumatology Society Registry of Primary SS) and RELESSER (Spanish Rheumatology Society Registry of SLE), and who fulfilled the 2002 American-European Consensus Group and 1997 American College of Rheumatology classification criteria, respectively, were included. A binomial logistic regression analysis was carried out to explore potential differences, making general adjustments for age, sex, and disease duration and specific adjustments for each variable, including CV risk factors and treatments, when appropriate. RESULTS: A total of 437 primary SS patients (95% female) and 2,926 SLE patients (89% female) were included. The mean age was 58.6 years (interquartile range [IQR] 50.0-69.9 years) for primary SS patients and 45.1 years (IQR 36.4-56.3 years) for SLE patients (P < 0.001), and disease duration was 10.4 years (IQR 6.0-16.7 years) and 13.0 years (IQR 7.45-19.76 years), respectively (P < 0.001). Smoking, dyslipidemia, and arterial hypertension were associated less frequently with primary SS (odds ratio [OR] 0.36 [95% confidence interval (95% CI) 0.28-0.48], 0.74 [95% CI 0.58-0.94], and 0.50 [95% CI 0.38-0.66], respectively) as were life-threatening CV events (i.e., stroke or myocardial infarction; OR 0.57 [95% CI 0.35-0.92]). Conversely, lymphoma was associated more frequently with primary SS (OR 4.41 [95% CI 1.35-14.43]). The prevalence of severe infection was lower in primary SS than in SLE (10.1% versus 16.9%; OR 0.54 [95% CI 0.39-0.76]; P < 0.001). CONCLUSION: Primary SS patients have a consistently less serious CV comorbidity burden and a lower prevalence of severe infection than those with SLE. In contrast, their risk of lymphoma is greater.

Dermatosis pustulosa subcórnea como debut de un paciente con lupus eritematoso sistémico

El lupus eritematoso sistémico es una enfermedad inflamatoria que afecta fundamentalmente a mujeres en edad fértil, aunque en ocasiones su debut llega en edades tempranas de la vida. Múltiples son las manifestaciones clínicas que pueden aparecer en el curso de la enfermedad y que afectan a todos los órganos y sistemas de órganos del cuerpo humano. Se describen diversas formas de debut de la enfermedad, dentro de las cuales los síntomas generales, afectación neurológica, dermatológica y renal han sido reportada como las más frecuentes. Se presenta el caso de un niño de 6 años de edad que debuta con un lupus eritematoso sistémico y que su lesión o signo de debut es una manifestación dermatológica: la dermatosis pustulosa subcornea

Systemic lupus erythematosus is an inflammatory disease that mainly affects women of childbearing age, although sometimes its debut comes at early ages of life. Multiple are the clinical manifestations that can appear in the course of the disease and that affect all organs and organ systems of the human body. Various forms of disease debut are described, within which the general symptoms, neurological, dermatological and renal involvement have been reported as the most frequent. We present the case of a 6-year-old boy who debuted with systemic lupus erythematosus and whose lesion or debut sign is a dermatological manifestation: the subcorneal pustular dermatosis

Tocilizumab in refractory aortitis: study on 16 patients and literature review.

OBJECTIVES: Non-infectious aortitis is often refractory to standard immunosuppressive therapy. Since IL-6 has been implicated in the pathogenesis of aortitis, we assessed the efficacy of the anti-IL6 receptor monoconal antibody tocilizumab (TCZ) in a series of patients with refractory non-infectious aortitis. METHODS: Review of 16 patients (14 women/2 men) with refractory aortitis diagnosed by imaging (CT angiography, MR angiography, and/or PET) that were treated with TCZ. RESULTS: The mean age±SD was 51.4±20.1 years. The underlying conditions were: Takayasu arteritis (TakA) (n=7 cases), giant cell arteritis (GCA) (n=7), relapsing polychondritis (RP) (n=1), and aortitis associated with retroperitoneal fibrosis (n=1). TCZ was the first biologic drug used in all patients with GCA and in the patient with aortitis associated with retroperitoneal fibrosis but in only 2 of 7 TakA patients. In the remaining cases anti-TNF inhibitors were prescribed before TCZ (standard dose was 8 mg/kg/iv/4 weeks). After a mean±SD follow-up of 11.8±6.6 months most patients experienced clinical improvement, showing reduction of erythrocyte sedimentation rate from 43±36 mm/1st h to 5±4 mm/1st h at last visit. At TCZ onset, 25% of patients had fever and 19% polymyalgia rheumatica. These manifestations disappeared after 3 months of TCZ therapy. A corticosteroid sparing effect was also achieved (from 27.3±17.6 mg/day of prednisone at TCZ onset to 4.2±3.8 mg/day at last visit). TCZ had to be discontinued in a patient because of severe neutropenia. CONCLUSIONS: TCZ appears to be effective and relatively safe in patients with inflammatory aortitis refractory to corticosteroids or to other biologic immunosuppressive drugs.

Anaphylactoid reaction to high-dose methotrexate and successful desensitization.

Anaphylactic/anaphylactoid reaction to methotrexate (MTX) is uncommon. It may occur with the first dose (non-allergic reactions) or after a previous exposure to the drug (allergic or specific reactions). Desensitization has been shown effective in children with allergic-type reactions permitting the continuation of high-dose methotrexate (HDMTX) therapy. We report the case of a child with localized osteosarcoma who developed an anaphylactoid reaction after a first HDMTX course. A desensitization protocol was successfully applied allowing the administration of four additional courses. In our experience, desensitization can be a safe and effective procedure in children with anaphylactoid reactions to HDMTX.

Multiple parosteal lipoma associated to polyarthritis.

Parosteal lipoma is a benign adipose tissue tumor situated directly in the bone cortex. All cases previously reported in the literature were described as solitary lesions. We describe a patient who presented with polyarthritis associated with multiple parosteal lipomatous involvement. A tissue sample from the distal portion of the forearm confirmed the presence of cumulative fat tissue with nodes of esteatonecrosis. To the best of our knowledge this is the first case of multiple parosteal lipoma associated to polyarthritis.