The impact of antinuclear antibodies seroconversion induced by anti-tumor necrosis factor α agents on the clinical outcomes in rheumatic patients.

INTRODUCTION: Anti-tumor necrosis factor α (anti-TNFα) agents can potentially induce the anti-nuclear antibodies (ANA) development over time. Evidence of the real impact of these autoantibodies on clinical response to treatment in rheumatic patients is still scarce. OBJECTIVES: To explore the impact of ANA seroconversion induced by anti-TNFα therapy on clinical outcomes in biologic-naïve patients with Rheumatoid arthritis (RA), axial spondylarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: An observational retrospective cohort study enrolling biologic-naïve patients with RA, axSpA and PsA who started their first anti-TNFα agent was conducted for 24 months(M). Sociodemographic data, laboratory findings, disease activity and physical function scores were collected at baseline, 12M and 24M. To examine the differences between the groups with and without ANA seroconversion, independent samples t-tests, Mann-Whitney U-tests and chi-square tests were performed. Linear and logistic regression models were used to assess the effects of ANA seroconversion on the clinical response to treatment. RESULTS: A total of 432 patients with RA (N=185), axSpA (N=171) and PsA (N=66) were included. ANA seroconversion rate at 24M was 34.6%, 64.3% and 63.6% for RA, axSpA and PsA, respectively. Regarding sociodemographic and clinical data in RA and PsA patients, no statistically significant differences between groups with and without ANA seroconversion were found. In axSpA patients, ANA seroconversion was more frequent in patients with higher body mass index (p=0.017) and significantly less frequent in patients treated with etanercept (p=0.01). Regarding disease activity, DAS28 for RA patients and ASDAS-CRP for axSpA patients were significantly higher in ANA seroconversion group at 12M (p=0.017 and p=0.009, respectively). For PsA patients, CDAI was significantly higher in ANA seroconversion group at 24M (p=0.043). Overall switching rate of biologic disease-modifying antirheumatic drugs (bDMARD) was significantly higher in the ANA seroconversion group over time (p=0.025). For RA patients, ANA seroconversion predicted DAS28 (ß=-0.21, 95%CI[-1.86;-0.18], p=0.017) at 12M. CONCLUSIONS: ANA seroconversion induced by anti-TNFα agents could interfere in clinical response of patients with rheumatic diseases. The presence of these autoantibodies can be considered as a potential predictor of poor treatment response and higher need for bDMARD switching over time.

FRAX 10-year fracture risk in rheumatoid arthritis assessed with and without bone mineral density - are we treating our patients under bDMARDs?

OBJECTIVE: This study aimed to identify the rheumatoid arthritis (RA) patients under biological therapy who have FRAX® scores classified as high fracture risk and to evaluate if they are receiving treatment for osteoporosis (OP). The authors also investigated the intra-individual agreement between FRAX® fracture risk calculated with and without bone mineral density (BMD). METHODS: A single-center retrospective cohort study was performed in a total of 303 patients with RA under biologics. Demographic and clinical data were collected using Rheumatic Diseases Portuguese Register (Reuma.pt), complemented with data from the hospital clinical records. FRAX scores with and without BMD were calculated. The Kendall's Tau coefficient was used to assess the agreement between FRAX risk categories. Correlations were evaluated by the Spearman test. Comparisons of distributions from independent variables used the Mann-Whitney test. RESULTS: When FRAX® score was calculated without BMD (n=303), 25% patients were categorized as high fracture risk. Among them, only 54% were receiving OP treatment. FRAX® assessment with BMD (n=231) identified 33% patients with high fracture risk, 52% in treatment for OP. Thirty patients (21%) previously classified as low fracture risk using FRAX® without BMD were recategorized as high risk (𝜏=0.570, p.

The Impact of COVID-19 on Nursing Homes: Study Design and Population Description.

Nursing homes for the elderly in Spain have experienced high rates of infection and mortality from COVID-19, although rates have varied from one region to another. Madrid is the region where most institutionalized older adults have died from the coronavirus. However, there is little known about the psychosocial and environmental factors involved in the high incidence of COVID-19 among the institutionalised population in this region. This article describes the protocol of a study on nursing homes during the SARS-CoV-2 pandemic in the Autonomous Community of Madrid (hereafter: Region of Madrid or Madrid Region) and provides information on the study design, measures used, and characteristics of the population studied. A questionnaire about life in nursing homes during the COVID-19 pandemic was designed and a total of 447 persons over 60 years of age without cognitive impairment-220 in private nursing homes and 227 in public nursing homes-participated by answering questions about different topics: personal situations during the pandemic, feelings and methods of coping, residential environment, health, quality of life, ageism, and self-perception of ageing. The institutionalised person profile discussed in this study was an old woman, widowed, without children, with a low level of education, with multimorbidity, and who perceived her health and quality of life positively. Most of the participants were very concerned about COVID-19 and its effects. In fact, 38% had been diagnosed with COVID-19, of whom 20% were admitted to hospital and 20% had suffered negative impacts, such as pain and neurological problems. In addition, 70% of the residents remained confined to their rooms, which increased their perceptions of loneliness and social isolation. The worst-rated aspects of the nursing home resulted from the restrictive measures imposed on nursing homes during the pandemic. This research offers useful material for understanding the pandemic and its consequences from the perspective of the older institutionalised population, which could provide insights for designing public policies.

Takotsubo Syndrome in a Rheumatoid Arthritis Patient Under Tofacitinib: A Case Report.

We describe a case of a 57-year-old white woman treated for rheumatoid arthritis (RA) with tofacitinib 10mg daily (started one year ago) and prednisolone 5mg daily. She presented to the emergency department with a tight squeezing chest pain and shortness of breath for 7h and the clinical evaluation revealed regional systolic dysfunction of the left ventricle, mimicking a myocardial infarction, in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. All changes were transient and resolved completely within 4 days. The diagnosis of Takotsubo cardiomyopathy (TKM) was established. This is, as far as we know, the first report of a case of TKM in a RA patient taking tofacitinib. Although the association has not been previously described and the precise cause cannot be identified in this patient, the association with tofacitinib should be considered given the etiopathogenic rationale and the absence of any other identifiable cause.

Renal involvement in Behçet´s Disease: a rare clinical challenge.

Although Behçet´s disease (BD) is a systemic inflammatory disease, renal involvement is uncommon and ranges from mild asymptomatic urinary abnormalities to severe disease with progressive renal failure. We describe the case of a 30 years-old woman with multiorgan BD, under ustekinumab, who presented with proteinuria, hematuria and impaired renal function. Kidney biopsy revealed histological findings of active renal vasculitis in the context of IgA nephropathy and tubulointerstitial nephritis and the patient was treated with corticosteroids and cyclophosphamide with excellent response. Our case highlights the importance of recognizing a possible renal involvement in BD patients, reinforcing the need for monitoring renal function and urinalysis in these patients.

Bone mineral density and fracture risk in a cohort of Portuguese systemic sclerosis patients.

Patients with Systemic Sclerosis (SSc) seem to have higher prevalence of low bone mineral density (BMD) and spine fracture risk. We performed a transversal study including patients with the diagnosis of SSc to determine, by conventional densitometry and using the fracture risk assessment tool (FRAX), the prevalence of low BMD and the fracture risk, respectively, in a SSc Portuguese cohort and its potential determinants. Ninety-seven patients were included; 88.7% females (n=86) with median age of 62 years [56, 70]. Low BMD was present in 45 patients (46.4%). BMD in the femoral neck (FN) presented a weak positive correlation with body mass index (BMI) and the risk for major fracture with and without BMD presented a positive correlation with spine fractures. No correlations were found between BMD-FN and disease manifestations. Our results showed that low BMD is prevalent in SSc patients and may be associated with low BMI. FRAX appears to be an useful instrument as it correlates with spine fracture risk and with BMD. This is the first study in Portugal evaluating prevalence of low BMD and fracture risk in a Portuguese SSc cohort.

Risk Factors for Infection, Predictors of Severe Disease, and Antibody Response to COVID-19 in Patients With Inflammatory Rheumatic Diseases in Portugal-A Multicenter, Nationwide Study.

Objective: To identify risk factors for SARS-CoV-2 infection and for severe/critical COVID-19, and to assess the humoral response after COVID-19 in these patients. Methods: Nationwide study of adult patients with inflammatory RMDs prospectively followed in the Rheumatic Diseases Portuguese Register-Reuma.pt-during the first 6 months of the pandemic. We compared patients with COVID-19 with those who did not develop the disease and patients with mild/moderate disease with those exhibiting severe/critical COVID-19. IgG antibodies against SARS-CoV-2 were measured ≥3 months after infection and results were compared with matched controls. Results: 162 cases of COVID-19 were registered in a total of 6,363 appointments. Patients treated with TNF inhibitors (TNFi; OR = 0.160, 95% CI 0.099-0.260, P < 0.001) and tocilizumab (OR 0.147, 95% CI 0.053-0.408, P < 0.001) had reduced odds of infection. Further, TNFi tended to be protective of severe and critical disease. Older age, major comorbidities, and rituximab were associated with an increased risk of infection and worse prognosis. Most patients with inflammatory RMDs (86.2%) developed a robust antibody response. Seroconversion was associated with symptomatic disease (OR 13.46, 95% CI 2.21-81.85, P = 0.005) and tended to be blunted by TNFi (OR 0.17, 95% CI 0.03-1.05; P = 0.057). Conclusions: TNFi and tocilizumab reduced the risk of infection by SARS-CoV-2. Treatment with TNFi also tended to reduce rates of severe disease and seroconversion. Older age, general comorbidities and rituximab were associated with increased risk for infection and worse prognosis, in line with previous reports. Most patients with RMDs developed a proper antibody response after COVID-19, particularly if they had symptomatic disease.

Clinical features and outcome of 1054 patients with Systemic Sclerosis: analysis of Reuma.pt/SSc registry.

BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disorder with heterogeneous manifestations and outcomes. Besides differences in disease characteristics among distinct ethnic groups and geographical regions, several questions regarding the impact of the disease and the effectiveness of treatments remain unanswered. To address these questions, the Rheumatic Diseases Portuguese Register (Reuma.pt) launched a specific protocol for the prospective follow-up of SSc patients. OBJECTIVES: To describe the baseline characteristics, disease subsets, treatments used and survival of SSc patients registered in Reuma.pt/SSc. METHODS: Data from adult patients with SSc included in Reuma.pt up to November 2020 were analysed. Demographic features, SSc subsets, fulfilment of classification criteria, main clinical and immunological features, comorbidities, treatments used and survival data were described and compared between diffuse cutaneous (dc) and limited cutaneous (lc) disease subsets. Survival was calculated for patients included in Reuma.pt within the first two years of diagnosis. RESULTS: In total, 1054 patients were included, 87.5% female, with a mean age at diagnosis of 52.7 +/- 14.8 years. The most common subset was lcSSc (56.3%), followed by dcSSc (17.5%), preclinical SSc (13%), overlap syndrome (9.8%) and SSc sine scleroderma (3.3%). Raynaud's phenomenon (93.4%) and skin thickening (76.9%) were the most frequently observed clinical manifestations. Gastrointestinal (62.8% versus 47.8%), pulmonary (59.5% versus 23%) and cardiac (12.8% versus 6.9%) involvements were significantly more prevalent in dcSSc than lcSSc. Ninety per-cent of patients were Antinuclear antibody positive, 52.5% were Anti-centromere antibody positive and 21% anti-topoisomerase positive, with significant differences between lcSSc and dcSSc. One-third of patients were treated with immunomodulators, 53.6% with vasodilators, 23% with glucocorticoids and 2.3% with biologics. During follow-up, 83 deaths (7.9%) were reported. The overall 1-, 2- and 5-year survivals were 98.0%, 96.8% and 92.6%, respectively, without significant differences between lcSSc and dcSSc. CONCLUSION: Reuma.pt/SSc data highlights the importance of registries in improving knowledge about rare and complex diseases, such as SSc. Clinical features of Portuguese SSc patients are similar to those of other populations. In recently diagnosed patients, 5-year survival is over 92%. To the best of our knowledge, this is the first study showing that clinical features of Portuguese SSc are similar to those of other cohorts.

Gender differences in clinical features and outcomes of a Portuguese systemic sclerosis cohort.

Evidence for the role of sex in the clinical manifestations of systemic sclerosis (SSc) patients is emerging. Some multicenter cohorts have shown that male SSc patients have more severe disease and worse survival. To assess the differences in clinical manifestations and survival in Portuguese SSc patients according to gender. Data from male and female adult SSc patients included in the Rheumatic Diseases Portuguese Register (Reuma.pt) were analysed and compared. Survival was calculated for patients included in Reuma.pt. within the first two years of diagnosis (inception cohort). In total, 1054 adult patients with SSc were included, 12.5% males. No differences in demographic features and comorbidities were found between the sexes, except for a higher rate of cigarette smokers among men. Diffuse cutaneous SSc and anti-topoisomerase antibodies were more prevalent in males than females. Additionally, male patients presented significantly more myositis, interstitial lung disease and gastric involvement. There were no differences in the patterns of drug use between the sexes. During follow-up, more deaths were reported in men than women (12.1% vs 7.3%, p = 0.04). The overall 1-, 3-, and 5-year survivals from diagnosis of the inception cohort (N = 469) for men vs women were 96.4% vs 98.2%, 93% vs 95.9%, and 75.8% vs 93.2%, respectively, with statistically significant differences (p < 0.01). This study confirms the existence of gender differences in clinical and immunological SSc features. Although SSc is less common in men than women, men have a more severe expression of skin and internal organ involvement and worse survival. Key Points • There are differences in SSc disease manifestations between sexes. • Males more commonly have diffuse cutaneous SSc, anti-topoisomerase antibodies, pulmonary and musculoskeletal involvement. • In the inception cohort, men had worse survival rates than women.

Multiple Sclerosis in rheumatic patients treated with tumor necrosis factor alpha inhibitors: a single-center retrospective case series and literature review.

Tumor necrosis factor alpha inhibitors (TNFi) are basilar treatments in a number of inflammatory rheumatic conditions and autoimmune phenomena such as de novo neuroinflammatory events were already described in these populations under TNFi. We conducted a single-center retrospective study in a cohort of rheumatic patients treated with TNFi to characterize neurological demyelinating/inflammatory disease in these patients. We report 3 cases (n= 744): all of them had spondyloarthritis, the onset of neurological manifestations occurred between 37 and 58 years old and all of them initially presented with an optic neuritis. The neurological symptoms emerged between 13 and 26 months after starting TNFi. All patients discontinued treatment with TNFi, but one resumed therapy with symptomatic worsening, having to interrupt treatment again. All patients, latter on, fulfilled multiple sclerosis (MS) McDonald criteria 1 and were diagnosed with relapsing-remitting MS. Our study support the prior view of a risk, disease-dependent or agent-dependent, although a causal relationship is yet to be enlightened.

Bone involvement in young adults with cystic fibrosis - a Portuguese cohort.

INTRODUCTION: Long-term survivors of cystic fibrosis (CF) have a dramatic increase in the risk of osteoporosis and incident fracture. The objective of this work is to characterize a CF related bone disease in a Portuguese cohort of CF patients. METHODS: We performed a cross-sectional, observational study on a cohort of CF adult patients. Clinical status, laboratory parametres, nutrition, lung function tests, genetics and bone mineral density (BMD) data were collected from a CF reference centre. RESULTS: Of 30 patients, 53.3% were males (n=16). Median age was 32.5 (27.0; 32,5) and median body mass index (BMI) was 22,04 (19,85; 24,55), with 4 patients (13.3%) being underweight (BMI<18.5 kg/m²). Four patients (13.3 %) were diagnosed with osteoporosis and 15 patients (50%) has low BMD. Among them, 2 (6.7%) had fragility fractures. A moderate correlation was found between the lumbar spine (LS) BMD and BMI and, as expected, femural neck BMD and LS BMD has moderate to strong correlations with BMD Z scores. CONCLUSION: Despite the young middle age we found a high prevalence of low BMD and osteoporosis in patients with CF. Early recognition and treatment are the most effective strategies for reducing the morbidity due to osteoporosis in these patients.

Takotsubo Syndrome in a Rheumatoid Arthritis Patient Under Tofacitinib: A Case Report.

We describe a case of a 57-year-old white woman treated for rheumatoid arthritis (RA) with tofacitinib 10mg daily (started one year ago) and prednisolone 5mg daily. She presented to the emergency department with a tight squeezing chest pain and shortness of breath for 7h and the clinical evaluation revealed regional systolic dysfunction of the left ventricle, mimicking a myocardial infarction, in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. All changes were transient and resolved completely within 4 days. The diagnosis of Takotsubo cardiomyopathy (TKM) was established. This is, as far as we know, the first report of a case of TKM in a RA patient taking tofacitinib. Although the association has not been previously described and the precise cause cannot be identified in this patient, the association with tofacitinib should be considered given the etiopathogenic rationale and the absence of any other identifiable cause.

Aseptic hypertrophic pachymeningitis in a patient with Rheumatoid Arthritis - a case of involvement of the central nervous system by the disease?

Hypertrophic pachymeningitis (HP) is a rare clinical entity which uncommonly occurs in rheumatoid arthritis (RA) patients. We describe the case of a rheumatoid factor and anti-citrullinated protein antibody positive RA male that was diagnosed with HP and multiple mononeuropathy. Although histological evaluation was not performed, after excluding infectious and neoplastic causes, it was possible to determine a probable inflammatory etiology. He was treated with glucocorticoids and rituximab with a good clinical evolution. This case represented a challenging differential diagnosis but the need for an accurate diagnosis should not delay the introduction of an effective therapy for a potentially lethal disease.

Early retirement attributed to rheumatoid arthritis and its predictors.

OBJECTIVE: To evaluate the rate of early retirement due to rheumatoid arthritis (RA) in Portugal. METHODS: Prospective cohort study involving 11 Portuguese centers, including patients with a clinical diagnosis of RA, based on Reuma.pt registry, enrolled between 2008 and 2019. RESULTS: 3231 patients were included (81.5% female, aged 60.8 ± 13.0 years, mean disease duration 18.0 ± 10.3 years). Until the present time, 37.6% of these patients retired, 59.6% due to RA. Early retirement due to RA translated into losing 7 years of active work when compared to patients retired to other causes. Compared to professionally active patients, retired patients due to RA were diagnosed later in the disease process (p=0.003), had longer disease duration (p < 0.001), were more frequently positive for rheumatoid factor (p=0.043), had more frequently erosive disease (p < 0.001), had a blue-collar occupation (p < 0.001) and had a lower educational level (p < 0.001). Independent predictors for early retirement due to RA were: delayed diagnosis (OR: 2.23; 95% CI 1.18-4.21/year, p=0.013), erosive disease (OR: 2.21 95% CI 1.54-3.16, p < 0.001), need for biologic therapy (OR: 1.32; 95%CI 1.01-1.73, p=0.045) and lower educational level (OR: 0.83; 95%CI 0.79-0.86/year, p < 0.001). CONCLUSION: RA is, itself, the leading cause of early retirement in RA patients, accounting for the loss of an average of 7 years of active work. Delayed diagnosis, erosive disease and lower educational level are the main predictors of early retirement associated with RA in this population.

Remission and low disease activity matrix tools: results in real-world rheumatoid arthritis patients under anti-TNF therapy.

BACKGROUND: Remission/ low disease activity (LDA) are the main treatment goals in rheumatoid arthritis (RA) patients. Two tools showing the ability to predict golimumab treatment outcomes in patients with RA were published. OBJECTIVES: To estimate the real-world accuracy of two quantitative tools created to predict RA remission and low disease activity. METHODS: Multicenter, observational study, using data from the Rheumatic Diseases Portuguese Register (Reuma.pt), including biologic naïve RA patients who started an anti-TNF as first-line biologic and with at least 6 months of follow-up. The accuracy of two matrices tools was assessed by likelihood-ratios (LR), sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under the ROC curve (AUC). RESULTS: 674 RA patients under first-line anti-TNF (266 etanercept, 186 infliximab, 131 adalimumab, 85 golimumab, 6 certolizumab pegol) were included. The median (IQR) age was 53.4 (44.7-61.1) years and the median disease duration was 7.7 (3.7-14.6) years. The majority were female (72%). Most patients were RF and/or ACPA positive (75.5%) and had erosive disease (54.9%); 58.6% had comorbidities. At 6-months, 157 (23.3%) patients achieved remission (DAS28 ESR < 2.6) and 269 (39.9%) LDA (DAS28 ESR ≤ 3.2). Area under the curve for remission in this real-world sample was 0.756 [IC 95% (0.713-0.799)] and for LDA was 0.724 [IC 95% (0.686 -0.763)]. The highest LR (8.23) for remission state was obtained at a cut-off ≥ 67%, with high specificity (SP) (99.6%) but low sensitivity (SN) (3.2%). A better balance of SN and SP (65.6% and 73.9%, respectively) was observed for a cut-off >30%, with a LR of 2.51, PPV of 43.3% and NPV of 87.6%. CONCLUSION: In this population, the accuracy of the prediction tool was good for remission and LDA. Our results corroborate the idea that these matrix tools could be helpful to select patients for anti-TNF therapy.

Genotoxicity assessment of four novel quinazoline-derived trypanocidal agents in the Drosophila wing somatic mutation and recombination test.

Chagas disease, caused by the protozoan Trypanosoma cruzi, has increased in the world due to migration, travelling and climate change; at present, the principal problem is that common trypanocidal agents have resulted in toxic or inconvenient side effects. We tested for genotoxicity in the standard (ST) and high bioactivation (HB) crosses of Drosophila wing somatic mutation and recombination test, four novel trypanocidal agents derived from 2, 4, 6-triaminquinazoline (TAQ): 2,4-diamino-6 nitro-1,3 diazonaftalene (S-1QN2-1), 2,4-diacetamino-6-amino 1,3 diazonaftalene (D-1), N6-(4,methoxybenzyl)quinazoline-2,4,6-triamine (GHPM) and N6-[4-(trifluoromethoxy)benzyl]quinazoline-2,4,6-triamine (GHPMF) at 1.9, 3.9, 7.9 and 15 µM, respectively. Also, high-pressure liquid chromatography (HPLC) analysis was run to determine the remanence of either drug in flare, and Oregon R(R)-flare flies emerged from treated larvae. S-1QN2-1 showed genotoxicity only in the ST cross, increasing the small, large and total spot frequencies at all concentrations and twin spots only at 1.9 µM; D-1 and GHPM showed significant increments of large spots only at 15 µM in the ST cross; GHPMF was not genotoxic at any concentration or either cross. In the mwh clones accumulated distribution frequencies analysis, associated with disrupted cell division, S-1QN2-1 caused alterations in the ST cross at all concentrations but only at 15 µM in the HB cross; D-1 caused alterations at 3.9, 7.9 and 15 µM in the ST cross and at 1.9 and 15 µM in the HB cross; GHPM caused alterations at 7.9 and 15 µM in the ST cross and also at 1.9, 3.9 and 7.9 µM in the HB cross; GHPMF caused those alterations at all concentrations in the ST cross and at 1.9, 3.9 and 7.9 µM in the HB cross. The HPLC results indicated no traces of either agent in the flare and Oregon R(R)-flare flies. We conclude that S-1QN2-1 is clearly genotoxic, D-1 and GHPM have an unclear genotoxicity and GHPMF was not genotoxic; all quinazoline derivatives disrupted cell division. GHPMF is a good candidate to be tested in other genotoxicity and cytotoxic bioassays. The differences in the genotoxic activity of these trypanocidal agents are correlated with differences in their chemical structure.

Cortical Visual Evoked Potentials and Growth in Infants Fed with Bioactive Compounds-Enriched Infant Formula: Results from COGNIS Randomized Clinical Trial.

Postnatal nutrition is essential for growth and neurodevelopment. We analyzed the influence of a new enriched-infant formula with bioactive compounds on growth, neurodevelopment, and visual function (VF) in healthy infants during their first 18 months of life. A total of 170 infants were randomized in the COGNIS randomized clinical trial (RCT) to receive a standard infant formula (SF = 85) or a new experimental infant formula supplemented with functional nutrients (EF = 85). As a control, 50 breastfed infants (BF) were enrolled. Growth patterns were evaluated up to 18 months of life; neurodevelopment was assessed by general movements at 2, 3, and 4 months; VF was measured by cortical visual evoked potentials at 3 and 12 months. No differences in growth and neurodevelopment were found between groups. Regarding VF, SF and EF infants presented prolonged latencies and lower amplitudes in the P100 wave than BF infants. In the EF group, a higher percentage of infants presented response at 7½'of arc at 12 months compared to 3 months of age; a similar proportion of BF and EF infants presented responses at 7½'of arc at 12 months of age. Early nutritional intervention with bioactive compounds could narrow the gap in growth and neurodevelopment between breastfed and formula-fed infants.