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Introduction: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status., Objective: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort., Results: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6., Conclusion: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability., Competing Interests: Declaration of competing interest Authors declare no conflict of interest regarding this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A Consensus of Psychoimmunology Experts (Pollak et al., 2019) established a set of red flags and proposed diagnostic criteria for psychosis of autoimmune origin (AIP). Previous studies on AIP are limited by the scarcity of CSF analysis, preventing the valorization of blood anti-neuronal antibodies (Ab). The aims of this study are to determine the relative frequency and characterize AIP in a cohort of psychotic patients that underwent CSF workup. This work is a retrospective study in a tertiary psychiatric hospital. Clinical and paraclinical data were collected from medical records, and patients were classified according to Pollak et al. (2019) criteria. From 68 patients, ten (14.7%) had positive anti-neuronal antibodies (Ab): n = 5 in CSF and blood (n = 4 anti-NMDAr, n = 1 -GAD65), and n = 5 in blood only (n = 1 anti-GABAb, n = 1 -GAD65, n = 1 -SOX1, n = 1 -NMDAr, n = 1 -zic4). After 5- (2-10)-year follow-up, n = 6/68 (8.8%) had AIP diagnosis in context of autoimmune encephalitis (AE), and the remaining (n = 4/10, blood-only Ab) alternative diagnoses (n = 2 dementia, n = 1 schizophrenia, n = 1 intellectual disability). Ten of the 13 patients that fulfilled criteria for possible AIP were mimics, and only three AE had criteria for probable AIP. All AIP developed neurological manifestations (mostly cognitive dysfunction); EEG was usually abnormal (66.7%), and all had normal MRI. We found statistically significant associations between AIP/AE and systemic autoimmune disease, presentation with seizures and EEG abnormalities. All AE developed neurological symptoms alongside psychosis. Ab positivity occurred predominantly in AE but also in other neuropsychiatric disorders. Clinical suspicion based on the knowledge of the described presentations of established Ab is crucial in the psychotic patient approach., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Anti-GAD65 antibodies are associated with several neurological phenotypes. Antibody titers are increasingly recognized as useful in diagnosis and prognosis., Objective: To describe a Portuguese cohort of patients with anti-GAD65-associated neurological syndromes., Methods: Retrospective analysis of all patients with positive anti-GAD65 antibodies and associated neurological syndromes followed in a tertiary referral center., Results: Nineteen anti-GAD65 antibody-positive neurological patients were identified, 62.3% female, with a mean age of onset of 56.0 (SD = 13.3) years. Comorbid autoimmune disorders were present in seven patients. Six patients had limbic encephalitis (31.6%), four had epilepsy (21.1%), four had cerebellar ataxia (21.1%), and three had stiff-person syndrome (15.8%). Two patients presented with isolated cognitive dysfunction (executive and mnesic) in the absence of other neurological symptoms. The mean follow-up time was 24.0 (14.0-42.0) months, at the end of which the mean modified Rankin Scale (mRS) value was 2.0 (1.0-4.0). Screening for malignancies was negative in all patients. Serum quantitative analysis was carried out in 18 patients, 10 of whom showed titers above previously defined cut-off points (>10,000 IU/L for ELISA and >20 mmol/L for RIA). Quantitative CSF analysis was performed in nine patients, with four showing above-threshold titers. There was no association between anti-GAD65 levels and clinical phenotype or the final mRS values. High-dose intravenous methylprednisolone and oral prednisolone were the most common acute and chronic treatment regimens, respectively., Conclusion: Anti-GAD65 antibodies are associated with varied neurological syndromes, and antibody titers alone should not be used to exclude a disease., Competing Interests: Conflicts of InterestThe authors declare no conflicts of interest., (© 2024 by the authors.)

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαβ+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αβ T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei., (© 2024 Guérin et al.)

Background: Anti-titin antibodies have been previously associated with thymoma-associated myasthenia gravis (MG) and a more clinically severe form of MG. While currently only serving as a disease biomarker, its possible utility as an indicator of underlying thymus malignancy may be of value in clinical practice., Methods: Data was retrospectively collected and analyzed from 2013 to 2022 using an institutional record of MG patients. Anti-titin antibodies were assessed using Line Blot immunoassay., Results: From 130 MG cases, 32 (24.6%) were anti-titin positive. Anti-titin positive cases were associated with older age of disease onset [median (IQR): 63.0 (44.3-70.8) vs. 35.5 (24.8-60.8) years] (P<0.01). Thymectomy was performed in 46 (35.4%) MG patients, 12 of which anti-titin positive (26.1%). Thymectomy samples from anti-titin positive patients comprised 10 (83.3%) cases of thymoma and 2 (16.7%) cases of thymus hyperplasia. There was a tendency towards anti-titin positive patients having more thymoma while anti-titin negative displayed more hyperplasia (P<0.01). Anti-titin positivity correlated with thymoma in patients with age of onset bellow 50 years (P=0.028). Anti-titin positivity was significantly associated with generalized MG in the late-onset group (P=0.005)., Conclusions: The presence of anti-titin antibodies appears to correlate with underlying thymoma in early-onset MG cases and with generalized MG in late-onset cases. Prospective studies are needed to further study this association., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-94/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: Gastric cancer (GC) stands as a prominent cause of cancer-related mortality and ranks second among the most frequently diagnosed malignancies in individuals with common variable immunodeficiency (CVID)., Objective: We sought to conduct a comprehensive, large-scale genetic analysis to explore the CVID-associated germline variant landscape within gastric adenocarcinoma samples and to seek to delineate the transcriptomic similarities between GC and CVID., Methods: We investigated the presence of CVID-associated germline variants in 1591 GC samples and assessed their impact on tumor mutational load. The progression of GC was evaluated in patients with and without these variants. Transcriptomic similarities were explored by matching differentially expressed genes in GC to healthy gastric tissue with a CVID transcriptomic signature., Results: CVID-associated germline variants were found in 60% of GC samples. Our analysis revealed a significant association between the presence of CVID-related genetic variants and higher tumor mutational load in GC ( P  < .0001); high GC mutational load seems to be linked to immunotherapy response and worse prognosis. Transcriptomic similarities unveiled key genes and pathways implicated in innate immune responses and tumorigenesis. We identified upregulated genes related to oncogene drivers, inflammation, tumor suppression, DNA repair, and downregulated immunomodulatory genes shared between GC and CVID., Conclusions: Our findings contribute to a deeper understanding of potential molecular modulators of GC and shed light on the intricate interplay between immunodeficiency and cancer. This study underscores the clinical relevance of CVID-related variants in influencing GC progression and opens avenues for further exploration into novel therapeutic approaches., (© 2023 The Author(s).)

Competing Interests: E. Santos is part of the advisory board for Biogen, Genzyme, Bayer, Merck, Alexion, and Novartis and received a grant from Octapharma. The remaining authors report no conflicts of interest.

Introduction: Anti-contactin-associated protein-like 2 (CASPR2) is classically associated with limbic encephalitis (LE), Morvan syndrome and peripheral nerve hyperexcitability (PNH). Additional clinical features have been previously recognized., Objective: To describe a cohort of patients with anti-CASPR2-associated neurological syndromes from a tertiary referral centre., Methods: Retrospective analysis of patients with positive serum anti-CASPR2 antibodies in the period between 2014 and 2021., Results: Nineteen patients were identified, 11 (57.9%) male, with a median age at symptom onset of 49.0 (31.3-63.0) years and a median time to diagnosis of 1.0 (0.0-1.8) years. The most common clinical syndromes were LE (7 cases, 36.8%), Morvan syndrome (4, 21.1%) and PNH (2, 10.5%). Six patients presented with atypical phenotypes (31.6%), comprising dysautonomia (orthostatic hypotension and Adie's Pupil), motor tics/stereotypies, obsessive-compulsive disorder, and brainstem involvement. The most common presenting symptoms were seizures (31.6%), PNH (21.1%) and cognitive dysfunction (15.8%). One LE patient had a disease duration of 2,5 years and was initially diagnosed with dementia. CSF was normal in most cases. Brain MRI showed temporal lobe hyperintensities in 4 LE cases (57.1%). All PNH cases had myokymic discharges of fasciculations in the electromyography. Two patients had associated thymoma and 1 had lung adenocarcinoma. Eight patients (42.1%) received treatment during the acute phase and 26.3% maintenance treatment. Approximately half of the treated cases improved or stabilised, with 4 (21.1%) deaths in the whole cohort., Conclusion: Anti-CASPR2-associated neurological disorders may present with isolated atypical phenotypes, a slowly progressive clinical course, and with normal CSF or imaging findings., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: During pregnancy, the maternal immune system is challenged to tolerate a semi-allogenic fetus. A proinflammatory profile has been linked to adverse pregnancy outcomes and poor placental development. In this study, the authors evaluated the number of circulating Tregs and Th17 cells in a group of patients diagnosed with preeclampsia(PE) and fetal growth restriction(FGR)., Methods: Prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed in a cohort of pregnant patients with PE, FGR, and a control group of healthy pregnant women., Results: The diagnosis of PE was associated with a significative higher number of circulating Th17 cells and a significative relative reduction in the Treg cell count. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4 + CD25 high FOXP3 + Treg ratio. In the FGR group, the Th17 cell count was significantly higher during the third trimester of pregnancy. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4 + CD25 high FOXP3 + Treg ratio. When we compare the immunological profiles of patients with PE and FGR we observed a higher number of proinflammatory Th17 cells and a significative lower number of Treg cells in PE patients. This is particularly expressed in the differences found between the Th17/ CD4 + CD25 high FOXP3 + Treg ratios of these two groups. Discussion/Conclusion Our data showed a that a proinflammatory profile and a relative excess of Th17 cells was associated with the diagnosis of PE and FGR. A more exuberant systemic proinflammatory profile present in the PE patients is absent in patients with FGR without preeclampsia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2023. Published by Elsevier B.V.)

Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin's lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an in-silico approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guevara-Hoyer, Fuentes-Antrás, de la Fuente-Muñoz, Fernández-Arquero, Solano, Pérez-Segura, Neves, Ocaña, Pérez de Diego and Sánchez-Ramón.)

Introduction: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype., Objective: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD)., Methods: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD., Results: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001)., Conclusions: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort., (Copyright © 2022. Published by Elsevier B.V.)

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder that affects women at childbearing age. During pregnancy, maternal immune system is challenged to tolerate a semi-allogenic fetus and a shift toward a tolerogenic profile is essential. Failure to develop this tolerogenic profile seems to be associated with the development of adverse obstetric outcomes. We conducted a prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed during pregnancy in a group of SLE patients and compared with healthy gestations. We observed a reduction in peripheric Treg cell count throughout all pregnancy in control patients, which was not observed in SLE patients. In contrast, the Th17 cell count remained stable in both groups. In the control group, the Treg/Th17 ratio decreased throughout pregnancy to the postpartum, which was not observed in the study group. These changes may be justified by the migration of the immunotolerant Treg cells to the maternal decidua and may lead to the establishment of a pro-inflammatory profile by the end of pregnancy in healthy pregnancies, which was not observed in the SLE pregnant patients. This pro-inflammatory state at the end of a healthy pregnancy may be necessary for the spontaneous beginning of labor and help to explain why systemic syndromes like preeclampsia develop during the second half of pregnancy. The lack of these findings in SLE patients may express a pro-inflammatory state from the beginning of pregnancy, the influence of immunomodulatory medication or an intrinsic deregulation of immune function, which is a characteristic of these patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite the existence of well-established diagnostic criteria for autoimmune encephalitis, there are diseases capable of mimicking it. This study sought to retrospectively evaluate the reasons for testing and the final diagnosis of patients admitted to a Neurology ward tested for anti-NMDAR antibodies and estimate sensitivity and specificity of current diagnostic criteria. The threshold for testing was lower than that of the prevailing diagnostic criteria, and the proportion of autoimmune encephalitis mimics was high. Searching for alternative diagnoses is of pivotal importance in cases of autoimmune encephalitis suspicion, and diagnostic criteria may need expanding so that no autoimmune encephalitis is missed., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pregnancy in systemic lupus erythematosus (SLE) patients is associated with an increased risk of adverse outcomes. During pregnancy, SLE patients have a higher rate of miscarriage, stillbirth, preterm delivery, fetal growth restriction, or hypertensive disorders of pregnancy. To date, only a few case-control studies were published with the purpose to evaluate the magnitude of risk associated with pregnancy in lupus patients. The aim of our study was to evaluate the maternal and fetal outcomes in a cohort of Portuguese SLE patients and to compare it with a group of healthy pregnant women. We conducted a retrospective case-control study that included all pregnant women with SLE managed at a Portuguese tertiary center, between 2010 and 2019. Pregnancy outcomes were compared between SLE patients and a group of matched healthy pregnant women. Baseline maternal data was collected, and maternal-fetal and neonatal outcomes were evaluated. One hundred twenty-four SLE pregnancies were included. Of the patients, 95.2% were in remission at conception. In 13.7% of cases, a lupus flare was diagnosed during gestation and in 17.9% in the postpartum period. The live birth rate was 84.6%, and the incidence of adverse outcomes was 40.3% (OR 2.64, 95% CI 1.67-4.18). Considering only patients in remission at conception, the presence of adverse outcomes remained significantly higher (36.8% vs. 20.3%, P < 0.01). Miscarriage rate was 15.3% (OR 5.85, 95% CI 2.57-13.34) and preterm delivery occurred in 12.4% of the patients (OR 1.72, 95% CI 0.83-3.57). Preeclampsia prevalence was higher in SLE patients (OR 3.92, 95% CI 1.32-11.57). In the SLE group, the newborn admission to an intensive care unit rate was increased (OR 4.99, 95% CI 1.47-16.90). No neonatal or maternal deaths were reported. In our study, pregnancy with SLE was associated with an increased incidence of adverse outcomes, even in a population of SLE patients with well-controlled disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Automated, technically simple analytical methods offering objective results are highly valued in clinical laboratories. Kappa free light chains (KFLC) in cerebrospinal fluid (CSF) are promising multiple sclerosis (MS) biomarkers, particularly kappa (K) index., Methods: KFLC were determined in CSF and serum samples of patients diagnosed with MS, clinically/radiologically isolated syndrome (N, 39), and controls (N, 152; inflammatory and non-inflammatory neurological disorders). Diagnostic performance of several KFLC parameters, previously determined oligoclonal band (OCB) testing, and IgG index, was assessed. A K index decision threshold for sample screening was identified and reduction in performed OCB analyses estimated accordingly., Results: Higher KFLC parameters were detected in the MS group and K index performed best among them (AUC 0.92). At a 7.25 cut-off it showed better sensitivity (85% vs. 77%) though less specificity (88% vs. 91%) than OCBs. Comparatively, IgG index's performance was inferior (AUC 0.83). A decision K index threshold of 2.55 (97% sensitivity) would reduce OCB testing by 52% in the studied population., Conclusions: The proposed 7.25 cut-off could assist MS diagnostics and identify some false negative cases from OCB studies. Sequential algorithms using K index for the decision to perform OCB detection would improve laboratory efficiency and substantially reduce costs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits., Objective: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics., Methods: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included., Results: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome., Conclusion: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Systemic lupus erythematosus (SLE) is a life-threatening disorder that affects women at reproductive age. We evaluate the clinical impact of pregnancy in a cohort of Portuguese SLE patients and the risk factors associated with maternal and fetal adverse outcomes., Methods: A retrospective observational study that included all pregnant women with SLE managed at a Portuguese tertiary hospital, between January 1993 and December 2019. Baseline maternal information was collected, and maternal-fetal and neonatal outcomes were evaluated. Disease activity before and during pregnancy was assessed., Results: We included 215 pregnancies from 143 patients. Lupus nephritis was present in 20.0% and antiphospholipid syndrome (APS) in 21.9% of the cases. Preconception consultation was performed in 86.9% of the pregnancies, and 92.5% of the patients had no or low disease activity at conception. During gestation, 79.6% of the patients were under treatment, and hydroxychloroquine (HCQ) was the most commonly used drug (63.7%). Low-dose acetylsalicylic acid (ASA) was prescribed at conception in 87.9% of the patients. The live birth rate was 84.2%. An adverse pregnancy outcome (APO) occurred in 41.4% of the pregnancies. A miscarriage rate of 15.3% and a preterm delivery rate of 15.4% were found. Preeclampsia and fetal growth restriction complicated 13.1% and 14.0% of the gestations, respectively. Neonatal lupus occurred in 7.1% of the newborns, and there were 2 cases of congenital heart block. Significant risk factors for the development of AOP were disease activity at conception, lupus flare, hypocomplementemia, positivity for lupus anticoagulant, and APS. The use of ASA was significantly associated with a reduced incidence of miscarriage. An SLE flare was diagnosed in 16.3% of the cases. We identified as risk factors for lupus flares the presence of active disease at conception, a previous history of lupus nephritis, and the use of chronic medication. HCQ use during pregnancy was associated with a significant reduction of flare incidence during pregnancy and postpartum., Conclusions: Pregnancy in an SLE patient is associated with an increased incidence of adverse obstetric outcomes. Good disease control before pregnancy and adequate treatment, especially with HCQ, is crucial to achieving the best obstetric results.

Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The broad and heterogeneous clinical spectrum that characterizes common variable immunodeficiency (CVID) is associated with quite different disease course and prognosis, highlighting the need to develop tools that predict complications. We developed a multianalyte VISUAL score (variable immunodeficiency score upfront analytical link) aimed to predict severity using individual CVID patient data at baseline of a cohort of 50 CVID patients from two different centers in Portugal and Spain. We retrospectively applied VISUAL to the CVID clinical severity scores proposed by Ameratunga and Grimbacher after 15 years follow-up of our cohort. VISUAL score at CVID diagnosis showed adequate performance for predicting infectious and non-infectious severe complications (Cluster B). Compared to switched memory B lymphocyte phenotype alone, VISUAL provided a more accurate identification of clinically meaningful outcome, with significantly higher sensitivity (85% vs 55%, p = 0.01), and negative predictive value (77% vs 58%) and AUC of the ROC curves (0.72 vs 0.64), with optimal cut-off level of 10. For every increase of 1 point in the VISUAL scale, the odds of being in the higher risk category (Cluster B) increased in 1.3 (p = 0.005) for Ameratunga's severity score and 1.26 (p = 0.004) for Grimbacher's severity score. At diagnosis of CVID, VISUAL score ≥ 10 showed 8.94-fold higher odds of severe prognosis than below this threshold. Kaplan-Meier estimates for the VISUAL ≥ 10 points showed significantly earlier progression to Cluster B than those with VISUAL < 10 (p = 0.0002). This prognostic laboratory score might allow close monitoring and more aggressive treatment in patients with scores ≥ 10 on a personalized basis approach. Further studies are needed to prospectively validate VISUAL score.

Objective: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis., Methods: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time., Results: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient., Conclusion: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases., (© 2020, American College of Rheumatology.)

Introduction: Screening for autoantibodies in HEp-2 cells by indirect immunofluorescence is currently accepted as the gold-standard test for the diagnosis of systemic autoimmune diseases. The main objective of the International Consensus on ANA Patterns is to achieve a consensus on the nomenclature and description of antinuclear antibody morphological patterns. This work aims to build on the International Consensus on ANA Patterns project to establish a nomenclature consensus in Portugal, thus contributing to harmonization in autoimmune diagnosis and promoting diagnostic quality in autoimmune systemic rheumatic diseases., Material and Methods: Participating laboratories identified all the nuclear and cytoplasmic pattern designations in the International Consensus on ANA Patterns (including the anti-cell pattern code), and matched them with the corresponding Portuguese nomenclature in use. The results were aggregated and used as a foundation for nomenclature harmonization work. Consensus meetings followed an iterative process, until a final consensual proposal was drafted., Results: Prior agreement between laboratories was over 75% for 23 of the total 29 anti-cell patterns. The degree to which each laboratory is aligned with the International Consensus on ANA Patterns international reference ranges from 22.1% to 100%. It was possible to write a consensual version of the International Consensus on ANA Patterns nomenclature for Portugal., Discussion: There was a good consensus basis for the nomenclature in the International Consensus on ANA Patterns, despite relevant differences with some translations. The study highlights the need for collaboration among laboratories towards an unambiguous description of laboratory results., Conclusion: This study shows that there is good potential for collaboration between laboratories in order to produce the consensus needed to improve diagnosis and patient follow-up.

Introduction: Paraneoplastic neurological syndromes (PNS) are immune-mediated diseases that occur in patients with tumors and can be associated with onconeural antibodies. Our aim was to describe our cohort of patients with PNS., Methods: Retrospective analysis of a cohort of patients followed in a Portuguese tertiary center, with autoantibodies against intracellular antigens from our PNS panel, between 2012 and 2017., Results: Among the 882 patients with suspected PNS (1029 samples), 37 (4.2%) had positive and 27 (3.1%) weak positive antibodies. A total of 17 (29.3%) PNS were diagnosed, 5 were classic syndromes. Autoantibodies found were anti-Yo, anti-Hu, anti-titin, anti-Ma2, anti-SOX1, anti-Ri and anti-CV2/CRMP5. They were associated with thymoma, breast, colon, parotid gland and lung (small-cell, neuroendocrine or carcinoid) cancer. Among the 17 PNS patients, no tumor was found in 4 (mean follow-up of 46 months); no patients improved with tumor treatment, while 8 improved with immunotherapy; ten patients (59%) died during follow-up. Twenty (60.6%) patients with positive antibodies and 21 (84.0%) with weak positive were not diagnosed with a PNS., Conclusions: PNS had highly heterogenous clinical presentations. Response to tumor treatment was overall poor, with an unfavorable prognosis. In our cohort, only 29.3% of the patients with positive antibodies were diagnosed with a PNS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Given the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies., Methods: We analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al. [1] that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications., Results: 76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was "cytopenia" (40%) followed by "polyclonal lymphocytic infiltration" (19%). The remaining 24% patients of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8 + CD45RO  +  T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4  +  T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to CVID onset in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05)., Conclusions: The phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohorts of patients, classification based in clinical and laboratory algorithms, provides more personalized treatment and follow-up strategies., Competing Interests: Declaration of Competing Interest The authors declare no other competing financial interests., (Copyright © 2020 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120&#95;134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Introduction: Up to 30% of patients treated with anti-tumor necrosis factor drugs do not respond adequately, and up to 50% lose response over time. Immunogenicity is now known to be one of the main causes of this loss of response., Methods: Serum levels of adalimumab and anti-drug antibodies (ADAs) were measured in 19 patients with psoriasis., Results: Eighty-nine percent of the patients were responders (Psoriasis Area Severity Index (PASI) > 75) and 11% were partial responders (PASI 50-75). The serum levels of adalimumab were lower than the cutoff in both of the partial responders and the ADAs were high, whereas the other 17 patients had adalimumab levels above the cutoff and low ADA levels. Both partial responders were obese and none of them were taking methotrexate. Both patients switched to ustekinumab, and a PASI 90 response was observed after 16 weeks., Conclusion: Immunogenicity is a risk of biological drugs. In this work, the detection of low levels of adalimumab and high levels of ADAs using a sandwich ELISA correlated with loss of clinical response. Testing immunogenicity and the drug pharmacokinetics of biological drugs in psoriasis patients will probably be part of the daily management of these patients in the future.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multi-organ inflammation, linked to loss of immune tolerance to self-antigens and the production of a diversity of autoantibodies, with a negative impact on the patients' quality of life. Regulatory T cells have been reported as deficient in number and function in SLE patients. However, some authors also described an enrichment of this cell type. The hypothesis that certain forms of autoimmunity may result from a conversion of Treg cells into a Th17 cell phenotype has been suggested by some studies. In fact, in SLE patients' sera, the IL-17 levels were observed as abnormally high when compared with healthy individuals. Environmental factors, such as vitamin D, that is considered a potential anti-inflammatory agent, combined with genetic and hormonal characteristics have been associated with SLE phenotype and with disease progression. The aim of this study was to evaluate the effect of vitamin D supplementation on FoxP3 expression and IL-17A-producing T cells, through FoxP3 + /IL-17A ratio. Additionally, disease evolution, serum vitamin D levels, serum autoantibodies levels and calcium metabolism (to assure safety) were also studied. We assessed 24 phenotypically well-characterized SLE patients. All patients were screened before vitamin D supplementation and 3 and 6 months after the beginning of this treatment. Peripheral blood lymphocyte's subsets were analysed by flow cytometry. Serum 25(OH)D levels significantly increased under vitamin D supplementation (p = 0.001). The FoxP3 + /IL-17A ratio in SLE patients after 6 months of vitamin D supplementation was higher than that in the baseline (p < 0.001). In conclusion, this study demonstrated that vitamin D supplementation provided favourable, immunological and clinical impact on SLE.

The innovative medicine initiative project called PRECISESADS will study 2.500 individuals affected by systemic autoimmune diseases (SADs) and controls. Among extensive OMICS approaches, multi-parameter flow cytometry analyses will be performed in eleven different centers. Therefore, the integration of all data in common bioinformatical and biostatistical investigations requires a fine mirroring of all instruments. We describe here the procedure elaborated to achieve this prerequisite. One flow cytometer chosen as reference instrument fixed the mean fluorescence intensities (MFIs) of 8 different fluorochrome-conjugated antibodies (Abs) using VersaComp Ab capture beads. The ten other centers adjusted their own PMT voltages to reach the same MFIs. Subsequently, all centers acquired Rainbow 8-peak beads data on a daily basis to follow the stability of their instrument overtime. One blood sample has been dispatched and concomitantly stained in all centers. Comparison of leukocytes frequencies and cell surface marker MFIs demonstrated the close sensitivity of all flow cytometers, allowing a multicenter analysis. The effective multi-center harmonization enables the constitution of a workable wide flow cytometry database for the identification of specific molecular signatures in individuals with SADs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation., Results: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin., Innovation: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans., Conclusion: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.

Chemotherapy is one of most significant therapeutic approaches to cancer. Immune system functional state is considered a major prognostic and predictive impact on the success of chemotherapy and it has an important role on patients' psychoemotional state and quality of life. In Chinese medicine, chemotherapy is understood as "toxic cold" that may induce a progressive hypofunctional state of immune system, thus compromising the fast recovery of immunity during chemotherapy. In this study, we performed a standardized acupuncture and moxibustion protocol to enhance immunity in cancer patients undergoing chemotherapy and to assess if the improvement of immunity status correlates with a better psychoemotional state and quality of life.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the reactivation of JC virus and occurs in patients with severe primary or secondary immunosuppression. Recently, PML is becoming relevant in autoimmune disorders, particularly in patients treated with biologic agents. However, systemic lupus erythematosus (SLE) appears to be associated with susceptibility to PML that cannot be entirely explained by the immunosuppressive therapy. The authors present two patients with the diagnosis of SLE and PML: One had a heavy immunosuppressive therapy history, and the other had never experienced biologic or cytotoxic therapeutics. Both patients had a profound T-CD4+ lymphopenia during their clinical history. These two cases emphasize the importance of CD4+ lymphopenia in SLE patients with and without immunosuppressors regarding opportunistic infections.