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Background: Anti-nuclear antibodies (ANA) assessed by immunofluorescence (IF) microscopy are associated with systemic autoimmune rheumatic diseases (SARD) and can be detected years before onset of clinical symptoms. Recent data indicate dysregulation of the immune system with increased levels of proinflammatory cytokines, including type I interferons (IFN), in ANA-positive versus ANA-negative individuals. Herein, the aims were to investigate IF-ANA, ANA fine specificities, and IFN-α protein levels in relation to self-reported symptoms, as well as clinical signs, of SARD in a large group of healthy blood donors (HBD)., Methods: Sera from 825 HBD (48.8% females) were included. IF-ANA was assessed, using HEp-2 cells, according to the routine at the accredited laboratory of Clinical Immunology, Linköping University Hospital. All samples were analyzed for IgG-ANA fine specificities using addressable laser bead assay (ALBIA) at the same laboratory. IFN-α was determined using ELISA. Antibody-positive individuals, and their sex- and age-matched antibody-negative controls, were asked to fill a questionnaire regarding symptoms associated with SARD., Results: In total, 130 HBD (15.8%) were positive with IF-ANA and/or ALBIA. Anti-U1RNP was significantly more common among women. Generally, self-reported symptoms correlated poorly with IF-ANA and/or ALBIA results. Two females with high levels of Ro60/SSA, Ro52/SSA and IFN-α reported mild sicca symptoms and were diagnosed with Sjögren's disease after clinical evaluation., Conclusion: A considerable proportion of apparently HBD are autoantibody positive, but without clear association to self-reported symptoms. Nevertheless, the combination of autoantibodies, relevant symptoms and high IFN-α levels identified the small proportion of individuals with SARD in the study population., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Andraos, Ahmad, Wirestam, Dahle, Frodlund, Rönnelid, Kastbom and Sjöwall.)

Background: Immunoglobulin G subclass deficiencies (IgGsd) comprise a wide clinical spectrum from no symptoms to repeated respiratory infections and risk for the development of lung damage. Our aims were to investigate whether the immunological phenotype of IgGsd patients on and off immunoglobulin replacement therapy (IgRT) was reflected in the clinical features of IgGsd., Method: Thirty patients with IgGsd were included in this prospective study of 18 months of IgRT, followed by 7-18 months of IgRT discontinuation. Blood samples were collected when patients were on and off IgRT and compared with samples from 34 cross-sectional healthy controls. An in-depth lymphocyte phenotyping was performed by flow cytometry and plasma levels of immune checkpoints were assessed., Results: IgG3 subclass deficiency was most common. Patients with IgGsd had decreased levels of activated T cells and B cells and plasma levels of negative immune checkpoint molecules correlated negatively with T cell and B cell activation. The decreased T cell activation level was unaffected by IgRT, while the B cell activation was partly restored. Of note, decreased levels of activated regulatory T cells (Tregs) were found in IgGsd patients and was partly restored during IgRT. The profile of comorbidities did not associate with Treg levels., Discussion: IgGsd is associated with decreased B cell and T cell activation including Tregs, and increased plasma levels of negative immune checkpoint molecules. The consequence of reduced activated Tregs in IgGsd remains unclear. Decreased immune cell activation was partly restored during IgRT, demonstrating that IgRT may contribute to improved immune function in patients with IgGsd., 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 © 2024 Wågström, Hjorth, Appelgren, Björkander, Dahle, Nilsson, Nilsdotter-Augustinsson, Ernerudh and Nyström.)

The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE ( n = 114), pSS ( n = 54) and MCTD ( n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger ( p < 0.0001); showed lower concentrations of complement protein 3 ( p = 0.03); had lower eosinophil ( p = 0.0005), lymphocyte ( p = 0.006) and monocyte ( p = 0.03) counts; and had accrued less organ damage ( p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

Objectives: Reliable biomarkers in the early stages of idiopathic arthritis (JIA) are scarce and the disease heterogeneity makes it clinically challenging to predict the risk of joint damage. Biomarkers with prognostic potential are warranted in order to individualize treatment and follow-up in JIA. The soluble urokinase plasminogen activator receptor (suPAR) has been reported as an easily measurable biomarker for prognosis and severity in several rheumatic diseases but it has never been studied in JIA., Methods: Sera from 51 well-characterized patients with JIA and 50 age- and sex-matched control subjects were collected and stored for later analysis of suPAR. Patients were carefully followed clinically over 3 years and analysis of erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed as part of clinical routine. Signs of joint erosions were evaluated by radiography., Results: Overall, the levels of suPAR did not differ significantly between JIA patients and controls but those with polyarticular involvement showed higher suPAR (p = 0.013). In addition, elevated suPAR were associated with joint erosions (p = 0.026). Two RF/anti-CCP negative individuals with erosions showed high levels of suPAR., Conclusions: We present new data on the biomarker suPAR in JIA. Our results indicate that, apart from RF and anti-CCP, analysis of suPAR could be of additional value in assessing the risk of erosions. Analysis of suPAR early could potentially guide treatment decision-making in JIA, but our observations should be confirmed in prospective studies., (© 2023. The Author(s).)

Background: Multiple sclerosis (MS) is a neuroinflammatory disease in which pregnancy leads to a temporary amelioration in disease activity as indicated by the profound decrease in relapses rate during the 3rd trimester of pregnancy. CD4 + and CD8 + T cells are implicated in MS pathogenesis as being key regulators of inflammation and brain lesion formation. Although Tcells are prime candidates for the pregnancy-associated improvement of MS, the precise mechanisms are yet unclear, and in particular, a deep characterization of the epigenetic and transcriptomic events that occur in peripheral T cells during pregnancy in MS is lacking., Methods: Women with MS and healthy controls were longitudinally sampled before, during (1st, 2nd and 3rd trimesters) and after pregnancy. DNA methylation array and RNA sequencing were performed on paired CD4 +  and CD8 +  T cells samples. Differential analysis and network-based approaches were used to analyze the global dynamics of epigenetic and transcriptomic changes., Results: Both DNA methylation and RNA sequencing revealed a prominent regulation, mostly peaking in the 3rd trimester and reversing post-partum, thus mirroring the clinical course with improvement followed by a worsening in disease activity. This rebound pattern was found to represent a general adaptation of the maternal immune system, with only minor differences between MS and controls. By using a network-based approach, we highlighted several genes at the core of this pregnancy-induced regulation, which were found to be enriched for genes and pathways previously reported to be involved in MS. Moreover, these pathways were enriched for in vitro stimulated genes and pregnancy hormones targets., Conclusion: This study represents, to our knowledge, the first in-depth investigation of the methylation and expression changes in peripheral CD4 +  and CD8 +  T cells during pregnancy in MS. Our findings indicate that pregnancy induces profound changes in peripheral T cells, in both MS and healthy controls, which are associated with the modulation of inflammation and MS activity., (© 2023. The Author(s).)

Background: The afferent visual pathway provides a unique opportunity to monitor clinical and subclinical optic neuritis and features of neuroaxonal degeneration in secondary progressive MS., Objective: To investigate the usefulness of visual evoked potentials (VEP) and optical coherence tomography (OCT) in evaluating SPMS, and the association between these modalities and clinical course and lesion load on the magnetic resonance imaging (MRI) in patients with SPMS with or without a history of optic neuritis (ON)., Methods: SPMS patients (n = 27) underwent clinical assessment with Expanded Disability Status Scale (EDSS) grading, visual acuity, OCT, and VEP examination. MRI of the brain and spinal cord were evaluated. Ordinal scores of VEP and MRI findings were used in the statistical analyses., Results: The ganglion cell and inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness correlated with VEP latency. VEP P100 score correlated with EDSS. Linear regression showed an association between GCIPL thickness and EDSS as well as VEP P100 latency and EDSS. The MRI analyses were negative., Conclusion: VEP latency and GCIPL thickness correlated with disability measured as EDSS in patients with SPMS and are useful in monitoring SPMS patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Objective: SLE, primary Sjögren's syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-α, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated., Methods: Samples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-α was quantified by ELISA. Self-reported data on Raynaud's phenomenon (RP) were available., Results: With exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-α levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%., Conclusions: The 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported., Competing Interests: Competing interests: RH is employed by Boehringer Ingelheim. The other authors declare no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Rheumatoid factor (RF) is a well-established marker for the diagnosis and classification of rheumatoid arthritis (RA). Most studies evaluated IgM RF or isotype-nonspecific total RF assays. We evaluated the added value of IgA RF in this context., Methods: An international sample cohort consisting of samples from 398 RA patients and 1073 controls was tested for IgA RF with 3 commercial assays. For all RA patients and 100 controls essential clinical and serological data for ACR/EULAR classification were available., Results: The sensitivity of IgA RF for diagnosing RA was lower than the sensitivity of IgM RF. Differences in numerical values between IgA RF assays were observed. With all assays, the highest IgA RF values were found in patients with primary Sjögren's syndrome. Double positivity for IgM RF and IgA RF had a higher specificity for RA than either IgM RF or IgA RF. The sensitivity of double positivity was lower than the sensitivity of either IgA RF or IgM RF. Single positivity for IgA RF was at least as prevalent in controls than in RA patients. Adding IgA RF to IgM RF and anti-citrullinated protein antibodies (ACPA) did not affect RA classification. However, combined positivity for IgA RF, IgM RF and IgG ACPA had a higher specificity and lower sensitivity for RA classification than positivity for either of the antibodies., Conclusions: IgA RF showed a lower sensitivity than IgM RF. Combining IgA RF with IgM RF and ACPA did not improve sensitivity of RA classification. Combined positivity (IgA-RF/IgM-RF/ACPA) increased specificity., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturer's recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

Introduction: Commercial assays measuring antibodies to citrullinated protein/peptide (ACPA) show poor quantitative agreement. The diagnostic industry has never adopted the International Union of Immunological Societies-Centers for Disease Control and Prevention (IUIS-CDC) ACPA reference standard. Recently, the National Institute for Biological Standards and Control (NIBSC) prepared a new candidate ACPA standard (18/204). We evaluated both reference materials using different commercially available ACPA assays., Materials and Methods: This is an international study in which the NIBSC candidate ACPA standard and the IUIS-CDC ACPA reference material were analysed together with 398 diagnostic samples from individuals with rheumatoid arthritis (RA) and in 1073 individuals who did not have RA using nine commercial ACPA assays., Results: For both reference materials and samples from individuals with RA and individuals who did not have RA, there were large differences in quantitative ACPA results between assays. For most assays, values for the IUIS-CDC standard were lower than values for NIBSC 18/204 and the IUIS-CDC/NIBSC ratio was comparable for several, but not all assays. When NIBSC 18/204 was used as a calibrator, an improvement in alignment of ACPA results across several of the evaluated assays was obtained. Moreover, NIBSC 18/204 could align clinical interpretation for some but not all assays., Conclusion: Adoption of an international standard for ACPA determination is highly desirable. The candidate NIBSC 18/204 standard improved the standardisation and alignment of most ACPA assays and might therefore be recommended to be used as reference in commercial assays., Competing Interests: Competing interests: XB, LVH, GS and DS have received speaker fees from Thermo Fisher Scientific and have been a consultant for Thermo Fisher Scientific; BL and IH has received speaker fees from Thermo Fisher Scientific. All participating diagnostic companies in-kind provided the ACPA assays and provided technical training and support:Thermo Fisher Scientific, Uppsala, Sweden; Roche Diagnostics, Mannheim, Germany; Svar Life Science, Malmö, Sweden; Immunodiagnostic Systems (IDS), Tyne and Wear, United Kingdom; Orgentec, Mainz, Germany; Abbott, Wiesbaden, Germany; Euroimmun, Lübeck, Germany; Bio-Rad Laboratories, Hercules, California, USA; and Siemens Healthineers, Sudbury, United Kingdom., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are important biomarkers for diagnosis of rheumatoid arthritis (RA). However, there is poor harmonisation of RF and ACPA assays. The aim of this study was to refine RF and ACPA interpretation across commercial assays., Materials and Methods: Six total RF isotype-non-specific assays, 3 RF IgM isotype-specific assays and 9 ACPA immunoglobulin G assays of 13 different companies were evaluated using 398 diagnostic samples from patients with RA and 1073 disease controls., Results: Using cut-offs proposed by the manufacturer, there was a large variability in diagnostic sensitivity and specificity between assays. Thresholds of antibody levels were determined based on predefined specificities and used to define test result intervals. Test result interval-specific likelihood ratios (LRs) were concordant across the different RF and ACPA assays. For all assays, the LR for RA increased with increasing antibody level. Higher LRs were found for ACPA than for RF. ACPA levels associated with LRs >80 were found in a substantial fraction (>22%) of patients with RA., Conclusion: Defining thresholds for antibody levels and assigning test result interval-specific LRs allows alignment of clinical interpretation for all RF and ACPA assays., Competing Interests: Competing interests: XB, LVH, GS and DS have received speaker fees from and have been a consultant for Thermo Fisher Scientific. LBernasconi and IH have received speaker fees from Thermo Fisher Scientific. DA and PJ are editorial board members of RMD Open. All participating diagnostic companies in-kind supported with RF/ACPA assays and technical training: Thermo Fisher Scientific, Uppsala, Sweden; Cambridge Life Science, Ely, UK; Ortho-Clinical Diagnostics, Raritan, New Jersey, USA; Diagam, Ghislenghien, Belgium; Roche Diagnostics, Mannheim, Germany; Svar Life Science, Malmö, Sweden; Immunodiagnostic Systems, Tyne and Wear, UK; Orgentec, Mainz, Germany; Abbott, Wiesbaden, Germany; Euroimmun, Lübeck, Germany; Bio-Rad Laboratories, Hercules, California, USA; and Siemens Healthineers, Sudbury, UK., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT., Method: Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion., Results: QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1., Conclusion: Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made., Competing Interests: PW and ÅN-A are members and JB is a former chair of the Swedish National Guideline Committee for primary immune deficiencies. The remaining 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 Wågström, Nilsdotter-Augustinsson, Nilsson, Björkander, Dahle and Nyström.)

Objectives: Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization., Methods: Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan-Meier and Mann-Whitney U test. Cox regression was used for risk estimation., Results: Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units., Conclusion: Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Time-variable gravity measurements from the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-On (GRACE-FO) missions have opened up a new avenue of opportunities for studying large-scale mass redistribution and transport in the Earth system. Over the past 19 years, GRACE/GRACE-FO time-variable gravity measurements have been widely used to study mass variations in different components of the Earth system, including the hydrosphere, ocean, cryosphere, and solid Earth, and significantly improved our understanding of long-term variability of the climate system. We carry out a comprehensive review of GRACE/GRACE-FO satellite gravimetry, time-variable gravity fields, data processing methods, and major applications in several different fields, including terrestrial water storage change, global ocean mass variation, ice sheets and glaciers mass balance, and deformation of the solid Earth. We discuss in detail several major challenges we need to face when using GRACE/GRACE-FO time-variable gravity measurements to study mass changes, and how we should address them. We also discuss the potential of satellite gravimetry in detecting gravitational changes that are believed to originate from the deep Earth. The extended record of GRACE/GRACE-FO gravity series, with expected continuous improvements in the coming years, will lead to a broader range of applications and improve our understanding of both climate change and the Earth system., (© The Author(s) 2021.)

Objectives: Impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on individuals with arthritis has been highlighted whereas data on other rheumatic diseases, e.g., systemic lupus erythematosus (SLE), are scarce. Similarly to SLE, severe SARS-CoV-2 infection includes risks for thromboembolism, an unbalanced type I interferon response, and complement activation. Herein, SARS-CoV-2 antibodies in longitudinal samples collected prior to vaccination were analyzed and compared with SLE progression and antinuclear antibody (ANA) levels., Methods: One hundred patients (83 women) with established SLE and a regular visit to the rheumatologist (March 2020 to January 2021) were included. All subjects donated blood and had done likewise prior to the pandemic. SARS-CoV-2 antibody isotypes (IgG, IgA, IgM) to the cell receptor-binding S1-spike outer envelope protein were detected by ELISA, and their neutralizing capacity was investigated. IgG-ANA were measured by multiplex technology., Results: During the pandemic, 4% had PCR-confirmed infection but 36% showed SARS-CoV-2 antibodies of ≥1 isotype; IgA was the most common (30%), followed by IgM (9%) and IgG (8%). The antibodies had low neutralizing capacity and were detected also in prepandemic samples. Plasma albumin ( p = 0.04) and anti-dsDNA ( p = 0.003) levels were lower in patients with SARS-CoV-2 antibodies. Blood group, BMI, smoking habits, complement proteins, daily glucocorticoid dose, use of hydroxychloroquine, or self-reported coronavirus disease 2019 (COVID-19) symptoms (except fever, >38.5°C) did not associate with SARS-CoV-2 antibodies., Conclusion: Our data from early 2021 indicate that a large proportion of Swedish SLE patients had serological signs of exposure to SARS-CoV-2 but apparently with a minor impact on the SLE course. Use of steroids and hydroxychloroquine showed no distinct effects, and self-reported COVID-19-related symptoms correlated poorly with all antibody isotypes., 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 © 2021 Sjöwall, Azharuddin, Frodlund, Zhang, Sandner, Dahle, Hinkula and Sjöwall.)

Abnormal liver function tests are frequently observed during follow-up of patients with systemic lupus erythematosus (SLE) but data on co-existence with autoimmune liver diseases (AILD) are scarce. This retrospective study aimed to describe the prevalence of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) among well-characterized subjects with SLE. We also evaluated whether the presence of autoantibodies to complement protein 1q (C1q) and/or ribosomal P protein (anti-ribP) are, directly or inversely, associated with AIH, as proposed in some reports. The number of screened patients was 287 (86% females), and all cases were included in a regional Swedish cohort. Each subject of the study population met the 1982 American College of Rheumatology classification criteria and/or the Fries' diagnostic principle. By applying the simplified diagnostic AIH criteria combined with persistent transaminasemia, 40 (13.9%) cases reached at least "probable AIH". However, merely 8 of these had been diagnosed with AIH (overall AIH prevalence 2.8%). Neither anti-C1q nor anti-ribP associated significantly with AIH. By applying the recent PBC guidelines, 6 (2.1%) cases were found, but only 3 of them had actually been diagnosed with PBC and one additional subject was not identified by the guidelines (overall PBC prevalence 1.4%). Compared to prevalence data from the general Swedish population, both AIH and PBC were highly overrepresented in our study population. The sensitivity of the diagnostic AIH criteria was impeccable but the specificity was less impressive, mainly due to positive ANA and hypergammaglobulinemia. Based on our findings, among subjects with SLE, the AIH criteria are less useful and liver biopsy combined with detection of other AILD-associated autoantibodies should be performed.

Background: Anti-phospholipid syndrome (APS) and systemic lupus erythematous (SLE) are autoimmune disorders that often co-occur. Anti-phospholipid antibodies (aPL) are typical of both conditions and may be associated with vascular events and pregnancy-related morbidities. Whereas, aPL-screening is mandatory for individuals with suspected SLE, the clinical value of longitudinal aPL analyses in established SLE is unclear. Methods: We investigated the occurrence and variation of IgG/IgA/IgM anti-cardiolipin (aCL) and anti-β2-glycoprotein-I (anti-β2GPI) antibodies, using both the manufacturer's cut-off and a cut-off based on the 99th percentile of 400 apparently healthy donors, in recent-onset SLE. Furthermore, we evaluated the relationships between aPL levels and SLE/APS manifestations, as well as the pharmacotherapy. Patients with SLE who met validated classification criteria were included in this prospective study ( N = 54). Samples were obtained at 0, 6, 12, 24, 36, 48, 60, 72, 84, and 96 months after SLE diagnosis. Results: Depending on the cut-off applied, 61.1 or 44.4% showed a positive result for at least one aPL isotype or the lupus anticoagulant test over time. Median values for all six aPL isotypes numerically decreased from inclusion to last follow-up, but none of the isotypes met statistical significance. Seroconversion (from positive to negative, or the opposite direction) was occasionally seen for both aCL and anti-β2GPI. IgA and IgM anti-β2GPI were the most common isotypes, followed by IgM aCL. Presence of IgG aCL associated significantly with myocardial infarction and miscarriage, and IgG/IgA anti-β2GPI with miscarriage. Conclusion: aPL were common during the first years of SLE. Even though the levels fluctuated over time, the patients tended to remain aPL positive or negative. Repeated aPL testing in the absence of new symptoms seems to be of uncertain value in patients with recent-onset SLE., 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 © 2021 Frodlund, Walhelm, Dahle and Sjöwall.)

Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjögren's syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2·9%) and three pSS (2·6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9·6%) had PBC-associated autoantibodies, 15 (5·5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7·4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7·4%). The prevalence of SMA (4·4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8·1%) had PBC-associated, 12 (10·8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients., (© 2020 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.

Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes., (Copyright © 2020 Nilsson, Palmer, Apostolou, Gottfries, Rizwan, Dahle and Rosén.)

To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≤ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information., Competing Interests: Declaration of Competing interest IH and KNE declare that they have no competing interests. JE has received honoraria for lectures from Biogen. MV has received unrestricted research grants from Biogen and Novartis, honoraria for lectures from Biogen and Genzyme and for advisory boards from Roche and Novartis. CD has received honoraria for lectures from Biogen, Teva, Genzyme and Novartis and for advisory boards from Roche, Novartis and Biogen., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS™ Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjögren's syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted., (© 2019 British Society for Immunology.)

Objective: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE., Methods: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI)., Results: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007)., Conclusion: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999-2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively).Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.What is Known:• An excess risk of pneumococcal infections has been demonstrated in individuals with celiac disease.• Infectious complications can depend on hyposplenism but alternative mechanisms are sparsely examined.What is New:• Complement activation in response to Streptococcus pneumoniae was examined in children with and without celiac disease but no differences could be demonstrated.

Background: Fatigue is common in multiple sclerosis and is associated with reduced quality of life. This study aimed to assess the correlation between fatigue scores and data from other self-assessment questionnaires, neuropsychological tests and neuroimaging, as well as data on neuroimmunological markers in cerebrospinal fluid (CSF) and serum/plasma, in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS)., Methods: Modified fatigue impact scale (MFIS) scores were determined in 38 patients with newly diagnosed CIS or RRMS at baseline and after one year in a prospective longitudinal cohort study. Non-parametric correlation analyses were used to assess associations between MFIS scores and other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36)), as well as with neuropsychological test performances (e.g. Auditory Consonant Trigram Test (ACTT)), clinical parameters (e.g. disease duration and expanded disability status scale (EDSS)), magnetic resonance imaging (MRI) data (number of T2 lesions in brain MRI and total brain volume) and several neurodegenerative/neuroinflammatory markers in CSF and serum/plasma (IL-1β, IL-6, CXCL1, CXCL10, CXCL13, CCL-22 in plasma; neurofilament light chain (NFL) in serum; IL-6, CXCL1, CXCL10, CXCL13, CCL22, NFL and chitinase-3-like-1 (CHI3L1) in CSF. CSF and serum/plasma from 21 age- and sex-matched healthy controls were available for comparison., Results: At both baseline and one-year follow-up, fatigue scores correlated significantly with HAD, MSIS-29 and SF-36 scores and ACTT performance (Spearman´s rho 0.45-0.78, all p ≤ 0.01) but not with the other neuropsychological test results, disease duration, EDSS ratings, number of T2 lesions, total brain volume or neurodegenerative/neuroinflammatory markers, including neurofilament light chain levels in CSF and serum. In group comparisons, MFIS scores were similar in patients fulfilling no evidence of disease activity-3 (NEDA-3) (n = 18) and patients not fulfilling NEDA-3 (n = 20) during one year of follow-up (p > 0.01)., Conclusions: In this cohort of patients with newly diagnosed CIS and RRMS, fatigue scores were associated with mood, disease impact on daily life and quality of life as well as with alterations of attentive functions. Study results indicate that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters like EDSS, T2 lesions and NFL levels., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Time-resolved satellite gravimetry has revolutionized understanding of mass transport in the Earth system. Since 2002, the Gravity Recovery and Climate Experiment (GRACE) has enabled monitoring of the terrestrial water cycle, ice sheet and glacier mass balance, sea level change and ocean bottom pressure variations and understanding responses to changes in the global climate system. Initially a pioneering experiment of geodesy, the time-variable observations have matured into reliable mass transport products, allowing assessment and forecast of a number of important climate trends and improve service applications such as the U.S. Drought Monitor. With the successful launch of the GRACE Follow-On mission, a multi decadal record of mass variability in the Earth system is within reach., Competing Interests: Competing financial interests The authors declare no competing financial interests.

Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some FcγR polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the FcγR-profile differs between individuals with IgGsd and a control population., Methods: Single nucleotide polymorphisms (SNPs) of FcγRIIa, FcγRIIIa and FcγRIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing., Results: In the IgGsd-group, homozygous frequency for FcγRIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical FcγRIIc-ORF (p = .03) and classical FcγRIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding FcγRIIIa., Conclusion: The gene for classical FcγRIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical FcγRIIc-ORF as well as low-binding capacity receptor FcγRIIa-R/R131 were more frequent. Further studies on the FcγR polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p = .0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p = .16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.

Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS., Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI®) were recorded during 4 years of follow-up., Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions., Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.

Objectives: Idiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of Östergötland, Sweden., Material and Methods: We reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented., Results: Four of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of Östergötland was 7.3 per million/year., Conclusions: The results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM.

Background: Multiple sclerosis (MS) is a neurological disorder that causes significantly reduced ability to work, and the Expanded Disability Status Scale (EDSS) is one of the main predictors for reduced work ability., Objectives: To investigate how work requirements, flexible work conditions and disease-modifying drugs (DMDs) influence the work ability in relation to different EDSS grades in two MS populations., Methods: Work ability was studied in two MS populations: one in the southern and one in the northern part of Sweden, both demographically similar. In the latter population, more active work-promoting interventions have been practised and second-generation DMDs have been widely used from the onset of disease for several years., Results: The proportion of MS patients who participated in the workforce or studied was significantly higher in the northern compared with the southern population ( p < 0.001). The employees in the northern population had significantly lower requirements, greater adapted work conditions and were able to work more hours per week. Higher EDSS was associated with lower reduction in number of worked hours per week in the northern population ( p = 0.042)., Conclusion: Our data indicated that treatment strategy and adjusted work conditions have impact on work ability in MS.

Objectives: Raised serum cartilage oligomeric matrix protein (sCOMP) has been reported to predict erosive disease in early rheumatoid arthritis (RA). In juvenile idiopathic arthritis (JIA), subnormal sCOMP levels have been associated with ongoing inflammation and growth retardation. In this study we aimed to assess sCOMP, C-reactive protein (CRP), and insulin-like growth factor (IGF)-1 in children/adolescents with JIA and in referents., Method: We enrolled 52 JIA patients at planned outpatient visits and 54 inpatients with ongoing infection ('infection referents'). A total of 120 referents testing negative for immunoglobulin (Ig)E-mediated allergy ('IgE referents') served as controls. All serum samples were analysed for COMP, IGF-1, and CRP., Results: The average sCOMP level was highest among the IgE referents and lowest among the infection referents. In the JIA patients, the level of sCOMP was not associated with the level of CRP or with clinical signs of disease activity., Conclusions: The results of this study do not support routine clinical analysis of sCOMP levels in patients with JIA.

Background and Purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS., Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study., Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results., Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity., (© 2017 EAN.)

Background and Purpose: Brain atrophy is related to clinical deterioration in multiple sclerosis (MS) but its association with intrathecal markers of inflammation or neurodegeneration is unclear. Our aim was to investigate whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration are associated with brain volume change in natalizumab-treated MS and whether this change is reflected in non-lesional white matter metabolites., Methods: About 25 patients with natalizumab-treated MS were followed for 3 years with assessment of percentage brain volume change (PBVC) and absolute quantification of metabolites with proton magnetic resonance spectroscopy ( 1 H MRS). Analyses of inflammatory [interleukin 1β (IL-1β), IL-6, C-X-C motif chemokine 8 (CXCL8), CXCL10, CXCL11, C-C motif chemokine 22] and neurodegenerative [neurofilament light protein (NFL), glial fibrillary acidic protein, myelin basic protein, tau proteins] markers were done at baseline and 1-year follow-up., Results: The mean decline in PBVC was 3% at the 3-year follow-up, although mean 1 H MRS metabolite levels in non-lesional white matter were unchanged. CSF levels of NFL and tau at baseline correlated negatively with PBVC over 3 years (r = -0.564, P = 0.012, and r = -0.592, P = 0.010, respectively)., Conclusions: A significant 3-year whole-brain atrophy was not reflected in mean metabolite change of non-lesional white matter. In addition, our results suggest that CSF levels of NFL and tau correlate with brain atrophy development and may be used for evaluating treatment response in inflammatory active MS., (© 2016 EAN.)

Neuromyelitis optica/spectrum disorder (NMO/SD) is a severe, inflammatory disease of the central nervous system (CNS). In the majority of patients, it is associated with the presence of pathogenic serum autoantibodies (the so-called NMO-IgGs) directed against the water channel aquaporin 4 (AQP4), and with the formation of large, astrocyte-destructive lesions in spinal cord and optic nerves. A large number of recent studies using optical coherence tomography (OCT) demonstrated that damage to optic nerves in NMO/SD is also associated with retinal injury, as evidenced by retinal nerve fiber layer (RNFL) thinning and microcystic inner nuclear layer abnormalities. These studies concluded that retinal injury in NMO/SD patients results from secondary neurodegeneration triggered by optic neuritis.However, the eye also contains cells expressing AQP4, i.e., Müller cells and astrocytes in the retina, epithelial cells of the ciliary body, and epithelial cells of the iris, which raised the question whether the eye can also be a primary target in NMO/SD. Here, we addressed this point in experimental NMO/SD (ENMO) induced in Lewis rat by transfer of AQP4268-285-specific T cells and NMO-IgG.We show that these animals show retinitis and subsequent dysfunction/damage of retinal axons and neurons, and that this pathology occurs independently of the action of NMO-IgG. We further show that in the retinae of ENMO animals Müller cell side branches lose AQP4 reactivity, while retinal astrocytes and Müller cell processes in the RNFL/ganglionic cell layers are spared. These changes only occur in the presence of both AQP4268-285-specific T cells and NMO-IgG.Cumulatively, our data show that damage to retinal cells can be a primary event in NMO/SD.

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

Dividing the sea-level budget into contributions from ice sheets and glaciers, the water cycle, steric expansion, and crustal movement is challenging, especially on regional scales. Here, Gravity Recovery And Climate Experiment (GRACE) gravity observations and sea-level anomalies from altimetry are used in a joint inversion, ensuring a consistent decomposition of the global and regional sea-level rise budget. Over the years 2002-2014, we find a global mean steric trend of 1.38 ± 0.16 mm/y, compared with a total trend of 2.74 ± 0.58 mm/y. This is significantly larger than steric trends derived from in situ temperature/salinity profiles and models which range from 0.66 ± 0.2 to 0.94 ± 0.1 mm/y. Mass contributions from ice sheets and glaciers (1.37 ± 0.09 mm/y, accelerating with 0.03 ± 0.02 mm/y(2)) are offset by a negative hydrological component (-0.29 ± 0.26 mm/y). The combined mass rate (1.08 ± 0.3 mm/y) is smaller than previous GRACE estimates (up to 2 mm/y), but it is consistent with the sum of individual contributions (ice sheets, glaciers, and hydrology) found in literature. The altimetric sea-level budget is closed by coestimating a remaining component of 0.22 ± 0.26 mm/y. Well above average sea-level rise is found regionally near the Philippines (14.7 ± 4.39 mm/y) and Indonesia (8.3 ± 4.7 mm/y) which is dominated by steric components (11.2 ± 3.58 mm/y and 6.4 ± 3.18 mm/y, respectively). In contrast, in the central and Eastern part of the Pacific, negative steric trends (down to -2.8 ± 1.53 mm/y) are detected. Significant regional components are found, up to 5.3 ± 2.6 mm/y in the northwest Atlantic, which are likely due to ocean bottom pressure variations.

Background: Multiple sclerosis (MS) often causes a reduced ability to work. Improved disease control as well as adjustment of working conditions may improve work ability in MS., Objectives: The objective of this article is to compare the degree of sickness absence in two MS populations that either have or have not received disease-modifying drug (DMD) treatments or active work-promoting measures., Methods: We investigated the occurrence of sickness absence in MS patients living in Västerbotten County, Sweden, in 2013, in which the majority of MS patients receive DMD treatment. The result was compared with a previous survey in the same area during a period when no DMD was available and no work-promoting measures for MS patients were practiced., Results: The proportion of MS patients active in the labor market or studying increased from 38% to 70% in the contemporary compared with the historic population ( p  < 0.001). The proportion of MS patients with a full-time disability pension decreased from 27% to 12% ( p  < 0.001). There was a significant decrease of sickness absence in several individual EDSS grades., Conclusions: Our data indicate that treatment with DMDs combined with active work-promoting measures lead to improved work ability in MS.

Objective: Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables., Methods: Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjögren syndrome (n = 54) served as controls., Results: CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher's exact test revealed striking differences between methods regarding associations with certain disease phenotypes., Conclusion: CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.

Purpose: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD., Methods: Clinical laboratory records from 654 pediatric IgA deficient patients, 4-13 years of age, were retrieved from five university hospitals in Sweden. Follow up in the children where IgA serum levels had been routinely measured was subsequently performed. In addition, follow up of the IgA-levels was also performed at 4, 8 and 16 years of age in children who were IgA deficient at the age of 4 years in a Swedish population-based birth cohort study in Stockholm (BAMSE)., Results: Nine out of 39 (23.1%) children who were identified as IgAD at 4 years of age subsequently increased their serum IgA level above 0.07 g/L. The average age of reversal was 9.53 ± 2.91 years. In addition, 30 out of the 131 (22.9%) children with serum IgAD when sampled between 5 and 9.99 years of age reversed their serum IgA level with time. The BAMSE follow up study showed a reversal of IgAD noted at 4 years of age in 8 out of 14 IgAD children at 16 years of age (5 at 8 years of age) where 4 were normalized their serum IgA levels while 4 still showed low serum levels of IgA, yet above the level defining IgAD. The results indicate that using 4 years of age, as a cut off for a diagnosis of IgAD may not be appropriate., Conclusions: Our findings suggest that a diagnosis of IgAD should not be made before the early teens using 0.07 g/L of IgA in serum as a cut off.

Background: Primary immune deficiency (PID) due to humoral defects is associated with recurrent respiratory tract infections (RTIs). Reliable clinical warning signs of PID would facilitate early diagnosis and thereby reduce long-term complications. The aim of the present study was to evaluate the accuracy of the warning sign, 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years,' for detecting PID among adults in a primary health-care setting., Methods: Fifty-three cases with 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years' were selected from a Swedish primary health-care registry of RTIs. In addition, 66 age- and sex-matched controls were selected having a maximum of one antibiotic-treated RTI during the period covered by the study. Levels of immunoglobulin (Ig) IgG, IgA, IgM, IgG subclasses, and IgG antibodies against Haemophilus influenzae and Streptococcus pneumoniae as well as the inflammatory markers, C-reactive protein, interleukin (IL)-6 and IL-8 were determined., Results: IgG subclass deficiencies (IgGsd) were found in 5/53 (9.4%) of the cases and in 7/66 (10.6%) controls. The most frequent deficiency was IgG3sd and this was found in three participants in the case group and seven in the control group. The mean level of IgG3 was lower in the control group (p = 0.02). The mean level of IL-8 was lower in the case group (p = 0.02)., Conclusion: The results show that physicians working in primary health care cannot solely rely on the frequency of antibiotic-treated RTIs as a warning sign for the detection of common humoral immune deficiencies.

We examined regional changes in brain volume in healthy adults (N=167, age 19-79years at baseline; N=90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the Hc, CbH, In, OF, and PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants modified shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1β C-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC, thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: In a retrospective study, we have previously shown that work ability was improved after the initiation of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS). In another prospective trial (TYNERGY) the effect on MS-related fatigue was evaluated after 12 months of treatment with natalizumab. A comprehensive Capacity for Work Questionnaire (CWQ) was used to collect data regarding number of working hours and sickness absence. The predefined intention-to-treat analysis regarding work ability did not, however, show significant results., Objectives: The objective of this paper is to assess the amount of sick leave in RRMS before and after one year of natalizumab treatment and correlate it to fatigue and walking ability., Methods: This is a post-hoc analysis of the complete data from the CWQ used in the TYNERGY trial., Results: MS patients receiving sickness benefit before start of treatment reduced their sickness benefit by an absolute change of 33% after one year of natalizumab treatment. Younger age and improvement of walking ability correlated significantly with reduction of sick leave., Conclusions: This ad-hoc analysis of prospectively collected data supported our previous retrospective study and thus indicates a positive relationship between natalizumab treatment and improvement in work ability., (© The Author(s) 2013.)

Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet., Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected., Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not., Conclusions: IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.

Background: Changes in the blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks., Methods: A broad panel of markers for lymphocyte populations, including states of activation and co-stimulation, as well as functional T cell responses to recall antigens and mitogens, were assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment., Results: Absolute numbers of all major lymphocyte populations increased after treatment, most markedly for NK and B cells. The fraction of both memory and presumed regulatory B cell subsets increased, as did CD3(-)CD56(dim) cytotoxic NK cells, whereas CD3(-)CD56(bright) regulatory NK cells decreased. The increase in cell numbers was further associated with a restored T cell responsiveness to recall antigens and mitogens in functional assays., Conclusions: Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK and B cells. This finding supports reduction of lymphocyte extravasation as a main mode of action, although the differential effects on subpopulation composition suggests that cell-signalling may also be affected. The systemic increase in T cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses may become correspondingly decreased.

Background: Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb.We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects., Methods: The number of CD3+ IELs was determined in specimens from the second part of the duodenum and from the bulb in 34 non-celiac subjects. The numbers of IELs in the villus tip and sides were counted and the quotient tip/side was calculated. HLA DQ2/DQ8 and serum antibodies against transglutaminase were analysed., Results: The mean number of IELs per 100 enterocytes (95% CI) in specimens was 14.7 (11.8-17.6) in the bulb, and 21.2 (17.0-25.5) in the second part of the duodenum (p<0.01). There was no difference in IEL count or distribution comparing patients carrying or lacking HLA DQ2/DQ8., Conclusions: IEL count in non-celiac, HLA DQ2/DQ8 positive or negative patients is significantly lower in the bulb than in the second part of the duodenum. These findings implicate that the site of biopsy should be taken into account when considering duodenal lymphocytosis.

Background: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP)., Objective: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort., Methods: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis., Results: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53)., Conclusion: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.