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ObjectiveTo evaluate health-related quality of life (HRQoL), in relation to support from work, social, as well as treatment satisfaction, in women with multiple sclerosis (MS). Further, to predict the satisfaction on these support dimensions based on sociodemographic and clinical variables.DesignCross-sectional survey: a web-based questionnaire conducted in 2021 of people with MS (PwMS) linked to Nationwide Swedish registers.SettingSweden.ParticipantsWorking women with MS, living in Sweden, aged 20–50 responding to the survey during the spring of 2021 (n=2967).Outcome measuresHealth-related quality of life was measured using the EuroQol Visual Analogue Scale (EQ-VAS). Linear regression models were applied to estimate the association between demographic and clinical factors, as well as reported survey answers with HRQoL. Odds of perceived satisfactory support in one, two or all three support dimensions (work, social or treatment) were performed with multinomial logistic regressions.ResultsLower MS severity and fatigue, higher cognitive processing speed, living in cities and higher educational attainment were individually associated with higher levels of HRQoL (p<0.001). Contrary, lower HRQoL was associated with progressive type of MS, self-reported visible or invisible symptoms, and no or unsatisfactory support from work, social and treatment (p<0.001). When explored altogether, higher levels in HRQoL were predominantly explained by lower MS severity (t=−9.318, p<0.001), less fatigue (t=−22.190, p<0.001) and more support from work (t=4.824, p<0.001) and to some extent, social support (t=−2.448, p=0.014). Further, compared with women who reported no support, those experiencing lower fatigue and receiving ongoing treatment were more likely to receive support in one or more of all three dimensions (work, social and satisfaction with their treatment). In contrast, higher HRQoL (OR=1.033; CI=1.015 to 1.052) was only significant when receiving simultaneous support from all three support dimensions.ConclusionClinical factors and support from work and social support are the strongest contributors to HRQoL in working women with MS. Further, support across several life dimensions is essential when assessing HRQoL. Particularly, satisfaction with the perceived support from work, which plays a crucial role in the HRQoL of women with MS. This underscores the importance of prioritising clinical management and strong support systems to significantly improve HRQoL outcomes in patients with MS.

BackgroundGranulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment.MethodsWe quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS).ResultsIn acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90–0.98 (specificity of 0.76–1.0, sensitivity of 0.87–1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated.ConclusionsGAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4− NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD.

Aimof this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma.Patients and methodsA total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17). Ninety-one patients received various systemic treatments prior to irradiation. Following an initial screening visit post-RT, two additional visits after 12 and 25 weeks were conducted including radiographic examination. In addition, general anamnesis and the co-medication were recorded. The endpoint was reached as soon as a pneumonitis was developed or at maximum of six months post-treatment.ResultsA pneumonitis incidence of 13% was determined. Of 91 patients with prior systemic therapy, 11 patients developed pneumonitis. Smoking history and chronic obstructive pulmonary disease (COPD) appeared to be positive predictors, whereas past pneumonia clearly promoted pneumonitis. Further pneumonitis-promoting predictors are represented by the applied field extensions (2 field radiotherapy [2FRT] < 3 field radiotherapy [3FRT] < 4 field radiotherapy [4FRT]) and the type of combined initial systemic therapies. As a consequence, all of the three patients in the study cohort treated with 4FRT and initial chemotherapy combined with anti-hormone and antibody protocols developed pneumonitis. A combination of the hormone antagonists tamoxifen and goserelin might enhance the risk for pneumonitis. Remarkably, none of the 11 patients co-medicated with statins suffered from pneumonitis.ConclusionsThe rapidly increasing use of novel systemic therapy schedules combined with radiotherapy (RT) needs more prospective studies with larger cohorts. Our results indicate that contribution to pneumonitis occurrence of various (neo)adjuvant therapy approaches followed by RT is of minor relevance, whereas mean total lung doses of >10 Gy escalate the risk of lung tissue complications. The validity of potential inhibitors of therapy-induced pneumonitis as observed for statin co-medication should further be investigated in future trials.

PurposeAs radionuclide therapy is gaining importance in palliative treatment of patients suffering from neuroendocrine tumour (NET) as well as castration resistant prostate cancer (CRPC), the radiation protection of patients, staff, family members and the general public is of increasing interest. Here, we determine patient discharge dates according to European guidelines.MethodsIn 40 patients with NET and 25 patients with CRPC organ and tumour doses based on the MIRD concept were calculated from data obtained during the first therapy cycle. Planar whole body images were recorded at 0.5, 4, 20, 68 und 92 h postinjection. Residence times were calculated from the respective time-activity-curves based on the conjugated view method. Residence times for critical organs were fitted into the commercially available OLINDA software to calculate the organ doses. The doses of tumours and salivary glands were calculated via their self-irradiation by approximation with spheres of equivalent volume. Kidney volumes were gained by organ segmentation, volumes of all other organs were estimated by means of OLINDA and hence were lean body mass corrected. Out of the whole body curves reference points for patient discharge were estimated.ResultsIn patients with NET discharge dates could be properly estimated from dosimetric data, which is not only crucial for radiation protection, but also makes therapy planning easier. For 177Lu-PSMA-617 ligand therapy it is difficult to seriously estimate a generalized discharge date due to large interpatient variation resulting from different tumor loads and heavy pre-treatment.ConclusionPatient release is predictable for 177Lu-DOTATATE therapy but not for 177Lu-PSMA ligand therapy.

Multiple sclerosis (MS) treatment options have improved significantly over the past decades, but the consequences of MS can still be devastating and the needs for monitoring treatment surveillance are considerable. In the current study we used affinity proteomics technology to identify potential biomarkers which could ultimately be used to as facilitate treatment decisions. We profiled the intra-individual changes in the levels of 59 target proteins using an antibody suspension bead array in serial plasma samples from 44 MS patients during treatment with natalizumab followed by fingolimod. Nine proteins showed decreasing plasma levels during natalizumab treatment, with PEBP1 and RTN3 displaying the most significant changes. Protein levels remained stable during fingolimod treatment for both proteins. The decreasing PEBP1 levels during natalizumab treatment could be validated using ELISA and replicated in an independent cohort. These results support the use of this technology as a high throughput method of identifying potentially useful biomarkers of MS treatment.

Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.

Patients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless they tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays using samples from patients with chronic inflammatory diseases collected prior to April 2019, thus defined as negative. Samples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and systemic lupus erythematosus (SLE, n=10) with or without RF, were analyzed for SARS-CoV-2 antibodies using 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed IgG multiplex bead-based assay. Six LFA and the in-house validated IgG assay correctly produced negative results for all samples. However, the majority of assays (n=13), gave false positive signal for samples from patients with RA and SLE. This was most notable in samples from RF positive RA patients. No false positive samples were detected in any assay using samples from patients with MS. Poor specificity of commercial serological assays could possibly be, at least partly, due to interfering antibodies in samples from patients with chronic inflammatory diseases. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.

A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNβ) therapy develop neutralizing antibodies (NAbs) that reduce drug efficacy. To investigate if HLA class I and II alleles are associated with development of NAbs against IFNβ we analyzed whether NAb status and development of NAb titers high enough to be biologically relevant (>150 tenfold reduction units/ml) correlated with the HLA allele group carriage in a cohort of 903 Swedish patients with multiple sclerosis treated with either intramuscular IFNβ-1a, subcutaneous IFNβ-1a or subcutaneous IFNβ-1b. Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titers. After stratification based on type of IFNβ preparation, HLA-DRB1*15 carriage was observed to increase the risk of developing NAbs as well as high NAb titers against both subcutaneous and intramuscular IFNβ-1a. Furthermore, in patients receiving subcutaneous IFNβ-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titers. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titers, and in a subgroup analysis of DRB1*04 alleles the risk for NAbs was increased in DRB1*04:01 carriers. In conclusion, there is a preparation-specific genetically determined risk to develop NAbs against IFNβ high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNβ preparation still remains the single most significant determinant for the risk of developing NAbs.

Objective To estimate risks for all‐cause mortality and for severe COVID‐19 in multiple sclerosis patients and across relapsing–remitting multiple sclerosis patients exposed to disease‐modifying therapies. Methods We conducted a Swedish nationwide population‐based multi‐register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age‐, sex‐, and region‐matched to five population‐based controls (n = 86,176 in March 2020) during March 2020–June 2021. We compared annual all‐cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID‐19 in relation to disease‐modifying therapy use, using Cox regression. Results Absolute all‐cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population‐based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID‐19 remained in line with those for all‐cause hospitalization, intensive care admission, and mortality. Among relapsing–remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID‐19 remained in the demographics‐, socioeconomic status‐, comorbidity‐, and multiple sclerosis severity‐adjusted model. Interpretation Risks of severe COVID‐19‐related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non‐COVID‐19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre‐pandemic years. The risk conveyed by disease‐modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.

Published estimates on age-dependent frequency of diabetes in cystic fibrosis (CF) vary widely, and are based mostly on older data. However, CF treatment and prevention of comorbidities changed over recent years. In many studies, definition of cystic fibrosis-related diabetes (CFRD) is not in line with current guideline recommendations. Therefore, we evaluated age-dependent occurrence of glucose abnormalities and associated risk factors in CF patients who participated in a multicenter screening program using oral glucose tolerance tests (OGTT). Between 2001 and 2010, 43 specialized CF centers from Germany and Austria serially performed 5,179 standardized OGTTs in 1,658 clinically stable, non-pregnant CF patients with no prior steroid medication or lung transplantation. Age-dependent occurrence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, one (DGT) or two consecutive (CFRD) diabetic OGTTs was analyzed, using Kaplan Meier curves. Cox proportional-hazards models were created to elucidate the influence of sex or underweight. At baseline/last OGTT, median age was 15.9 years/18.2 years and 30.6%/31.8% of patients were underweight. 25% of patients showed IFG at age 14.3 years; IGT at age 16.3 years; IFG+IGT combined at age 17.7 years. DGT was observed in 25% of patients at age 22.6 years; CFRD at age 34.5 years. Females had a 3.54 [95% CI 1.23-10.18] times higher risk for CFRD; risk for DGT was 2.21 [1.22-3.98] times higher. Underweight was a risk factor for IGT (HR [95% CI]: 1.38 [1.11-1.71]) and IFG+IGT (1.43 [1.11-1.83]), and in males also for DGT (1.49 [1.09-2.04]). If confirmation of diabetes by a second test is required, as recommended in current guidelines, age at CFRD diagnosis was higher compared to most previous studies. However, known risk factors for glucose abnormalities in CF were confirmed. Confirmation of diabetic OGT by a repeat test is important for a consistent diagnosis of CFRD.