INTRODUCTION:Understanding patients' everyday experience is essential to improve patient centered care in sarcoidosis. So far, patient perspectives are based on survey- and qualitative research. AIM:We aimed to assess patient-driven perspectives on their care trajectories using a novel machine learning-driven approach (MLD). METHODS:We used the largest Dutch sarcoidosis patient platform as the data source of patient stories. The patients' stories were extracted with permission. We applied topic modelling (to generate topics among the posts), and sentiment analysis (to find tone of voice in the topics). To validate the findings, we read the top 50 most relevant posts of each topic. An in-depth patients' disease trajectory map was made. RESULTS:Based on 4969 forum posts, 30 final topics and 10 upper themes were generated, which formed the basis for the "patient journey-map" which shows patients' perspective across the care pathway. Important decision moments could be identified, as well as care "tracks" at home and hospital and topics associated with positive or negative emotions. Most patients' perspectives were about symptoms (mainly negative sentiment), disease-modifying medication (mainly neutral sentiment), and quality of life (negative, neutral and positive). DISCUSSION:A major part of living with sarcoidosis takes place outside the view of the hospital, but this part often remains invisible. MLD is an innovative approach, providing a comprehensive overview of patients' perspectives on health and care. Integrating, these findings in the design of health care delivery has the potential to improve patient-centered care.

Having sarcoidosis often has a major impact on quality of life of patients and their families. Improving quality of life is prioritized as most important treatment aim by many patients with sarcoidosis, but current evidence and treatment options are limited. In this narrative review, we describe the impact of sarcoidosis on various aspects of daily life, evaluate determinants of health-related quality of life (HRQoL), and provide an overview of the different patient-reported outcome measures to assess HRQoL in sarcoidosis. Moreover, we review the current evidence for pharmacological and non-pharmacological interventions to improve quality of life for people with sarcoidosis.

Abstract Background The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. Methods We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. Results Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed. Conclusions Increased proportions of circulating PD-1+CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy. Trial registration NL44805.078.13

Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG(n=1–5) resulting in enhanced cellular retention. In this study we address the question whether different MTXPG(n) concentrations in red blood cells (RBC) of patients with sarcoidosis after 3 months of MTX therapy correlate with response to treatment. We retrospectively included patients with sarcoidosis that had started on MTX therapy and from whom blood samples and FDG-PET/CT were available 3 and 6–12 months after MTX initiation, respectively. FDG-uptake was measured by SUVmax in the heart, lungs and thoracic lymph nodes. Changes in SUVmax was used to determine anti-inflammatory response after 6–12 months of MTX therapy. MTXPG(n) concentrations were measured from whole blood RBC using an LC–MS/MS method. Pearson correlation coefficients were calculated to evaluate the relationship between changes in the SUVmax and MTXPG(n) concentrations. We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG3 and MTXPG4 a significant negative relation between the absolute changes in SUVmax and MTXPG(n) was found r = − 0.312 (n = 42, p = 0.047) for MTXPG3 and r = − 0.336 (n = 42, p = 0.031 for MTXPG4). The other MTXPG(n) did not correlate to changes in SUVmax. These results suggest a relation between MTXPG(n) concentrations and the anti-inflammatory effect in patients with sarcoidosis. Further prospective validation is warranted, but if measuring MTXPG concentrations could predict treatment effect of MTX this would be a step in the direction of personalized medicine.

RATIONALE:Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome. OBJECTIVES:To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome. METHODS:We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro. MEASUREMENTS AND MAIN RESULTS:We observed significant differences between patients and HCs in several T cell populations, including CD8+ and CD4+ T cells, Th1/Th17 subsets, CD4+ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4+ T cells and increased frequencies of Tregs and CD8+ γδ T cells correlated with worse outcome. Naïve CD4+ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs. CONCLUSIONS:Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.

Background Sarcoidosis-associated fatigue is highly prevalent and is often reported as the most burdensome symptom of sarcoidosis. Management of fatigue is challenging, and evidence-based therapies are lacking. In this TIRED trial, we aimed to assess the effects of a 12-week online mindfulness-based cognitive therapy (eMBCT) on fatigue. Methods This study was a prospective, open-label, multicentre randomised controlled trial, conducted at three centres in the Netherlands. Eligible patients were 18 years or older, had stable sarcoidosis, and a score of more than 21 points on the Fatigue Assessment Scale (FAS). Patients were randomised into either the eMBCT or the control group. Participants completed patient-reported outcome measures at baseline, after intervention (T1), and 12 weeks after completion of eMBCT (T2). The primary outcome was the change in FAS score at T1 in the eMBCT group compared with the control group, assessed with the independent students' t test in all patients who started the study. Secondary outcomes included within-group difference in FAS score at T1 and T2, between-group difference in FAS score at T2, and changes in the Hospital Anxiety and Depression Scale, the Freiburg Mindfulness Inventory-Short Form, and the Kings Sarcoidosis Questionnaire. The study was registered at the Netherlands Trial Register, NL7816.Findings Between June 5, 2019, and Oct 28, 2021, 99 patients were randomly assigned to the eMBCT (n=52) or the control (n=47) groups.Six patients withdrew consent after psychological screening before the start of eMBCT. Baseline FAS score was similar in both groups (3457 [SD 607] for 46 patients in the eMBCT group and 3551 [465] for 47 patients in the control group).Mean change in FAS score at T1 was -453 (SD 577; p<00001) in the eMBCT group and -128 (380; p=0026) in the control group (between-group difference 326 [95% CI 118 to 533; p=00025]). Furthermore, the eMBCT group had a significant improvement in anxiety (mean between-group difference 169, 95% CI 022-316; p=0025), depressive symptoms (152, 008-295; p=0039), mindfulness (31, 070-549; p=0022), and general health status (628, 251-1006; p=0002) at T1, compared with the control group.Interpretation 12 week eMBCT improves fatigue, anxiety, depression, mindfulness, and health status in patients with sarcoidosis-associated fatigue.

Introduction: Anxiety and depression are associated with fatigue and common in patients with sarcoidosis. In a RCT we showed that online mindfulness-based cognitive therapy (eMBCT) improved fatigue in patients with sarcoidosis. Here we report the effect of eMBCT on psychological wellbeing. Methods: We included patients with stable sarcoidosis and fatigue in this RCT. The intervention group underwent a 12-week eMBCT program. Patients completed the Hospital Anxiety and Depression Scale (HADS) and Freiburg Mindfulness Inventory (FMI) at baseline and 12 weeks. HADS scores range from 0-21, a score >7 indicates anxiety/depression. Differences were tested with t-tests. Results: 81 patients (34 intervention, 47 control) completed HADS and FMI at baseline and 12 weeks. At baseline, the presence of anxiety was 52% (mean 8.0±4.0) and depression 51% (mean 7.8±4.3), and similar for both groups. In the intervention group there was a clinically significant improvement in anxiety (meanΔ-2.1±3.7, p=0.002) and depression (Δ-2.3±3.7, p=0.001)(Fig 1). Between-group difference in change after 12 weeks was 1.8±0.7 (p=0.016) for anxiety, 1.6±0.7 (p=0.033) for depression, and 3.1±1.4 (p=0.033) for mindfulness. Conclusion: This RCT showed that eMBCT improved anxiety, depression, and mindfulness in patients with sarcoidosis-associated fatigue. eMBCT is an effective intervention and can easily be implemented in clinical care.

A perspective on the recently published ERS clinical practice guideline on treatment of sarcoidosis: although knowledge of the pathogenesis of sarcoidosis has improved, this has not yet translated into better evidence-based therapieshttps://bit.ly/3qaBIpg

Currently prednisone is the first-line pharmacological treatment option for pulmonary sarcoidosis. Methotrexate is used as second-line therapy and seems to have fewer side-effects. No prospective comparative studies of first-line treatment with methotrexate exist. In this study, we evaluated patient reported presence and bothersomeness of side-effects of prednisone and methotrexate in a sarcoidosis population to guide the design of a larger prospective study. During a yearly patient information meeting 67 patients completed a questionnaire on medication use; 11 patients never used prednisone or methotrexate and were excluded from further analysis. Of the remaining 56 patients, 89% used prednisone and 70% methotrexate (present or former). Significantly more side-effects were reported for prednisone than for methotrexate, 78% versus 49% (p = 0.006). In conclusion, methotrexate seems to have fewer and less bothersome side-effects than prednisone. These findings need to be confirmed in a prospective study.

Introduction: Prednisone is the cornerstone of treatment for pulmonary sarcoidosis. Treatment and tapering regimes are largely based on expert opinion. Previously, we reported on the short-term response to prednisone in patients with pulmonary sarcoidosis (ERJ PMID:29348185). Here, we report long-term data of this study. Methods: In this prospective study, treatment naïve patients with pulmonary sarcoidosis (FVC<85%) were treated with prednisone, starting at a dose of 40mg/d tapered to a maintenance dose of 10mg/d (wk 10). After 12 weeks treatment regimen was up to local physician. We collected data on lung function, biomarkers and patient-reported outcomes (MRC dyspnea, Fatigue Assessment Scale (FAS), King’s Sarcoidosis Questionnaire (KSQ) till 1 year. Results: 25 patients were included, 68% male, mean age 42.9±10.6. FVC improved between baseline (69.9%±13.6) and 1 month (81.4%±13.5; ∆+11.5%±8.5, p<0.001). Hereafter, FVC remained stable up to 1 year (83.8%±12.8; ∆+2.5%±8.2, p=0.19). The same trend was found for DLCO, sIL-2R, KSQ, FAS and MRC (fig.1). Weight increased with 8.2kg ±6.2 (p<0.001) in 1 year. Conclusion: In newly treated sarcoidosis patients, major clinical improvement occurred within 1 month after start of prednisone. After 1 month, lung function and symptoms remained stable up until 1 year irrespective of prednisone tapering schedule. These results can help optimize treatment schedules and inform future trial design.

PURPOSE OF REVIEW:Patients with sarcoidosis may be at higher risk of coronavirus disease-19 (COVID-19) as over 90% of the patients have pulmonary involvement and many are treated with immunosuppressive agents. This review will summarize the current literature regarding sarcoidosis and COVID-19, with a particular focus on susceptibility, clinical outcomes, management, and approach to vaccination.RECENT FINDINGS:Data about COVID-19 and sarcoidosis include a number of case series and reports, cohort studies, and registries. Literature is not conclusive whether patients with sarcoidosis have increased susceptibility to COVID-19. Patients with moderate to severe impaired pulmonary function may be at increased risk of adverse outcomes and mortality. Whether immunosuppressive medication increases risk of COVID-19 severity or affects vaccination response is not yet clear. Novel approaches, such as telemedicine and home monitoring programs, are promising to ensure continuity of care for patients with sarcoidosis during the COVID-19 pandemic.SUMMARY:Current evidence about the risk and clinical outcomes of COVID-19 infection in patient with sarcoidosis, is mainly extrapolated from other immune-mediated diseases. Hence, further research that focuses on the sarcoidosis population is warranted.

Abstract Background Treatment of pulmonary sarcoidosis is recommended in case of significant symptoms, impaired or deteriorating lung function. Evidence-based treatment recommendations are limited and largely based on expert opinion. Prednisone is currently the first-choice therapy and leads to short-term improvement of lung function. Unfortunately, prednisone often has side-effects and may be associated with impaired quality of life. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects. Objective The primary objective of this trial is to investigate the effectiveness and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared with prednisone. The primary endpoint of this study will be the change in hospital-measured Forced Vital Capacity (FVC) between baseline and 24 weeks. Secondary objectives are to gain more insights in response to therapy in individual patients by home spirometry and patient-reported outcomes. Blood biomarkers will be examined to find predictors of response to therapy, disease progression and chronicity, and to improve our understanding of the underlying disease mechanism. Methods/design In this prospective, randomized, non-blinded, multi-center, non-inferiority trial, we plan to randomize 138 treatment-naïve patients with pulmonary sarcoidosis who are about to start treatment. Patients will be randomized in a 1:1 ratio to receive either prednisone or methotrexate in a predefined schedule for 24 weeks, after which they will be followed up in regular care for up to 2 years. Regular hospital visits will include pulmonary function assessment, completion of patient-reported outcomes, and blood withdrawal. Additionally, patients will be asked to perform weekly home spirometry, and record symptoms and side-effects via a home monitoring application for 24 weeks. Discussion This study will be the first randomized controlled trial comparing first-line treatment of prednisone and methotrexate and provide valuable data on efficacy, safety, quality of life and biomarkers. If this study confirms the hypothesis that methotrexate is as effective as prednisone as first-line treatment for sarcoidosis but with fewer side-effects, this will lead to improvement in care and initiate a change in practice. Furthermore, insights into the immunological mechanisms underlying sarcoidosis pathology might reveal new therapeutic targets. Trial registration The study was registered on the 19th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; ID NCT04314193.

Fatigue is one of the most burdensome symptoms in interstitial lung disease (ILD) and can have a major impact on quality of life, social interactions, and work capacity. The cause of fatigue is complex; it is caused or aggravated by a combination of different predisposing, precipitating, and perpetuating factors. There is no uniform definition of fatigue, but it is often divided in physical and mental components. Several validated questionnaires can be used for structural assessment of fatigue in daily care. Although the high burden of fatigue in ILD is recognized increasingly, studies that have investigated pharmacologic and nonpharmacologic treatment options are scarce. Because fatigue in ILD is often a multifactorial problem, therapeutic interventions ideally should be aimed at different domains. One of the first steps is to optimize treatment of the underlying disease. Subsequently, treatable causes of fatigue should be identified and treated. Recently, an increasing number of studies showed that supportive measures have the potential to improve fatigue. However, evidence-based treatment guidelines are lacking, and more research is highly needed in this field. In clinical practice, a comprehensive, multidisciplinary, and individually tailored approach seems best fit to optimize treatment of fatigue in patients with ILD.

Sarcoidosis is a multisystem granulomatous disease, associated with significant morbidity and impaired quality of life. Treatment is aimed at recovering organ function, reducing symptom burden and improving quality of life. Because of the heterogeneity and variable disease course, a comprehensive, multidisciplinary approach to care is needed. Comprehensive care includes not only pharmacological interventions, but also supportive measures aimed at relieving symptoms and improving quality of life. The purpose of this review is to summarize the most recent knowledge regarding different aspects of care and propose a structured approach to sarcoidosis management.

Objective: To define age-specific reference values for cerebrospinal fluid (CSF) total protein levels for children and validate these values in children with Guillain-Barre syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS).Methods: Reference values for CSF total protein levels were determined in an extensive cohort of diagnostic samples from children (<18 year) evaluated at Erasmus Medical Center/Sophia Children's Hospital. These reference values were confirmed in children diagnosed with disorders unrelated to raised CSF total protein level and validated in children with GBS, ADEM and MS.Results: The test results of 6145 diagnostic CSF samples from 3623 children were used to define reference values. The reference values based on the upper limit of the 95% CI (i.e. upper limit of normal) were for 6 months-2 years 0.25 g/L, 2-6 years 0.25 g/L, 6-12 years 0.28 g/L, 12-18 years 0.34 g/L. These reference values were confirmed in a subgr oup of 378 children diagnosed with disorders that are not typically associated with increased CSF total protein. In addition, the CSF total protein levels in these children in the first 6 months after birth were highly variable (median 0.47 g/L, IQR 0.26-0.65). According to these new reference values, CSF total protein level was elevated in 85% of children with GBS, 66% with ADEM and 23% with MS.Conclusion: More accurate age-specific reference values for CSF total protein levels in children were determined. These new reference values are more sensitive than currently used values for diagnosing GBS and ADEM in children. (C) 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

To describe the key diagnostic features of pediatric Guillain–Barré syndrome (GBS) and validate the Brighton criteria. Retrospective cohort study of all children (<18 years) diagnosed with GBS between 1987 and 2013 at Sophia Children’s Hospital, Erasmus MC, Rotterdam. Clinical information was collected and the sensitivity of the Brighton criteria was calculated. 67 children (35 boys) were included, with a median age of 5.0 years [interquartile range (IQR) 3.0–10.0 years]. Bilateral limb weakness was present at hospital admission in 93% of children, and at nadir in all patients. Children presented with tetraparesis in 70% or with paraparesis in 23%. Reduced reflexes in paretic limbs were observed at hospital admission in 82% and during follow-up in all children. The progressive phase lasted median 6 days (IQR 3–8 days) and less than 4 weeks in all children. A monophasic disease course was seen in 97%, including 5 children with a treatment-related fluctuation. Two children had a later relapse at 9 weeks and 19 weeks after onset. 77% of the children showed an elevated protein level in CSF. Nerve conduction studies showed evidence for a poly(radiculo)neuropathy in 91% of the children. 46 children had a complete data set, the sensitivity of the Brighton criteria level 1 was 72% (95% CI 57–84) and 96% (95% CI 85–99) for level 2 and 98% (95% CI 88–100) for level 3. The majority of the pediatric GBS patients presented in this cohort fulfilled the current diagnostic criteria.

A 49-year-old woman with a medical history of rheumatoid arthritis presented to the emergency room, with high fever and painful knees. In addition, she had had a mild headache for several days and some hearing loss over several months. We saw an ill patient with arthritis of both knees, from which purulent fluid was aspirated. Antibiotics were started for septic arthritis of both knees and her condition improved rapidly. However, the headache persisted and the hearing loss worsened. At the time, meningitis was suspected. Initial knee aspiration culture was positive for Neisseria meningitidis PCR of the cerebrospinal fluid sample also was positive for N. meningitidis The patient was finally diagnosed with bilateral septic gonarthritis secondary to a bacterial meningitis caused by N. meningitidis.