Increased proportions of circulating PD-1+ CD4+ memory T cells and PD-1+ regulatory T cells associate with good response to prednisone in pulmonary sarcoidosis.

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 Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Quality of life in sarcoidosis.

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.

Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

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.

Online mindfulness-based cognitive therapy for fatigue in patients with sarcoidosis (TIRED): a randomised controlled trial.

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 (34·57 [SD 6·07] for 46 patients in the eMBCT group and 35·51 [4·65] for 47 patients in the control group). Mean change in FAS score at T1 was -4·53 (SD 5·77; p<0·0001) in the eMBCT group and -1·28 (3·80; p=0·026) in the control group (between-group difference 3·26 [95% CI 1·18 to 5·33; p=0·0025]). Furthermore, the eMBCT group had a significant improvement in anxiety (mean between-group difference 1·69, 95% CI 0·22-3·16; p=0·025), depressive symptoms (1·52, 0·08-2·95; p=0·039), mindfulness (3·1, 0·70-5·49; p=0·022), and general health status (6·28, 2·51-10·06; p=0·002) 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. FUNDING: Dutch Sarcoidosis Patient Association (Sarcoidose.nl). TRANSLATION: For the Dutch translation of the summary see Supplementary Materials section.

Patient reported side-effects of prednisone and methotrexate in a real-world sarcoidosis population.

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.

COVID-19 infection in patients with sarcoidosis: susceptibility and clinical outcomes.

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.

Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study.

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 .

Managing Fatigue in Patients With Interstitial Lung Disease.

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.

Comprehensive Care for Patients with Sarcoidosis.

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.

Diagnosis of Guillain-Barré syndrome in children and validation of the Brighton criteria.

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.

Painful knees and hearing-loss: a rare presentation of meningococcal disease.

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.