Organ involvement and assessment in sarcoidosis.

PURPOSE OF REVIEW: In recent years new recommendations have been published about organ assessment in the diagnosis of sarcoidosis. RECENT FINDINGS: Screening for pulmonary, cardiac, ocular, neurologic and renal involvement and hypercalcemia is recommended in the work-up for sarcoidosis, additionally, screening for hypercalciuria at the time of the diagnosis might be beneficial. SUMMARY: One of the goals in the work-up of sarcoidosis is to assess the extent and severity of organ involvement. Timely and accurate assessment leads to determination of treatment indication. Screening for pulmonary involvement should include pulmonary imaging and pulmonary function tests. Screening for cardiac involvement should include a clear history including palpitations and collapse and a baseline electrocardiogram or 24-h Holter monitoring. At diagnosis, ophthalmological assessment is recommended. Furthermore, serum calcium level and serum creatinine level should be obtained. Although routine 24-h urinary calcium excretion is not included in the guidelines, performing this test routinely can be considered. On indication, neurologic, rheumatologic or dermatologic assessment can be performed.

Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

18F-fluorodeoxyglucose positron emission tomography for the assessment of endo-bronchial involvement in granulomatosis with polyangiitis.

Bronchial stenosis is an uncommon but potentially life-threatening complication of granulomatosis with polyangiitis (GPA). The development of lower respiratory tract stenoses in patients with GPA is thought to be the result of persistent inflammation of the cartilaginous tissue. New assessment methods for this severe GPA complication are highly needed. Herein, we show the value of 18F-fluorodeoxyglycose positron emission tomography/computed tomography (18F-FDG-PET/CT) in the diagnosis, prediction of progression to bronchial stenosis and response to treatment of endobronchial involvement in a patient with GPA.

Safety and tolerability of pirfenidone in asbestosis: a prospective multicenter study.

BACKGROUND: Pirfenidone slows down disease progression in idiopathic pulmonary fibrosis (IPF). Recent studies suggest a treatment effect in progressive pulmonary fibrosis other than IPF. However, the safety and effectiveness of pirfenidone in asbestosis patients remain unclear. In this study, we aimed to investigate the safety, tolerability and efficacy of pirfenidone in asbestosis patients with a progressive phenotype. METHODS: This was a multicenter prospective study in asbestosis patients with progressive lung function decline. After a 12-week observational period, patients were treated with pirfenidone 801 mg three times a day. Symptoms and adverse events were evaluated weekly and patients completed online patient-reported outcomes measures. At baseline, start of therapy, 12 and 24 weeks, in hospital measurement of lung function and a 6 min walking test were performed. Additionally, patients performed daily home spirometry measurements. RESULTS: In total, 10 patients were included of whom 6 patients (66.7%) experienced any adverse events during the study period. Most frequently reported adverse events were fatigue, rash, anorexia and cough, which mostly occurred intermittently and were reported as not very bothersome. No significant changes in hospital pulmonary function (forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), 6 min walking test or patient-reported outcomes measures before and after start of pirfenidone were found. Home spirometry demonstrated a FVC decline in 12 weeks before start of pirfenidone, while FVC did not decline during the 24 week treatment phase, but this difference was not statistically significant. CONCLUSIONS: Treatment with pirfenidone in asbestosis has an acceptable safety and tolerability profile and home spirometry data suggest this antifibrotic treatment might attenuate FVC decline in progressive asbestosis. Trial registration MEC-2018-1392; EudraCT number: 2018-001781-41.

Patient Activation for Self-Management in Patients with Idiopathic Pulmonary Fibrosis or Sarcoidosis.

BACKGROUND: Self-management is considered important in the management of patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, data about the degree of activation for self-management is lacking. OBJECTIVES: The aim of the study was to determine the degree of activation for self-management in patients with IPF or sarcoidosis using the Patient Activation Measure (PAM) and to evaluate the association between PAM scores, clinical characteristics, and health-related outcomes. STUDY DESIGN AND METHODS: This cross-sectional prospective study assessed besides the PAM also demographics, lung function, dyspnea (modified Medical Research Council [mMRC]), fatigue (Checklist Individual Strength-Fatigue [CIS-Fatigue]), anxiety/depression (Hospital Anxiety and Depression Scale [HADS-A/HADS-D]), and generic health status (EuroQol five-dimensional-five-level [EQ-5D-5L]). RESULTS: Mean PAM was 55.0 (9.1) points in patients with IPF (n = 59) and low levels of patient activation for self-management (PAM ≤55.1 points) were present in 56% of the patients. PAM Scores correlated significantly (p < 0.05) with mMRC (ρ = -0.476), HADS-A (ρ = -0.326), HADS-D (ρ = -0.459), and EQ-5D-5L (ρ = 0.393). In patients with sarcoidosis (n = 59), the mean PAM score was 55.7 (11.0) points, and 46% of the patients reported low PAM levels. Significant correlations were found with mMRC (ρ = -0.356), HADS-A (ρ = -0.394), HADS-D (ρ = -0.478), and EQ-5D-5L (ρ = 0.313). CONCLUSION: About half of the outpatients with IPF or sarcoidosis have a low degree of activation for self-management, and these patients generally report more dyspnea, anxiety, depression, and a lower health status. Whether patients with a low degree of activation can be successful in self-managing their disease remains to be determined.

Aortic intramural haematoma associated with the use of nintedanib.

We report a 74-year-old patient who developed an acute aortic syndrome (AAS) with intramural haematoma (IMH) during treatment with nintedanib, a tyrosine kinase inhibitor. As we suspected a role for nintedanib, this was immediately interrupted. Four months later, a computed tomographic angiography (CTA) showed significant regression of the IMH. Therefore, we state that, when patients use nintedanib and develop acute chest or back pain, diagnostic work-up for AAS should be considered. Furthermore, other risk factors for AAS, such as hypertension, genetic diseases and comedication should be taken into account when prescription of medication of this class is considered.

Hemocytometric characteristics of COVID-19 patients with and without cytokine storm syndrome on the sysmex XN-10 hematology analyzer.

OBJECTIVES: COVID-19 is an ongoing global pandemic. There is an urgent need for identification and understanding of clinical and laboratory parameters related to progression towards a severe and fatal form of this illness, often preceded by a so-called cytokine-storm syndrome (CSS). Therefore, we explored the hemocytometric characteristics of COVID-19 patients in relation to the deteriorating clinical condition CSS, using the Sysmex XN-10 hematology analyzer. METHODS: From March 1st till May 16th, 2020, all patients admitted to our hospital with respiratory complaints and suspected for COVID-19 were included (n=1,140 of whom n=533 COVID-19 positive). The hemocytometric parameters of immunocompetent cells in peripheral blood (neutrophils [NE], lymphocytes [LY] and monocytes [MO]) obtained upon admission to the emergency department (ED) of COVID-19 positive patients were compared with those of the COVID-19 negative ones. Moreover, patients with CSS (n=169) were compared with COVID-19 positive patients without CSS, as well as with COVID-19 negative ones. RESULTS: In addition to a significant reduction in leukocytes, thrombocytes and absolute neutrophils, it appeared that lymphocytes-forward scatter (LY-FSC), and reactive lymphocytes (RE-LYMPHO)/leukocytes were higher in COVID-19-positive than negative patients. At the moment of presentation, COVID-19 positive patients with CSS had different neutrophils-side fluorescence (NE-SFL), neutrophils-forward scatter (NE-FSC), LY-FSC, RE-LYMPHO/lymphocytes, antibody-synthesizing (AS)-LYMPHOs, high fluorescence lymphocytes (HFLC), MO-SSC, MO-SFL, and Reactive (RE)-MONOs. Finally, absolute eosinophils, basophils, lymphocytes, monocytes and MO-FSC were lower in patients with CSS. CONCLUSIONS: Hemocytometric parameters indicative of changes in immunocompetent peripheral blood cells and measured at admission to the ED were associated with COVID-19 with and without CSS.

Home Monitoring in Patients with Idiopathic Pulmonary Fibrosis. A Randomized Controlled Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly disease with increasingly impaired health-related quality of life (HRQOL). eHealth technologies facilitate collection of physiological outcomes and patient-reported outcomes at home, but randomized controlled trials (RCTs) on the effects of eHealth are scarce.Objectives: To investigate whether a home monitoring program improves HRQOL and medication use for patients with IPF.Methods: We performed a multicenter RCT in newly treated patients with IPF. Patients were randomly assigned to standard care or a home monitoring program on top of standard care for 24 weeks. The home monitoring program included home spirometry, reporting of symptoms and side effects, patient-reported outcomes, information, a medication coach, and eConsultations. The primary endpoint was between-group difference in change in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) score at 24 weeks.Measurements and Main Results: A total of 90 patients were randomized (46 assigned to the home monitoring group and 44 to the standard care group). After 24 weeks, no statistically significant difference was found in K-BILD total score, with a 2.70-point increase in the home monitoring group (SD = 9.5) and a 0.03-point increase in the standard care group (SD = 10.4); between-group difference was 2.67 points (95% confidence interval [CI], -1.85 to 7.17; P = 0.24). Between-group difference in psychological domain score was 5.6 points (95% CI, -1.13 to 12.3; P = 0.10), with an increase of 5.12 points in the home monitoring group (SD = 15.8) and a decline of 0.48 points in the standard care group (SD = 13.3). In the home monitoring group, medication was more often adjusted (1 vs. 0.3 adjustments per patient; 95% CI, 0.2 to 1.3; P = 0.027). Patient satisfaction with the home monitoring program was high. Home-based spirometry was highly correlated with hospital-based spirometry over time.Conclusions: The results of this first-ever eHealth RCT in IPF showed that a comprehensive home monitoring program did not improve overall HRQOL measured with K-BILD but tended to improve psychological well-being. Home monitoring was greatly appreciated by patients and allowed for individually tailored medication adjustments.Clinical trial registered with www.clinicaltrials.gov (NCT03420235).

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study.

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study.

BACKGROUND: Clinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population. AIM: To determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands. METHODS: Two large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument. RESULTS: Between 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis. CONCLUSIONS: High-risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.

The role of the PET scan in the management of sarcoidosis.

PURPOSE OF REVIEW: It is important to gain knowledge and understanding about the appropriate use of PET scan in the management of sarcoidosis patients. This means that, in view of the radiation dose and costs, defining appropriate indications for PET scanning in sarcoidosis patients is vital. RECENT FINDINGS: PET has been shown to be a very sensitive technique for the assessment of inflammatory activity in sarcoidosis by detecting and quantifying the degree of inflammatory and granulomatous reactions that occur in the lungs and elsewhere in the body. SUMMARY: PET is not indicated in the standard workup, but can be of great value to complement more routinely used techniques. On the basis of the current findings, PET offers added value in sarcoidosis patients with unexplained persistent disabling symptoms. PET appears especially helpful in those persistently symptomatic patients without serological signs of inflammatory activity, in patients with radiologic signs of fibrosis and in the detection of active cardiac sarcoidosis. The use of PET to assess the extent of disease can uncover a suitable location for biopsy to obtain histological evidence for the diagnosis or to explain the (mainly extrathoracic) symptoms. Furthermore, the detection of unexpected organ involvement may offer prognostic value.

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.