Decreased serpin C1 in extracellular vesicles predicts response to methotrexate treatment in patients with pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function deteriorates. In pulmonary sarcoidosis, prednisone and methotrexate (MTX) are the most common anti-inflammatory therapies. However, there is large inter-patient variability in response to treatment, and predictive response markers are currently lacking. OBJECTIVE: In this study, we investigated the predictive potential of biomarkers in extracellular vesicles (EVs) isolated from biobanked serum of patients with pulmonary sarcoidosis stored prior to start of therapy. METHODS: Protein concentrations of a four-protein test panel of inflammatory proteins were measured in a discovery (n = 16) and replication (n = 129) cohort of patients with sarcoidosis and 47 healthy controls. Response to therapy was defined as an improvement of the absolute score of > 5% forced vital capacity (FVC) and/or > 10% diffusion lung of carbon monoxide (DLCO) after 24 weeks compared to baseline (before treatment). RESULTS: Serum protein levels differed between EV fractions and serum, and between sarcoidosis cases and controls. Serpin C1 concentrations in the low density lipid particle EV fraction were lower at baseline in the group of patients with a good response to MTX treatment in both the discovery cohort (p = 0.059) and in the replication cohort (p = 0.032). EV Serpin C1 showed to be a significant predictor for response to treatment with MTX (OR 0.4; p = 0.032). CONCLUSION: This study shows that proteins isolated from EVs harbor a distinct signal and have potential as new predictive therapy response biomarkers in sarcoidosis.

ERS International Congress 2023: highlights from the Interstitial Lung Diseases Assembly.

This article summarises a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the International Congress of the European Respiratory Society in 2023. Translational and clinical studies focused on the whole spectrum of ILDs, from (ultra)rare ILDs to sarcoidosis, ILDs associated with connective tissue disease and idiopathic pulmonary fibrosis. The main topics of the 2023 Congress presentations were improving the diagnostic process of ILDs, better prediction of disease course and investigation of novel treatment options.

Biomarkers in Sarcoidosis: Beginning of a New Era?

At present, no biomarker exists which is truly specific for sarcoidosis and the ones available have modest sensitivity and specificity. The clinical context should dictate the choice of biomarker(s) used to address different clinical questions such as diagnosis, monitoring disease activity or monitoring response to treatment. In the future, in addition to known serum biomarkers, it seems fruitful to further explore a possible role of imaging, exhaled air and even biopsy-related biomarkers in sarcoidosis to guide clinical management.

Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

Fully Automatic, Semiautomatic, and Manual Corneal Nerve Fiber Analysis in Patients With Sarcoidosis.

Purpose: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semiautomatic, and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis. Methods: We included 20 healthy controls and 80 patients with sarcoidosis, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics, and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA. Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ, and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relation between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and seem to be less comparable owing to differences between automatic and manual techniques. Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not seem to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis. Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN.

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.

Thermal threshold testing: call for a balance between the number of measurements and abnormalities in the diagnosis of sarcoidosis-associated small fiber neuropathy.

Introduction: Several recent studies of diagnosing small fiber neuropathy (SFN) have shown a lack of uniformity in thermal threshold testing (TTT) or quantitative sensory testing (QST) which makes it a challenge to compare the data. It is known that the chance of finding an abnormality increases with increasing number of measurements. Objectives: With this study, we first wanted to investigate whether TTT could benefit from a new approach focusing on the balance between the number of measurements, depending on the selection of parameters and measuring sites, and on number of abnormalities (NOAs). Second, we wanted to address the role of the method of levels (MLe) in possible desensitization during TTT measurements. Methods: One hundred seventeen participants were included (48 patients with sarcoidosis with probable SFN, 49 without SFN, and 20 healthy controls). Thermal threshold testing measurements and Small Fiber Neuropathy Screening List (SFNSL) questionnaire were used to assess SFN. Results: A combination of measuring all thermal threshold parameters at both feet except for MLe showed the best diagnostic performance. Increasing TTT NOAs correlates with the severity of SFN. Adding the SFNSL questionnaire further improves diagnostic performance. Discussion: Looking at TTT NOAs in all TTT parameters except for MLe at both feet should be considered as a new approach to improve the consistency and balance between the selection of TTT parameters, measuring sites, and definition of "abnormal QST." Moreover, the SFNSL questionnaire is a valuable tool to quantify SFN symptoms and could improve SFN diagnosis.

Simultaneous Assessment of mTORC1, JAK/STAT, and NLRP3 Inflammasome Activation Pathways in Patients with Sarcoidosis.

The unknown etiology of sarcoidosis, along with the variability in organ involvement and disease course, complicates the effective treatment of this disease. Based on recent studies, the cellular inflammatory pathways involved in granuloma formation are of interest regarding possible new treatment options, such as the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) pathway, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The aim of this study was to explore the potential coexpression of these three inflammatory pathways in patients with sarcoidosis and see whether possible differences were related to disease outcome. The tissue of 60 patients with sarcoidosis was used to determine the activity of these three signaling pathways using immunohistochemistry. The activation of NLRP3 was present in 85% of all patients, and the activation of mTORC1 and JAK/STAT was present in 49% and 50% of patients, respectively. Furthermore, the presence of NLRP3 activation at diagnosis was associated with a chronic disease course of sarcoidosis. Our finding of different new conceptual inflammatory tissue phenotypes in sarcoidosis could possibly guide future treatment studies using the available inhibitors of either NLRP3, JAK-STAT, and mTORC1 inhibitors in a more personalized medicine approach.

Improved Survival of IPF patients Treated With Antifibrotic Drugs Compared With Untreated Patients.

PURPOSE: Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. RESEARCH QUESTIONS: Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPFAF) compared with an untreated cohort (IPFnon-AF)? Is this different for patients with GAP stage I, II, or III. METHODS: This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPFAF and IPFnon-AF. This was repeated after stratification for GAP stage. RESULTS: In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPFAF (n = 313) and 2.2 years in IPFnon-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPFAF (n = 143) and IPFnon-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPFAF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPFAF with GAP III was also significantly lower (19.0% vs 65.0%). CONCLUSION: This large real-world study showed a survival benefit in IPFAF compared with IPFnon-AF. This especially holds true for patients with GAP stage II and III.

Delineating associations of progressive pleuroparenchymal fibroelastosis in patients with pulmonary fibrosis.

Background: Computer quantification of baseline computed tomography (CT) radiological pleuroparenchymal fibroelastosis (PPFE) associates with mortality in idiopathic pulmonary fibrosis (IPF). We examined mortality associations of longitudinal change in computer-quantified PPFE-like lesions in IPF and fibrotic hypersensitivity pneumonitis (FHP). Methods: Two CT scans 6-36 months apart were retrospectively examined in one IPF (n=414) and one FHP population (n=98). Annualised change in computerised upper-zone pleural surface area comprising radiological PPFE-like lesions (Δ-PPFE) was calculated. Δ-PPFE >1.25% defined progressive PPFE above scan noise. Mixed-effects models evaluated Δ-PPFE against change in visual CT interstitial lung disease (ILD) extent and annualised forced vital capacity (FVC) decline. Multivariable models were adjusted for age, sex, smoking history, baseline emphysema presence, antifibrotic use and diffusion capacity of the lung for carbon monoxide. Mortality analyses further adjusted for baseline presence of clinically important PPFE-like lesions and ILD change. Results: Δ-PPFE associated weakly with ILD and FVC change. 22-26% of IPF and FHP cohorts demonstrated progressive PPFE-like lesions which independently associated with mortality in the IPF cohort (hazard ratio 1.25, 95% CI 1.16-1.34, p<0.0001) and the FHP cohort (hazard ratio 1.16, 95% CI 1.00-1.35, p=0.045). Interpretation: Progression of PPFE-like lesions independently associates with mortality in IPF and FHP but does not associate strongly with measures of fibrosis progression.

ERS International Congress 2022: highlights from the Interstitial Lung Diseases Assembly.

This article contains a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the hybrid European Respiratory Society International Congress 2022. Early Career Members of Assembly 12 summarise recent advances in translational and clinical research in idiopathic interstitial pneumonias, ILDs of known origin, sarcoidosis and other granulomatous diseases, and rare ILDs. Many studies focused on evaluation of diagnostic and prognostic (bio)markers, and novel pharmacological and nonpharmacological treatment options for different ILDs. In addition, new insights in clinical, physiological and radiological features of various rare ILDs were presented.

Prednisone vs methotrexate in treatment naïve cardiac sarcoidosis.

BACKGROUND: Side effects limit the long-term use of glucocorticoids in cardiac sarcoidosis (CS), and methotrexate has gained attention as steroid sparing agent although the supporting evidence is poor. This study compared prednisone monotherapy, methotrexate monotherapy or a combination of both, in the reduction of myocardial Fluorine-18 fluorodeoxyglucose (FDG) uptake and clinical stabilization of CS patients. METHODS AND RESULTS: In this retrospective cohort study, 61 newly diagnosed and treatment naïve CS patients commenced treatment with prednisone (N = 21), methotrexate (N = 30) or prednisone and methotrexate (N = 10) between January 2010 and December 2017. Primary outcome was metabolic response on FDG PET/CT and secondary outcomes were treatment patterns, major adverse cardiovascular events, left ventricular ejection fraction, biomarkers and side effects. At a median treatment duration of 6.2 [5.7-7.2] months, 71.4% of patients were FDG PET/CT responders, and the overall myocardial maximum standardized uptake value decreased from 6.9 [5.0-10.1] to 3.4 [2.1-4.7] (P < 0.001), with no significant differences between treatment groups. During 24 months of follow-up, 7 patients (33.3%; prednisone), 6 patients (20.0%; methotrexate) and 1 patient (10.0%; combination group) experienced at least one major adverse cardiovascular event (P = 0.292). Left ventricular ejection fraction was preserved in all treatment groups. CONCLUSIONS: Significant suppression of cardiac FDG uptake occurred in CS patients after 6 months of prednisone, methotrexate or combination therapy. There were no significant differences in clinical outcomes during follow-up. These results warrant further investigation of methotrexate treatment in CS patients.

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.

Infliximab decreases inflammatory activity but has no effect on small fiber neuropathy related symptoms in Dutch patients with sarcoidosis

BACKGROUND AND AIM: Small fiber neuropathy (SFN) may present as complication in sarcoidosis.(1) SFN can potentially result into a large range of symptoms with a high impact on quality of life.(2) Although treatment of the underlying disease of SFN is paramount, little research has been performed to investigate SFN improvement as consequence of sarcoidosis treatment. This retrospective study investigates whether there is an association between the anti-inflammatory effects of infliximab and SFN-symptoms Methods: The Small Fiber Neuropathy Screening List (SFNSL) was used to measure changes in SFN symptoms during infliximab treatment. Maximal standardized uptake value (SUVmax) from Fluordeoxyglucose Positron Emission Tomography (FDG-PET) was used as a measure for inflammatory activity. RESULTS: 36 sarcoidosis patients were eligible for analysis. SFNSL-score showed a mean decrease of -1,9 points (p = 0.446). SUVmax did improve with a mean of -3.7 (p<0.001). No correlation between a decrease of SUVmax and SFNSL screening list could be found (p=0.610). CONCLUSIONS: Our data reveal no association between anti-inflammatory effect of infliximab and SFN-related symptoms in patients with sarcoidosis, which contradicts previous case-reports and case-series.(3-6) Given the major negative impact of SFN-related symptoms on the quality of life in patients with sarcoidosis, it is necessary that the possible beneficial effect of anti-inflammatory therapy will be further addressed in future prospective studies.1.

The Role of Cutibacterium acnes in Sarcoidosis: From Antigen to Treatable Trait?

Cutibacterium acnes (C. acnes, formerly Propionibacterium acnes) is considered to be a non-pathogenic resident of the human skin, as well as mucosal surfaces. However, it also has been demonstrated that C. acnes plays a pathogenic role in diseases such as acne vulgaris or implant infections after orthopedic surgery. Besides a role in infectious disease, this bacterium also seems to harbor immunomodulatory effects demonstrated by studies using C. acnes to enhance anti-tumor activity in various cancers or vaccination response. Sarcoidosis is a systemic inflammatory disorder of unknown causes. Cultures of C. acnes in biopsy samples of sarcoidosis patients, its presence in BAL fluid, tissue samples as well as antibodies against this bacterium found in serum of patients with sarcoidosis suggest an etiological role in this disease. In this review we address the antigenic as well as immunomodulatory potential of C. acnes with a focus on sarcoidosis. Furthermore, a potential role for antibiotic treatment in patients with sarcoidosis will be explored.

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.

ANXA11 rs1049550 Associates with Löfgren's Syndrome and Chronic Sarcoidosis Patients.

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case-control association study to investigate if ANXA11 associates with benign (Löfgren's syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48-0.77, p = 3 × 10-5). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52-0.92, p = 0.01 and OR 0.51, 95% CI 0.36-0.70, p = 4 × 10-5, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66-0.75, p = 3.58 × 10-29). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease.