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  1. Article ; Online: Decreased serpin C1 in extracellular vesicles predicts response to methotrexate treatment in patients with pulmonary sarcoidosis.

    Kraaijvanger, Raisa / Janssen Bonás, Montse / Grutters, Jan C / Paspali, Ioanna / Veltkamp, Marcel / de Kleijn, Dominique P V / van Moorsel, Coline H M

    Respiratory research

    2024  Volume 25, Issue 1, Page(s) 166

    Abstract: 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) ... ...

    Abstract 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.
    MeSH term(s) Humans ; Sarcoidosis, Pulmonary/diagnosis ; Sarcoidosis, Pulmonary/drug therapy ; Methotrexate/therapeutic use ; Antithrombin III ; Sarcoidosis ; Biomarkers ; Extracellular Vesicles
    Chemical Substances Methotrexate (YL5FZ2Y5U1) ; Antithrombin III (9000-94-6) ; Biomarkers
    Language English
    Publishing date 2024-04-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041675-1
    ISSN 1465-993X ; 1465-993X
    ISSN (online) 1465-993X
    ISSN 1465-993X
    DOI 10.1186/s12931-024-02809-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects.

    Kraaijvanger, Raisa / Janssen Bonás, Montse / Vorselaars, Adriane D M / Veltkamp, Marcel

    Frontiers in immunology

    2020  Volume 11, Page(s) 1443

    Abstract: Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and ... ...

    Abstract Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease.
    MeSH term(s) Biomarkers/blood ; Clinical Decision-Making ; Diagnostic Imaging ; Humans ; Peptidyl-Dipeptidase A/blood ; Prognosis ; Receptors, Interleukin-2/blood ; Sarcoidosis/diagnosis
    Chemical Substances Biomarkers ; Receptors, Interleukin-2 ; ACE protein, human (EC 3.4.15.1) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
    Language English
    Publishing date 2020-07-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.01443
    Database MEDical Literature Analysis and Retrieval System OnLINE

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

    Janssen Bonás, Montse / Sundaresan, Janani / Keijsers, Ruth G M / Struys, Eduard A / Peters, Bas J M / Kahlmann, Vivienne / Wijsenbeek, Marlies S / de Rotte, Maurits C F J / Grutters, Jan C / Veltkamp, Marcel

    Lung

    2023  Volume 201, Issue 6, Page(s) 617–624

    Abstract: 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. ...

    Abstract 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
    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
    Results: We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG
    Conclusion: These results suggest a relation between MTXPG
    MeSH term(s) Humans ; Methotrexate ; Pilot Projects ; Chromatography, Liquid ; Retrospective Studies ; Fluorodeoxyglucose F18 ; Positron Emission Tomography Computed Tomography ; Tandem Mass Spectrometry ; Sarcoidosis/diagnostic imaging ; Sarcoidosis/drug therapy ; Anti-Inflammatory Agents
    Chemical Substances methotrexate polyglutamate (82334-40-5) ; Methotrexate (YL5FZ2Y5U1) ; Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Anti-Inflammatory Agents
    Language English
    Publishing date 2023-11-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 6165-7
    ISSN 1432-1750 ; 0341-2040
    ISSN (online) 1432-1750
    ISSN 0341-2040
    DOI 10.1007/s00408-023-00656-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Prevalence and clinical associations of myositis antibodies in a large cohort of interstitial lung diseases.

    Moll, Sofia A / Platenburg, Mark G J P / Platteel, Anouk C M / Vorselaars, Adriane D M / Janssen Bonàs, Montse / Kraaijvanger, Raisa / Roodenburg-Benschop, Claudia / Meek, Bob / van Moorsel, Coline H M / Grutters, Jan C

    PloS one

    2022  Volume 17, Issue 11, Page(s) e0277007

    Abstract: Background: Serologic testing for autoantibodies is recommended in interstitial lung diseases (ILDs), as connective tissue diseases (CTDs) are an important secondary cause. Myositis antibodies are associated with CTD-ILD, but clinical associations with ... ...

    Abstract Background: Serologic testing for autoantibodies is recommended in interstitial lung diseases (ILDs), as connective tissue diseases (CTDs) are an important secondary cause. Myositis antibodies are associated with CTD-ILD, but clinical associations with other ILDs are unclear. In this study, associations of myositis antibodies in various ILDs were evaluated.
    Methods: 1463 ILD patients and 116 healthy subjects were screened for myositis antibodies with a line-blot assay on serum available at time of diagnosis. Additionally, bronchoalveolar lavage fluid (BALf) was analysed.
    Results: A total of 394 patients demonstrated reactivity to at least one antibody, including anti-Ro52 (36.0%), anti-Mi-2β (17.3%) and anti-Jo-1 (10.9%). Anti-Jo-1 (OR 6.4; p<0.100) and anti-Ro52 (OR 6.0; p<0.001) were associated with CTD-ILD. Interestingly, anti-Mi-2β was associated with idiopathic pulmonary fibrosis (IPF; OR 5.3; p = 0.001) and hypersensitivity pneumonitis (HP; OR 5.9; p<0.001). Furthermore, anti-Mi-2β was strongly associated with a histological usual interstitial pneumonia (UIP) pattern (OR 6.5; p < 0.001). Moreover, anti-Mi-2β reactivity was identified in BALf and correlated with serum anti-Mi-2β (r = 0.64; p = 0.002). No differences were found in survival rates between ILD patients with and without serum Mi-2β reactivity (hazard ratio 0.835; 95% CI 0.442-1.575; p = 0.577).
    Conclusion: In conclusion, novel associations of antibody Mi-2β with fibrotic ILD were found. Furthermore, serum anti-Mi-2β was associated with a histological UIP pattern and presence of anti-Mi-2β in BALf. Possibly, anti-Mi-2β could be implemented as a future diagnostic biomarker for fibrotic ILD.
    MeSH term(s) Humans ; Prevalence ; Lung Diseases, Interstitial/complications ; Myositis/epidemiology ; Myositis/diagnosis ; Idiopathic Pulmonary Fibrosis/complications ; Connective Tissue Diseases/complications ; Connective Tissue Diseases/epidemiology ; Retrospective Studies
    Language English
    Publishing date 2022-11-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0277007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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

    Kahlmann, Vivienne / Janssen Bonás, Montse / Moor, Catharina C / van Moorsel, Coline H M / Kool, Mirjam / Kraaijvanger, Raisa / Grutters, Jan C / Overgaauw, Mayka / Veltkamp, Marcel / Wijsenbeek, Marlies S

    BMC pulmonary medicine

    2020  Volume 20, Issue 1, Page(s) 271

    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 ...

    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 .
    MeSH term(s) Clinical Trials, Phase IV as Topic ; Equivalence Trials as Topic ; Glucocorticoids/administration & dosage ; Humans ; Immunosuppressive Agents/administration & dosage ; Methotrexate/administration & dosage ; Multicenter Studies as Topic ; Prednisone/administration & dosage ; Prospective Studies ; Quality of Life ; Randomized Controlled Trials as Topic ; Respiratory Function Tests ; Sarcoidosis, Pulmonary/drug therapy ; Sarcoidosis, Pulmonary/physiopathology ; Spirometry ; Treatment Outcome ; Vital Capacity
    Chemical Substances Glucocorticoids ; Immunosuppressive Agents ; Prednisone (VB0R961HZT) ; Methotrexate (YL5FZ2Y5U1)
    Language English
    Publishing date 2020-10-19
    Publishing country England
    Document type Clinical Trial Protocol ; Comparative Study ; Journal Article
    ZDB-ID 2059871-3
    ISSN 1471-2466 ; 1471-2466
    ISSN (online) 1471-2466
    ISSN 1471-2466
    DOI 10.1186/s12890-020-01290-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Prevalence of Novel Myositis Autoantibodies in a Large Cohort of Patients with Interstitial Lung Disease.

    Moll, Sofia A / Platenburg, Mark G J P / Platteel, Anouk C M / Vorselaars, Adriane D M / Janssen Bonàs, Montse / Roodenburg-Benschop, Claudia / Meek, Bob / van Moorsel, Coline H M / Grutters, Jan C

    Journal of clinical medicine

    2020  Volume 9, Issue 9

    Abstract: Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence ...

    Abstract Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in ILD are presented. A total of 1194 patients with ILD and 116 healthy subjects were tested for antibodies specific for Ks, Ha, Zoα, and cN1A with a line-blot assay on serum available at the time of diagnosis. Autoantibodies were demonstrated in 63 (5.3%) patients and one (0.9%) healthy control (
    Language English
    Publishing date 2020-09-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm9092944
    Database MEDical Literature Analysis and Retrieval System OnLINE

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