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The present recommendations on the therapy of sarcoidosis of the German Respiratory Society (DGP) was written in 2023 as a German-language supplement and update of the international guidelines of the European Respiratory Society (ERS) from 2021. It contains 5 PICO questions (Patients, Intervention, Comparison, Outcomes) agreed in the consensus process, which are explained in the background text of the four articles: Confirmation of diagnosis and monitoring of the disease under therapy, general therapy recommendations, therapy of cutaneous sarcoidosis, therapy of cardiac sarcoidosis., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Introduction: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a standard procedure in cases of enlarged mediastinal lymph nodes. Recently, new tools were developed aiming to improve the diagnostic yield. A novel crown-cut needle is considered to obtain tissue cores which can be beneficial for the evaluation by the pathologist. This study aimed to compare the novel 22G crown-cut needle with a conventional 22G needle with EBUS guidance in the diagnosis of sarcoidosis., Methods: We designed a single-center prospective randomized clinical trial between March 2020 and January 2021 with 30 patients with mediastinal lymphadenopathy and suspected sarcoidosis., Results: 24 patients (mean age 49.5 vs 54.1, mean FVC 73.7% vs 86.7%, mean DLCO 72.4% vs 72.5% for crown-cut needle vs conventional needle, respectively) were diagnosed with sarcoidosis. In the remaining six patients, sarcoidosis was reasonably excluded. The diagnostic yield for sarcoidosis was 77% with the crown-cut needle vs. 82% with the conventional needle (p > 0.05). In patients with histopathologic hallmarks typical of sarcoidosis (n = 19), the crown-cut needle was superior in detecting granulomas (8.3 vs 3.8 per cytoblock, p < 0.05) and histiocytes (502 vs 186 per cytoblock, p < 0.05). Four of seven bronchoscopists experienced difficulties passing through the bronchial wall with the crown-cut needle and one episode of bleeding occurred in this group which made interventions necessary., Conclusions: Despite equivalence in diagnostic accuracy, the crown-cut needle was superior to the conventional needle in detecting granulomas and histiocytes. This indicates greater potential for obtaining higher quality sample material with the crown-cut needle in cases of granulomatous inflammation., (© 2022. The Author(s).)

Introduction: IL-9, mainly produced by T helper 9 (Th9) cells, promotes allergic airway inflammation and remodeling through the interaction with its receptor (IL-9R). Th9 cells and IL-9 have also been implicated in tissue fibrosis and autoimmunity pathways. However, the role of IL-9/IL-9R in the pathogenesis of interstitial lung disease (ILD) is unknown., Aim: To evaluate IL-9/IL-9R expression in bronchoalveolar lavage fluid (BALF) lymphocytes of patients with various ILDs., Methods: Consecutive patients with ILD, who underwent BAL for diagnostic purposes, were studied. As control group, consecutive patients without evidence of ILD were included. Immunocytochemical staining of BALF lymphocytes for IL-9 and IL-9R was performed and evaluated by two independent readers., Results: 45 patients, of them 8 had idiopathic pulmonary fibrosis (IPF), 12 nonspecific interstitial pneumonia (NSIP), 10 sarcoidosis, 9 hypersensitivity pneumonitis (HP), 6 cryptogenic organizing pneumonia (COP), and 24 controls were studied. In the ILD group, the highest BALF lymphocyte count was seen in HP followed by NSIP, COP, sarcoidosis, and IPF (p < 0.05 for HP vs IPF). The highest percentages of IL-9 and IL-9R positive lymphocytes were seen in COP. Conversely, NSIP showed the lowest rate of IL-9, and sarcoidosis the lowest rate of IL-9R positive lymphocytes. Only in NSIP, a direct correlation between IL and 9 and IL-9R positive lymphocytes was seen (r = 0.639, p = 0.025)., Conclusion: BALF lymphocytes IL-9 and IL-9R expression differs between various ILDs and could reflect different pathogenetic mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Sarcoidosis is a granulomatous systemic disease of unknown etiology most commonly affecting the lungs and thoracic lymph nodes. The diagnosis is based on typical clinical radiologic appearance and histology with evidence of noncaseating epithelioid cell granulomas without central necrosis. In the acute form, Löfgren's syndrome, histologic confirmation may not be necessary. Approximately half of patients may develop a chronic form, and extrathoracic organ involvement should be investigated during the course. Indications for therapy are based on functional limitations, marked organ-related or systemic symptoms, and life-threatening organ manifestations (cardiac, central nervous system, renal, and ocular sarcoidosis). To date, there is no approved drug therapy for sarcoidosis. Administration of immunosuppressants such as glucocorticosteroids and as add-on or sequential, methotrexate, azathioprine or mycophenolate mofetil is recommended in the currently published international guideline., Competing Interests: Erklärung zu finanziellen InteressenForschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht-Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein.Erklärung zu nicht-finanziellen InteressenDie Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin or other manifestations. While glucocorticoids remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. Glucocorticoid-sparing alternatives are available. The presented treatment guidelines aim to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations., Methods: A European Respiratory Society Task Force committee composed of clinicians, methodologists and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations., Results: The Task Force committee delivered 12 recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac and neurologic disease as well as fatigue. One PICO question regarding small-fibre neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation., Conclusions: There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment., Competing Interests: Conflict of interest: R.P. Baughman reports grants from Gilead, Genentech, Bayer, aTyr and Bellephron, grants and personal fees for consultancy from Novartis, personal fees for consultancy from Methial, grants and personal fees for consultancy and lectures from Mallinckrodt, grants and personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: P. Korsten reports grants and personal fees from GlaxoSmithKline, personal fees from AbbVie, Pfizer, Chugai, Novartis Pharma, Sanofi-Aventis, Lilly and Gilead, outside the submitted work. Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: W.A. Wuyts has nothing to disclose. Conflict of interest: A. Wells reports personal fees for lectures and advisory board work from Boehringer Ingelheim and Roche, during the conduct of the study. Conflict of interest: P. Rottoli has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: E.E. Lower reports grants from Gilead, Genentech, Bayer and aTYR, grants and personal fees for consultancy from Novartis, outside the submitted work. Conflict of interest: M.A. Judson received grant support for his institution from Mallickrodt. Conflict of interest: D. Israël-Biet has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: M. Drent has nothing to disclose. Conflict of interest: D.A. Culver reports grants and personal fees from aTyr, Mallinckrodt, Boehringer Ingelheim and Foundation for Sarcoidosis Research, personal fees from Roche, outside the submitted work. Conflict of interest: F. Bonella reports personal fees and non-financial support from Boehringer Ingelheim, Roche, Galapagos, BMS and Savara Pharma, outside the submitted work. Conflict of interest: K. Antoniou has nothing to disclose. Conflict of interest: F. Martone has nothing to disclose. Conflict of interest: B. Quadder has nothing to disclose. Conflict of interest: G. Spitzer has nothing to disclose. Conflict of interest: B. Nagavci acts as an ERS methodologist. Conflict of interest: T. Tonia acts as an ERS methodologist. Conflict of interest: D. Rigau acts as an ERS methodologist. Conflict of interest: D.R. Oullette reports grants from PCORI (Patient-Centred Outcomes Research Institute, US Federal) and Sanofi, outside the submitted work; and has provided expert witness work for venous thromboembolic disease., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Purpose of Review: Sarcoidosis is a complex granulomatous disease of unknown cause. Corticosteroids and immune suppressants are often given long term in chronic disease, which may result in substantial toxicity. Validated strategies for selecting patients at risk for disease progression, who might benefit from early and targeted treatment, are lacking. Consequently, the unmet need for new treatment options in sarcoidosis is high. In this review, we critically discuss potential therapeutic targets and ongoing clinical trials in sarcoidosis., Recent Findings: Despite the heterogeneous clinical manifestations and the lack of a reliable animal model, our knowledge and understanding of the pathogenesis of sarcoidosis has improved in recent years, which has resulted in the identification of several potential therapeutic strategies. They include the inhibition of cytokines involved in maturation of macrophages, activation of dendritic cells, and maturation and activation of pathogenic T-lymphocytes. The inflammasome and the autophagy are additional areas for future research. Antifibrotic therapy might also be a reasonable choice in selected patients, although the best treatment strategy in progressive fibrotic sarcoidosis remains undetermined., Summary: In this article, we review novel approaches to sarcoidosis treatment and potential therapeutic targets.

Background: Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis., Case Presentation: Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32-70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12-17.6 months), two patients experienced melanoma relapse., Conclusions: In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment., Competing Interests: Conflict of interest statement E.C.: reports travel support from Bristol-Myers Squibb, MSD SHARP & DOHME and Novartis.T.K.: reports travel support from Novartis, Amgen, Celgene, Lilly and Pierre-Fabre. L.Z.: served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and travel support from MSD, BMS, Amgen, Pierre Fabre and Novartis. E.H.: reports no conflict of interest. S.U.: reports grants, personal fees and non-financial support from Novartis, grants and non-financial support from BMS, personal fees and non-financial support from Roche, personal fees from MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work. E.G.: reports travel support from Pierre-Fabre. A.R.: reports grants, personal fees and non-financial support from Novartis, grants and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from Roche, personal fees from MSD Sharp & Dohme, non-financial support from Amgen, outside the submitted work . F.B.: reports personal fees and non-financial support from Boehringer Ingelheim and Roche Pharma, personal fees from Galapagos, outside the submitted work. T.E.W: reports no conflict of interest. J.W.: reports no conflict of interest. D.T.: reports no conflict of interest. D.S: reports grants and other from BMS, personal fees from BMS, during the conduct of the study; personal fees from Amgen, personal fees from Boehringer Ingelheim, personal fees from InFlarX, personal fees and other from Roche, grants, personal fees and other from Novartis, personal fees from Incyte, personal fees and other from Regeneron, personal fees from 4SC, personal fees from Sanofi, personal fees from Neracare, personal fees from Pierre Fabre, personal fees and other from Merck-EMD, personal fees from Pfizer, personal fees and other from Philiogen, personal fees from Array, personal fees and other from MSD, outside the submitted work. E.L.: served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Amgen, Pierre Fabre, Sunpharma and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. Hence, sarcoidosis patients may suffer from a great variety of symptoms. The aim of this study was to compare the self-reported burden of sarcoidosis patients in Denmark, Germany and the Netherlands, especially the prevalence of fatigue and small fiber neuropathy (SFN)-related symptoms, as well as differences in treatment strategies., Methods: A cross-sectional web-based anonymous survey about complaints was conducted among sarcoidosis patients. Patients were invited to take part through the sarcoidosis patient societies as well as through outpatient sarcoidosis clinics in these countries., Results: The questionnaire was completed by 1072 sarcoidosis patients (152 Danish, 532 German and 388 Dutch). Almost all patients reported having sarcoidosis-associated symptoms (organ-related as well as non-specific, non-organ related). Fatigue was reported by almost all respondents (90%), followed by pulmonary symptoms (72.4%). More than 50% of the respondents were being treated with prednisone, which was comparable in all three countries. In contrast, second- and third-line treatment differed substantially between Denmark, Germany and the Netherlands., Conclusion: Sarcoidosis patients in Denmark, Germany and the Netherlands present with similar self-reported symptoms, organ-related as well as non-specific, non-organ related. Fatigue (90%) and symptoms associated with SFN (86%) were highly prevalent in all three countries.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Sarcoidosis is a systemic disease of unknown aetiology. Typical histology shows epithelioid cell granulomas, and typical immunopathology enhanced Th1 type immune responses in the involved organs. The disease occurs worldwide, but more frequently in northern countries than in the south. In Germany, the incidence is estimated to be 10 per 100,000, and the prevalence 44-48 per 100,000. Sarcoidosis usually affects adults under 50 years of age, but can also be seen in children, adolescents and in the elderly. Women are more frequently affected than men. Familial clusters can occur. The clinical presentation of sarcoidosis varies widely and depends on the manifestations in the individual organ. Systemic symptoms include fatigue, night sweats, weight loss, fever, arthralgia and myalgia. Organ-specific symptoms include cough and dyspnoea, with pulmonary involvement, headache and palsy in neurosarcoidosis, arrhythmias and heart failure in cardiac sarcoidosis, and manifold skin lesions with skin involvement. Relapses are rarely seen in acute sarcoidosis, whereas the chronic form tends to relapse more frequently. Löfgren's syndrome, a specific phenotype of acute sarcoidosis, is characterised by bihilar lymphadenopathy, ankle arthritis and erythema nodosum. Chronic sarcoidosis can be asymptomatic, despite radiological changes, which may be extensive. By definition, sarcoidosis has become chronic after 2 years of disease with ongoing signs of activity. The long-term prognosis is generally good, but depends on the different organ manifestations and complications., Competing Interests: Interessenkonflikt: Nein., (Georg Thieme Verlag KG Stuttgart · New York.)

The diagnosis of sarcoidosis, a systemic granulomatous disease, is based on a compatible clinical-radiological picture and the histological evidence of noncaseating granulomas. Other diseases mimicking sarcoidosis, mostly infections and other granulomatoses, have to be excluded. There is no single test for sarcoidosis, and the presence of granulomas alone does not establish the diagnosis. Symptoms of sarcoidosis are not specific and can be markedly different according to organ involvement and disease course. Respiratory symptoms and fatigue are the most common symptoms at any stage of disease. Histological confirmation is not needed for Löfgren's or Heerfordt's syndrome and asymptomatic bihilar lymphadenopathy. The radiological staging system is still based on chest radiography, and computed tomography is not mandatory for routine follow-up. (18)F-fluorodeoxyglucose positron emission tomography may be of value in special cases. For assessment of lung involvement and follow-up, pulmonary function tests are necessary with vital capacity being the most important single parameter and diffusion capacity the most sensitive. Bronchoscopy with biopsy is the most common procedure for detection of granulomas, when there is no easier biopsy site like skin or peripheral lymph nodes. Endobronchial ultrasonography-guided transbronchial needle aspiration has replaced mediastinoscopy for evaluation of mediastinal and hilar lymph nodes with a high diagnostic yield. Despite numerous studies, no single biomarker can be reliably used for correct diagnosis or exclusion of sarcoidosis. Genetic testing, despite promising advances, has still not been included in routine care for sarcoidosis patients. The long-term prognosis of sarcoidosis depends on the different organ manifestations: Cardiac or central nervous involvement, together with respiratory complications, is critical. A multidisciplinary approach is necessary for comprehensive care of the sarcoidosis patient.

Advances have been made in minimally invasive diagnostic procedures in sarcoidosis, including bronchoalveolar lavage (BAL), endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA), and positron emission tomography (PET). Several independent groups found almost identical predictive values of the CD4:CD8 ratio in BAL for the diagnosis of sarcoidosis. A CD4:CD8 ratio greater than 3.5 shows a high specificity of 93 to 96% for sarcoidosis, but the sensitivity is low (53 to 59%). EBUS-TBNA is a safe and useful tool for diagnosing sarcoidosis stage I and II with a sensitivity of 83 to 93% and a specificity of 100%. Novel imaging techniques have been explored, such as PET using L-[3- (18)F] fluoro-alpha-methyltyrosine ( (18)F-F MT), which is more specific for malignancy than (18)F-fluorodeoxyglucose ( (18)F-FDG)-PET. The combined modality of FMT-PET with FDG-PET could successfully discriminate sarcoidosis from malignancy. These recent developments including novel biopsy procedures and novel imaging techniques could be of value to diagnosing sarcoidosis., (Copyright Thieme Medical Publishers.)

The original version of this article unfortunately contained a mistake in coauthor's given name. The abbreviated given name "M.D." for coauthor M.D.P. Elfferich's name has been inadvertently deleted during the production process. [ABSTRACT FROM AUTHOR]