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Saw PE, Song E. The 'inflammazone' in chronic inflammatory diseases: psoriasis and sarcoidosis. Trends Immunol 2025; 46:121-137. [PMID: 39875239 DOI: 10.1016/j.it.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/26/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Chronic inflammatory diseases show significant heterogeneity in their phenotypes, with diverse immune cells and mediators interacting in response to various stimuli. This review proposes the concept of the 'inflammazone' framework - which maps the distribution of immune components driving disease pathogenesis - using sarcoidosis and psoriasis as examples. Sarcoidosis features granulomatous inflammation with macrophages and CD4+ T cells, which can spread to lymph nodes and other organs. Psoriasis, affecting primarily the skin, involves Th1, Th17, and Th22 pathways with CD8+ T cells and dendritic cells. Human sarcoidosis exhibits geographic and racial variability, while psoriasis shows varying morphologies and disease courses. Sarcoidosis has more extensive distal immune signaling, whereas psoriasis remains more localized. Understanding the inflammazone is crucial for advancing personalized treatments for inflammatory diseases.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China; Department of General Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Nanhai Clinical Translational Center, Sun Yat-sen Memorial Hospital, Foshan, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Zenith Institute of Medical Sciences, Guangzhou 510120, China.
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Raza FA, Kumar S, Mohammad A, Amin A, Ahmad F, Tousif S, Kamran U, Sahab LB, Ali S, Changez MIK, Goyal A. Shifting temporal trends and disparities in sarcoidosis mortality in the United States: A retrospective analysis from 1999 to 2020. PLoS One 2025; 20:e0317237. [PMID: 39792876 PMCID: PMC11723600 DOI: 10.1371/journal.pone.0317237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
INTRODUCTION Sarcoidosis is an inflammatory disease characterized by granulomas, the etiology of which remains unclear. This study examines sarcoidosis-related mortality trends in the United States from 1999 to 2020, with a focus on disparities pertaining to patient sex, geographical location, and urbanization status. METHODS We analyzed death certificate data from the CDC WONDER database, using ICD-10 code D86. Age-adjusted mortality rates (AAMR) per 1,000,000 people were calculated. Trends were analyzed using Joinpoint regression models to determine annual percentage changes (APC). RESULTS A total of 37,956 Sarcoidosis-related deaths were documented from 1999 to 2020 in the United States. The AAMR increased from 3.9 in 1999 to 6.4 in 2020. Significant mortality increases were observed from 1999-2001 and again from 2018-2020. Mortality rates were consistently higher among women compared to men. A significant difference in AAMR was observed across states, with highest mortality in the South region and lowest in the West region. Urbanization trends shifted from higher AAMR rates in metropolitan to non-metropolitan areas post-2018. Non-Hispanic Black individuals experienced the highest mortality rates throughout the study period. CONCLUSIONS This study highlights significant racial and geographic disparities in sarcoidosis-related mortality. Women, Black patients, and those residing in non-metropolitan areas are at the highest risk for Sarcoidosis associated mortality. Targeted public health interventions are required to address these prevalent disparities.
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Affiliation(s)
- Fatima Ali Raza
- Department of Medicine, Karachi Medical and Dental College, Karachi, Pakistan
| | - Sumeet Kumar
- Department of Medicine, Dow University of Health Science, Karachi, Pakistan
| | - Ayesha Mohammad
- Department of Medicine, Comanche County Memorial Hospital, Lawton, Oklahoma, United States of America
| | - Areej Amin
- Department of Medicine, Rawal institute of Health Sciences, Islamabad, Pakistan
| | - Farooq Ahmad
- Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Sohaib Tousif
- Department of Medicine, Ziauddin Medical University, Karachi, Pakistan
| | - Urwah Kamran
- Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Lamea Bint Sahab
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Sajjad Ali
- Department of Medicine, Ziauddin Medical University, Karachi, Pakistan
| | - Mah I. Kan Changez
- Department of Cardiothoracic Surgery, Yale University, New Haven, Connecticut, United States of America
| | - Aman Goyal
- Department of Internal Medicine, Seth GS Medical College and KEM Hospital, Mumbai, India
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Obi ON, Saketkoo LA, Maier LA, Baughman RP. Developmental drugs for sarcoidosis. J Autoimmun 2024; 149:103179. [PMID: 38548579 DOI: 10.1016/j.jaut.2024.103179] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 12/15/2024]
Abstract
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA; University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, USA; Louisiana State University School of Medicine, Section of Pulmonary Medicine, New Orleans, LA, USA; Tulane University School of Medicine, Undergraduate Honors Department, New Orleans, LA, USA
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Robert P Baughman
- Emeritus Professor of Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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Di Francesco AM, Pasciuto G, Verrecchia E, Sicignano LL, Gerardino L, Massaro MG, Urbani A, Manna R. Sarcoidosis and Cancer: The Role of the Granulomatous Reaction as a Double-Edged Sword. J Clin Med 2024; 13:5232. [PMID: 39274446 PMCID: PMC11396756 DOI: 10.3390/jcm13175232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/16/2024] Open
Abstract
Background/Objectives: The relationship between sarcoidosis and the occurrence of neoplasia deserves to be investigated, but this relation has been observed in different and heterogeneous populations, leading to conflicting data. To clarify the causal relationship between these two diseases, different risk factors (e.g., smoking), concurrent comorbidities, corticosteroid therapy, and metastasis development-as an expression of cancer aggressiveness-were investigated. Methods: In a retrospective study on 287 sarcoidosis outpatients at the Pneumological Department of the Gemelli Foundation (Rome, Italy) between 2000 and 2024, the diagnosis of cancer was recorded in 36 subjects (12.5%). Results: The reciprocal timeline of the diseases showed three different scenarios: (1) cancer preceding sarcoidosis or sarcoid-like reactions (63.8%); (2) cancer arising after sarcoidosis diagnosis (8.3%); and (3) sarcoidosis accompanying the onset of malignancy (27.8%). Only two subjects with sarcoidosis and cancer showed metastasis, and one of them was affected by lymphoma. Conclusions: These data suggest that granulomatous inflammation due to sarcoidosis may assume an ambivalent role as a "double-edged sword", according to the M1/M2 macrophage polarization model: it represents a protective shield, preventing the formation of metastasis through the induction of immune surveillance against cancer while, on the other hand, it can be a risk factor for carcinogenesis due to the persistence of a chronic active inflammatory status. Low-dose steroid treatment was administered in only 31.6% of the cancer-sarcoidosis subjects for less than six months to control inflammation activity, with no promotive effect on carcinogenesis observed.
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Affiliation(s)
- Angela Maria Di Francesco
- Periodic Fever and Rare Diseases Research Centre, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Giuliana Pasciuto
- Complex Pneumology Operational Unit, A. Gemelli Policlinic Foundation IRCCS, 00168 Rome, Italy
| | - Elena Verrecchia
- Department of Aging, Orthopaedic and Rheumatological Sciences, A. Gemelli Policlinic Foundation IRCCS, 00168 Rome, Italy
| | - Ludovico Luca Sicignano
- Department of Aging, Orthopaedic and Rheumatological Sciences, A. Gemelli Policlinic Foundation IRCCS, 00168 Rome, Italy
| | - Laura Gerardino
- Department of Aging, Orthopaedic and Rheumatological Sciences, A. Gemelli Policlinic Foundation IRCCS, 00168 Rome, Italy
| | - Maria Grazia Massaro
- Periodic Fever and Rare Diseases Research Centre, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Andrea Urbani
- Department of Chemistry, Biochemistry and Molecular Biology, A. Gemelli Policlinic Foundation IRCCS, 00168 Rome, Italy
| | - Raffaele Manna
- Periodic Fever and Rare Diseases Research Centre, Catholic University of Sacred Heart, 00168 Rome, Italy
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Merzel Šabović EK, Starbek Zorko M, Hosta V, Žgavec B, Bajuk V. Microblading reaction as a manifestation of systemic sarcoidosis: two case reports and a review of the literature. J Med Case Rep 2024; 18:221. [PMID: 38654341 DOI: 10.1186/s13256-024-04439-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 02/07/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Sarcoidosis is a multisystemic disease characterized by granulomatous inflammation. Sarcoidosis often poses a diagnostic challenge owing to its nonspecific or mild clinical features. In 20-35% of cases, sarcoidosis initially presents on skin. However, skin lesions commonly mimic dermatological conditions. Therefore, it is important to not underestimate the skin manifestations and perform histopathological examinations to make a timely diagnosis. CASE PRESENTATION We present two cases of 33-year-old Caucasian female patients with orange-red macules and plaques that developed in the eyebrow area 1 and 6 years after microblading, respectively. Histopathological examination confirmed a diagnosis of sarcoidosis. The lymph nodes and lungs were also affected in both patients. CONCLUSION Our two reports suggest that an esthetic procedure involving dermal or subcutaneous injection of foreign materials can trigger the development of cutaneous and systemic sarcoidosis. However, this relationship has not been described yet. Physicians should, therefore, be aware of this complication to properly evaluate and treat such patients in a timely manner.
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Affiliation(s)
- Eva Klara Merzel Šabović
- Dermatology and Venereology Clinic, University Medical Centre Ljubljana, Gradiskova 10, 1000, Ljubljana, Slovenia.
- Medical Faculty Ljubljana, University of Ljubljana, Ljubljana, Slovenia.
| | - Mateja Starbek Zorko
- Dermatology and Venereology Clinic, University Medical Centre Ljubljana, Gradiskova 10, 1000, Ljubljana, Slovenia
- Medical Faculty Ljubljana, University of Ljubljana, Ljubljana, Slovenia
| | - Violeta Hosta
- Dermatology and Venereology Clinic, University Medical Centre Ljubljana, Gradiskova 10, 1000, Ljubljana, Slovenia
| | - Borut Žgavec
- Dermatology and Venereology Clinic, University Medical Centre Ljubljana, Gradiskova 10, 1000, Ljubljana, Slovenia
| | - Vid Bajuk
- Dermatology and Venereology Clinic, University Medical Centre Ljubljana, Gradiskova 10, 1000, Ljubljana, Slovenia
- Medical Faculty Ljubljana, University of Ljubljana, Ljubljana, Slovenia
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Vu PQ, Pathak PR, Patel S, Basu AK, Antony MA, Reddy AD, Mathew J. Extra-pulmonary Cutaneous Sarcoidosis Presenting With Granulomatous Cranial Lesions and Cardiac Complications: A Case Report. Cureus 2024. [DOI: https:/doi.org/10.7759/cureus.53290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025] Open
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Vu PQ, Pathak PR, Patel S, Basu AK, Antony MA, Reddy AD, Mathew J. Extra-pulmonary Cutaneous Sarcoidosis Presenting With Granulomatous Cranial Lesions and Cardiac Complications: A Case Report. Cureus 2024; 16:e53290. [PMID: 38435864 PMCID: PMC10905987 DOI: 10.7759/cureus.53290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 01/31/2024] [Indexed: 03/05/2024] Open
Abstract
Sarcoidosis is a non-caseating granulomatous disorder affecting multiple organs. Although the lungs are the most common site of presentation, extra-pulmonary manifestations involving the skin and heart can occur. Sarcoidosis affecting skull bone is uncommon and involvement of skin, heart, and skull bone all together, without pulmonary manifestations, is extremely rare. We report a 63-year-old Caucasian woman with a past history of cutaneous sarcoidosis and granulomatous skull bone lesions who presented with recurrent syncope. An ambulatory cardiac monitor detected intermittent high-grade atrioventricular block and cardiac MRI confirmed the diagnosis of cardiac sarcoidosis. This case represents an extremely unique journey of sarcoidosis and suggests potential consideration for cardiac sarcoidosis screening in patients with a history of extra-cardiac manifestations.
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Affiliation(s)
- Paul Q Vu
- Internal Medicine, Alabama College of Osteopathic Medicine, Dothan, USA
| | - Prutha R Pathak
- Internal Medicine, North Alabama Medical Center, Florence, USA
| | | | | | - Mc Anto Antony
- Endocrinology, Diabetes, and Metabolism, Medical University of South Carolina, Anderson, USA
| | - Amogh D Reddy
- Internal Medicine, Alabama College of Osteopathic Medicine, Dothan, USA
| | - Jason Mathew
- Internal Medicine, Alabama College of Osteopathic Medicine, Dothan, USA
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Nelson NC, Kogan R, Condos R, Hena KM. Emerging Therapeutic Options for Refractory Pulmonary Sarcoidosis: The Evidence and Proposed Mechanisms of Action. J Clin Med 2023; 13:15. [PMID: 38202021 PMCID: PMC10779381 DOI: 10.3390/jcm13010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 01/12/2024] Open
Abstract
Sarcoidosis is a systemic disease with heterogenous clinical phenotypes characterized by non-necrotizing granuloma formation in affected organs. Most disease either remits spontaneously or responds to corticosteroids and second-line disease-modifying therapies. These medications are associated with numerous toxicities that can significantly impact patient quality-of-life and often limit their long-term use. Additionally, a minority of patients experience chronic, progressive disease that proves refractory to standard treatments. To date, there are limited data to guide the selection of alternative third-line medications for these patients. This review will outline the pathobiological rationale behind current and emerging therapeutic agents for refractory or drug-intolerant sarcoidosis and summarize the existing clinical evidence in support of their use.
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Affiliation(s)
| | | | | | - Kerry M. Hena
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, New York University, 301 E 17th St Suite 550, New York, NY 10003, USA
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Enke JS, Reitsam NG, Schaller T, Claus R, Lapa C, Dierks A. Sarcoidosis mimicking nodal manifestations of marginal zone lymphoma. Eur J Nucl Med Mol Imaging 2023; 50:3151-3152. [PMID: 37099133 PMCID: PMC10382329 DOI: 10.1007/s00259-023-06237-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 01/21/2023] [Indexed: 04/27/2023]
Affiliation(s)
- Johanna S Enke
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Nic G Reitsam
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Tina Schaller
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Rainer Claus
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Internal Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Constantin Lapa
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
| | - Alexander Dierks
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
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Zhang H, Jiang D, Zhu L, Zhou G, Xie B, Cui Y, Costabel U, Dai H. Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype. Front Immunol 2023; 14:1185443. [PMID: 37520566 PMCID: PMC10374842 DOI: 10.3389/fimmu.2023.1185443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/14/2023] [Indexed: 08/01/2023] Open
Abstract
Rationale Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. Objectives We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. Methods We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. Measurements and results An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. Conclusion A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.
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Affiliation(s)
- Hui Zhang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
- Department of Pulmonary and Critical Care Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Dingyuan Jiang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
| | - Lili Zhu
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
| | - Guowu Zhou
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
| | - Bingbing Xie
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
| | - Ye Cui
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Ulrich Costabel
- Center for Interstitial and Rare Lung Diseases, Pneumology Department, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences Peking Union Medical University, Beijing, China
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Cedarbaum JJ, Rao DA, Hatabu H, Walker KH, Loscalzo J. A Bumpy Road to Diagnosis. N Engl J Med 2023; 389:72-77. [PMID: 37407005 DOI: 10.1056/nejmcps2304844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Affiliation(s)
- Jacob J Cedarbaum
- From the Departments of Medicine (J.J.C., D.A.R., K.H.W., J.L.) and Radiology (H.H.), Brigham and Women's Hospital, Boston
| | - Deepak A Rao
- From the Departments of Medicine (J.J.C., D.A.R., K.H.W., J.L.) and Radiology (H.H.), Brigham and Women's Hospital, Boston
| | - Hiroto Hatabu
- From the Departments of Medicine (J.J.C., D.A.R., K.H.W., J.L.) and Radiology (H.H.), Brigham and Women's Hospital, Boston
| | - Katherine H Walker
- From the Departments of Medicine (J.J.C., D.A.R., K.H.W., J.L.) and Radiology (H.H.), Brigham and Women's Hospital, Boston
| | - Joseph Loscalzo
- From the Departments of Medicine (J.J.C., D.A.R., K.H.W., J.L.) and Radiology (H.H.), Brigham and Women's Hospital, Boston
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Kc P, Ayele FK, Karki S, Waleed MS. Whipple's Disease Mimicking Sarcoidosis. Cureus 2023; 15:e41839. [PMID: 37575808 PMCID: PMC10423070 DOI: 10.7759/cureus.41839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2023] [Indexed: 08/15/2023] Open
Abstract
Whipple's disease is a rare systemic disease caused by a Tropheryma whipplei infection. Although older literature reports a low rate of incidence, case reports continue to rise due to increased awareness of the disease. Classic Whipple's disease presents as weight loss, diarrhea, and arthralgia and may involve the heart, central nervous system (CNS), or any other organ system. Some patients with Whipple's disease do not have the classic signs and symptoms of the disease. We present a case of Whipple's disease in a patient with poor appetite, weight loss, and granulomatous inflammation of various organs, including the kidneys and spleen, mimicking sarcoidosis. She had presented three years earlier with acute kidney injury (AKI) and hypercalcemia. The renal biopsy revealed diffuse granulomatous interstitial nephritis. Both AKI and hypercalcemia resolved with prednisone; however, her weight loss and decreased appetite continued. The initial positron emission tomography (PET) scan showed increased fluorodeoxyglucose (FDG) avidity in the spleen and large intestine, and the splenic biopsy revealed non-caseating granulomas. A diagnosis of sarcoidosis was made, and she was started on methotrexate with prednisone. Nevertheless, the weight loss and poor appetite were relentless. A repeat PET scan showed increased FDG avidity in loops of the small and large intestines. A small intestinal biopsy revealed positive periodic acid-Schiff (PAS) and negative acid-fast bacilli (AFB) revealing the diagnosis of Whipple's disease. Whipple's disease should be considered in the differential diagnosis of sarcoidosis, especially in those patients worsening on standard immunosuppression.
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Affiliation(s)
- Pawan Kc
- Rheumatology, Emory University School of Medicine, Atlanta, USA
| | | | - Sabin Karki
- Internal Medicine, Suburban Community Hospital (Lower Bucks Hospital), Bristol, USA
| | - Madeeha S Waleed
- Internal Medicine, Suburban Community Hospital (Lower Bucks Hospital), Bristol, USA
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Plichta J, Kuna P, Panek M. Biologic drugs in the treatment of chronic inflammatory pulmonary diseases: recent developments and future perspectives. Front Immunol 2023; 14:1207641. [PMID: 37334374 PMCID: PMC10272527 DOI: 10.3389/fimmu.2023.1207641] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 05/22/2023] [Indexed: 06/20/2023] Open
Abstract
Chronic inflammatory diseases of the lung are some of the leading causes of mortality and significant morbidity worldwide. Despite the tremendous burden these conditions put on global healthcare, treatment options for most of these diseases remain scarce. Inhaled corticosteroids and beta-adrenergic agonists, while effective for symptom control and widely available, are linked to severe and progressive side effects, affecting long-term patient compliance. Biologic drugs, in particular peptide inhibitors and monoclonal antibodies show promise as therapeutics for chronic pulmonary diseases. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers and even Alzheimer disease, while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. Several biologic agents are currently being developed for the treatment of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pulmonary sarcoidosis. This article is a review of the biologics already employed in the treatment of chronic inflammatory pulmonary diseases and recent progress in the development of the most promising of those treatments, with particular focus on randomised clinical trial outcomes.
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Affiliation(s)
- Jacek Plichta
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
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Mocanu A, Bogos RA, Trandafir LM, Cojocaru E, Ioniuc I, Alecsa M, Lupu VV, Miron L, Lazaruc TI, Lupu A, Miron IC, Starcea IM. The Overlap of Kidney Failure in Extrapulmonary Sarcoidosis in Children-Case Report and Review of Literature. Int J Mol Sci 2023; 24:7327. [PMID: 37108489 PMCID: PMC10138650 DOI: 10.3390/ijms24087327] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Sarcoidosis is a non-necrotizing granulomatous inflammatory multisystemic disorder of unknown etiology. In children, as in adults, it can involve a few or all organ systems to a varying extent and degree, entailing multisystemic manifestations. Kidney involvement in pediatric-onset adult-type sarcoidosis is rare, with a wide range of renal manifestations, most of them related to calcium metabolism. Children with renal sarcoidosis tend to be more symptomatic than adults, although male patients have a higher prevalence. We present the case of a 10-year-old boy who presented with advanced renal failure with nephrocalcinosis and important hepatosplenomegaly. The diagnosis was established by histopathological examination, with consequent cortisone therapy and hemodialysis. This review emphasizes that sarcoidosis should be considered in the differential diagnosis of pediatric patients with acute kidney insufficiency or chronic kidney disease of an unknown etiology. As far as we know, this is the first study regarding extrapulmonary sarcoidosis in children from Romania.
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Affiliation(s)
- Adriana Mocanu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Nephrology Division, St. Mary’s Emergency Children Hospital, 700309 Iasi, Romania
| | - Roxana Alexandra Bogos
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Nephrology Division, St. Mary’s Emergency Children Hospital, 700309 Iasi, Romania
| | - Laura Mihaela Trandafir
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Elena Cojocaru
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Ileana Ioniuc
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Mirabela Alecsa
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Vasile Valeriu Lupu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Lucian Miron
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Tudor Ilie Lazaruc
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Ancuta Lupu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Ingrith Crenguta Miron
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Iuliana Magdalena Starcea
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Nephrology Division, St. Mary’s Emergency Children Hospital, 700309 Iasi, Romania
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15
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Anuja AK, Mehta P, Singh MK, Singh H, Nath A, Hashim Z, Khan A, Gupta M, Misra DP, Agarwal V, Gupta L. Peripheral T helper subset profiling in idiopathic inflammatory myositis: Proof of concept. REUMATOLOGÍA CLÍNICA 2023; 19:143-149. [DOI: 10.1016/j.reuma.2022.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
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16
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Anuja AK, Mehta P, Singh MK, Singh H, Nath A, Hashim Z, Khan A, Gupta M, Misra DP, Agarwal V, Gupta L. Peripheral T helper subset profiling in idiopathic inflammatory myositis: Proof of concept. REUMATOLOGIA CLINICA 2023; 19:143-149. [PMID: 36906390 DOI: 10.1016/j.reumae.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 03/10/2022] [Indexed: 03/11/2023]
Abstract
INTRODUCTION There is a dearth of biomarkers in Idiopathic Inflammatory Myopathies (IIM) to recognize ongoing muscle inflammation and distinguish damage from activity. Since IIM is an autoantibody-mediated disease with tertiary lymphoid organogenesis reported in the diseased muscles, we aimed to study the peripheral blood T helper (Th) subset profiling as a plausible reflection of ongoing muscle inflammation. METHODS Fifty-six patients of IIM were compared with 21 healthy controls (HC) and 18 patients with sarcoidosis. Th1, Th17, Th17.1, and Treg cells were identified after stimulation assays (BD Biosciences). Myositis autoantibodies were tested by line immunoassay (Euroimmune, Germany). RESULTS All Th subsets were elevated in IIM as compared with HC. As compared to HC, PM had elevated Th1 and Treg while Th17 and Th17.1 populations were higher in OM. Patients with sarcoidosis had higher Th1 and Treg but lower Th17 population as compared to IIM {Th1(69.1% vs 49.65%, p<0.0001), {Treg (12.05% vs 6.2%, p<0.0001), {Th17 (2.49% vs 4.4%, p<0.0001)}. Similar results were obtained when sarcoidosis ILD was compared with IIM ILD with a higher Th1 and Treg population but lower Th17 population in the former. No difference in T cell profile was observed after stratification for MSA positivity, type of MSA, clinical features of IIM and disease activity. CONCLUSION Th subsets in IIM are distinct from sarcoidosis and HC with a TH17 predominant paradigm, creating a case of exploring Th17 pathway and IL-17 blockers for the treatment of IIM. However, cell profiling cannot distinguish active from inactive disease limiting its predictive potential as a biomarker of activity in IIM.
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Affiliation(s)
- Anamika Kumari Anuja
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Pankti Mehta
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mantabya Kumar Singh
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Harshit Singh
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Alok Nath
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Zia Hashim
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Ajmal Khan
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mansi Gupta
- Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Durga P Misra
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Vikas Agarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
| | - Latika Gupta
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India; Department of Rheumatology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK; City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK; Division of Musculoskeletal and Dermatological Sciences, Centre for Musculoskeletal Research, School of Biological Sciences, The University of Manchester, Manchester, UK.
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17
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Eroglu TE, Folke F, Coronel R, Torp-Pedersen C, Gislason GH. Risk of out-of-hospital cardiac arrest in patients with sarcoidosis: a Danish nationwide nested case-control study. Open Heart 2023; 10:openhrt-2022-002088. [PMID: 36759010 PMCID: PMC9923298 DOI: 10.1136/openhrt-2022-002088] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 01/20/2023] [Indexed: 02/11/2023] Open
Abstract
ObjectiveSarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish whether sarcoidosis is associated with out-of-hospital cardiac arrest (OHCA) in the general population.MethodsWe conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. OHCA cases from presumed cardiac causes were matched 1:10 by sex and age on OHCA date with non-OHCA controls from the general population. The association between sarcoidosis and OHCA was assessed using Cox regression by calculating HR and 95% CIs. Models were adjusted for cardiovascular disease. Finally, stratified analyses were performed according to sex, heart failure and ischaemic heart disease. RESULTS: We identified 35 195 OHCA cases and 351 950 matched controls without OHCA (median age 72 years and 66.8% male). Patients with sarcoidosis had higher rate of OHCA compared with the general population after adjustments for common OHCA risk factors (HR 1.51, 95% CI 1.19 to 1.92). This increased OHCA rate occurred in women (HR 2.11, 95% CI 1.42 to 3.12) but not in men (HR 1.27, 95% CI 0.93 to 1.72; p value interaction=0.033), and was larger in patients with than without heart failure (HRheart failure: 2.59, 95% CI 1.42 to 4.73; HRno heart failure: 1.33, 95% CI 1.01 to 1.74; p value interaction: 0.007). The HR associated with sarcoidosis did not vary by the presence of ischaemic heart disease. CONCLUSION: Patients with sarcoidosis have a higher OHCA rate than the general population. This increased OHCA rate occurred in women but not in men, and was larger in patients with than without heart failure.
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Affiliation(s)
- Talip E Eroglu
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Fredrik Folke
- Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark,Copenhagen University Hospital – Copenhagen Emergency Medical Services, Copenhagen, Denmark,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ruben Coronel
- Department of Experimental and Clinical Cardiology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
| | - Christian Torp-Pedersen
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark,Department of Cardiology, Nordsjællands Hospital, Hillerod, Denmark
| | - Gunnar Hilmar Gislason
- Department of Cardiology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark,The Danish Heart Foundation, Copenhagen, Denmark
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Duo M, Liu Z, Li P, Wang Y, Zhang Y, Weng S, Zheng Y, Fan M, Wu R, Xu H, Ren Y, Cheng Z. Integrative bioinformatics analysis to explore a robust diagnostic signature and landscape of immune cell infiltration in sarcoidosis. Front Med (Lausanne) 2022; 9:942177. [PMID: 36405616 PMCID: PMC9672334 DOI: 10.3389/fmed.2022.942177] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 10/10/2022] [Indexed: 04/28/2025] Open
Abstract
BACKGROUND The unknown etiology of sarcoidosis with variable clinical features leads to delayed diagnosis and limited therapeutic strategies. Hence, exploring the latent mechanisms and constructing an accessible and reliable diagnostic model of sarcoidosis is vital for innovative therapeutic approaches to improve prognosis. METHODS This retrospective study analyzed transcriptomes from 11 independent sarcoidosis cohorts, comprising 313 patients and 400 healthy controls. The weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were performed to identify molecular biomarkers. Machine learning was employed to fit a diagnostic model. The potential pathogenesis and immune landscape were detected by bioinformatics tools. RESULTS A 10-gene signature SARDS consisting of GBP1, LEF1, IFIT3, LRRN3, IFI44, LHFPL2, RTP4, CD27, EPHX2, and CXCL10 was further constructed in the training cohorts by the LASSO algorithm, which performed well in the four independent cohorts with the splendid AUCs ranging from 0.938 to 1.000. The findings were validated in seven independent publicly available gene expression datasets retrieved from whole blood, PBMC, alveolar lavage fluid cells, and lung tissue samples from patients with outstanding AUCs ranging from 0.728 to 0.972. Transcriptional signatures associated with sarcoidosis revealed a potential role of immune response in the development of the disease through bioinformatics analysis. CONCLUSIONS Our study identified and validated molecular biomarkers for the diagnosis of sarcoidosis and constructed the diagnostic model SARDS to improve the accuracy of early diagnosis of the disease.
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Affiliation(s)
- Mengjie Duo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Pengfei Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Youyang Zheng
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingwei Fan
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruhao Wu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhe Cheng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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19
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Controversies in neuroimmunology: multiple sclerosis, vaccination, SARS-CoV-2 and other dilemas. BIOMEDICA : REVISTA DEL INSTITUTO NACIONAL DE SALUD 2022; 42:78-99. [PMID: 36322548 PMCID: PMC9714524 DOI: 10.7705/biomedica.6366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Indexed: 12/04/2022]
Abstract
Neuroimmunology is a discipline that increasingly broadens its horizons in the understanding of neurological diseases. At the same time, and in front of the pathophysiological links of neurological diseases and immunology, specific diagnostic and therapeutic approaches have been proposed. Despite the important advances in this discipline, there are multiple dilemmas that concern and filter into clinical practice. This article presents 15 controversies and a discussion about them, which are built with the most up-to-date evidence available. The topics included in this review are: steroid decline in relapses of multiple sclerosis; therapeutic recommendations in MS in light of the SARS-CoV-2 pandemic; evidence of vaccination in multiple sclerosis and other demyelinating diseases; overview current situation of isolated clinical and radiological syndrome; therapeutic failure in multiple sclerosis, as well as criteria for suspension of disease-modifying therapies; evidence of the management of mild relapses in multiple sclerosis; recommendations for prophylaxis against Strongyloides stercolaris; usefulness of a second course of immunoglobulin in the Guillain-Barré syndrome; criteria to differentiate an acute-onset inflammatory demyelinating chronic polyneuropathy versus Guillain-Barré syndrome; and, the utility of angiotensin-converting enzyme in neurosarcoidosis. In each of the controversies, the general problem is presented, and specific recommendations are offered that can be adopted in daily clinical practice.
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20
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Obi ON, Saketkoo LA, Russell AM, Baughman RP. Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches. Front Med (Lausanne) 2022; 9:991783. [PMID: 36314034 PMCID: PMC9596775 DOI: 10.3389/fmed.2022.991783] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/17/2022] [Indexed: 12/04/2022] Open
Abstract
Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States,*Correspondence: Ogugua Ndili Obi,
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, LA, United States,University Medical Center—Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, LA, United States,Section of Pulmonary Medicine, Louisiana State University School of Medicine, New Orleans, LA, United States,Department of Undergraduate Honors, Tulane University School of Medicine, New Orleans, LA, United States
| | - Anne-Marie Russell
- Exeter Respiratory Institute University of Exeter, Exeter, United Kingdom,Royal Devon and Exeter NHS Foundation Trust, Devon, United Kingdom,Faculty of Medicine, Imperial College and Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Robert P. Baughman
- Department of Medicine, University of Cincinnati, Cincinnati, OH, United States
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21
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Perspective of sarcoidosis in terms of rheumatology: a single-center rheumatology clinic experience. Rheumatol Int 2022; 42:2191-2197. [PMID: 36006458 DOI: 10.1007/s00296-022-05193-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/16/2022] [Indexed: 10/15/2022]
Abstract
Sarcoidosis may present with many rheumatological symptoms as well as mimic and/or may occur concomitantly with many other rheumatic diseases. We examined the demographic, clinical and laboratory characteristics of patients diagnosed with sarcoidosis in the rheumatology department. This study planned as retrospective cross-sectional study. Medical records of patients who applied to our rheumatology outpatient clinic due to complain of musculoskeletal problems and then diagnosed sarcoidosis were retrospectively investigated. Joint findings, extrapulmonary involvements, and coexisting rheumatic disease were evaluated. Fifty-six patients (41.21 ± 7.83 years, 75% female) were included. The duration of the disease was 49.61 ± 29.11 months, and the follow-up period was 26.66 ± 13.26 months. All patients had pulmonary system involvement. Arthralgia was present in 91.10% of 56 patients and arthritis in 89.29% of patients. Examining the subtypes of the arthritis findings, mono-arthritis was found in 31/50 (62%) patients, oligo-arthritis in 15/50 (30%) patients, and polyarthritis in 4/50 (8%) patients. A total of 11 (19.60%) patients were diagnosed with uveitis. Excision of the mediastinal LAP was performed in a total of 37 patients (66.1%) and became the most commonly employed method. Considering the treatment distribution of the patients under followed-up, it is seen that non-steroidal anti-inflammatory treatments were used in 15 (26.8%) patients, corticosteroids in a total of 40 (71.4%) patients, methotrexate in a total of 15 patients (26.8%), azathioprine in six (10.7%) patients, hydroxychloroquine in 14 (25%) patients, and infliximab in one (1.8%) patient. As sarcoidosis is a mimicking disease, a good differential diagnosis should be made to avoid misdiagnosis and in order not to be late in diagnosis and treatment. Physicians, especially rheumatologists, should remember sarcoidosis more frequently as the disease may overlap with other rheumatological diseases and may occur with many rheumatological manifestations.
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22
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Wu JH, Imadojemu S, Caplan AS. The Evolving Landscape of Cutaneous Sarcoidosis: Pathogenic Insight, Clinical Challenges, and New Frontiers in Therapy. Am J Clin Dermatol 2022; 23:499-514. [PMID: 35583850 DOI: 10.1007/s40257-022-00693-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2022] [Indexed: 12/13/2022]
Abstract
Sarcoidosis is a multisystem disorder of unknown etiology characterized by accumulation of granulomas in affected tissue. Cutaneous manifestations are among the most common extrapulmonary manifestations in sarcoidosis and can lead to disfiguring disease requiring chronic therapy. In many patients, skin disease may be the first recognized manifestation of sarcoidosis, necessitating a thorough evaluation for systemic involvement. Although the precise etiology of sarcoidosis and the pathogenic mechanisms leading to granuloma formation, persistence, or resolution remain unclear, recent research has led to significant advances in our understanding of this disease. This article reviews recent advances in epidemiology, sarcoidosis clinical assessment with a focus on the dermatologist's role, disease pathogenesis, and new therapies in use and under investigation for cutaneous and systemic sarcoidosis.
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Affiliation(s)
- Julie H Wu
- Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, 240 East 38th Street, 11th Floor, New York, NY, 10016, USA
| | - Sotonye Imadojemu
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Avrom S Caplan
- Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, 240 East 38th Street, 11th Floor, New York, NY, 10016, USA.
- New York University Sarcoidosis Program, New York University Grossman School of Medicine, New York, NY, USA.
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23
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Zhao M, Tian C, Cong S, Di X, Wang K. From COVID-19 to Sarcoidosis: How Similar Are These Two Diseases? Front Immunol 2022; 13:877303. [PMID: 35615369 PMCID: PMC9124764 DOI: 10.3389/fimmu.2022.877303] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/12/2022] [Indexed: 12/21/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leads to the dysregulation of the immune system, exacerbates inflammatory responses, and even causes multiple organ dysfunction syndrome in patients with severe disease. Sarcoidosis is an idiopathic granulomatous multisystem disease characterized by dense epithelioid non-necrotizing lesions with varying degrees of lymphocytic inflammation. These two diseases have similar clinical manifestations and may also influence each other and affect their clinical courses. In this study, we analyzed some possible connections between sarcoidosis and COVID-19, including the role of the renin–angiotensin system in the respiratory system, immune response, and cell death pathways, to understand the underlying mechanisms of SARS-CoV-2 infection, predisposing patients to severe forms of COVID-19. This review will provide a new prospect for the treatment of COVID-19 and an opportunity to explore the pathogenesis and development of sarcoidosis.
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24
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Zhang H, Costabel U, Dai H. The Role of Diverse Immune Cells in Sarcoidosis. Front Immunol 2021; 12:788502. [PMID: 34868074 PMCID: PMC8640342 DOI: 10.3389/fimmu.2021.788502] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/04/2021] [Indexed: 12/19/2022] Open
Abstract
Sarcoidosis is a systemic inflammatory disorder of unknown etiology characterized by tissue infiltration with macrophages and lymphocytes and associated non-caseating granuloma formation. The disease primarily affects the lungs. Patients suffering from sarcoidosis show a wide range of clinical symptoms, natural history and disease outcomes. Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay among diverse immune cells. This review highlights recent advances in the pathogenesis of sarcoidosis, with emphasis on the role of different immune cells. Accumulative evidence suggests Th17 cells, IFN-γ-producing Th17 cells or Th17.1 cells, and regulatory T (Treg) cells play a critical role. However, their specific actions, whether protective or pathogenic, remain to be clarified. Macrophages are also involved in granuloma formation, and M2 polarization may be predictive of fibrosis. Previously neglected cells including B cells, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells were studied more recently for their contribution to sarcoid granuloma formation. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with hope to open up new therapeutic avenues and if possible, to develop preventive measures.
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Affiliation(s)
- Hui Zhang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Peking Union Medical College, Beijing, China
| | - Ulrich Costabel
- Center for Interstitial and Rare Lung Diseases, Pneumology Department, Ruhrlandklinik, University Hospital, Essen, Germany
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China
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25
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Yoo Y, Choi E, Kim Y, Cha Y, Um E, Kim Y, Kim Y, Lee YS. Therapeutic potential of targeting cathepsin S in pulmonary fibrosis. Biomed Pharmacother 2021; 145:112245. [PMID: 34772578 DOI: 10.1016/j.biopha.2021.112245] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 11/16/2022] Open
Abstract
Cathepsin S (CTSS), a lysosomal protease, belongs to a family of cysteine cathepsin proteases that promote degradation of damaged proteins in the endolysosomal pathway. Aberrant CTSS expression and regulation are associated with the pathogenesis of several diseases, including lung diseases. CTSS overexpression causes a variety of pathological processes, including pulmonary fibrosis, with increased CTSS secretion and accelerated extracellular matrix remodeling. Compared to many other cysteine cathepsin family members, CTSS has unique features that it presents limited tissue expression and retains its enzymatic activity at a neutral pH, suggesting its decisive involvement in disease microenvironments. In this review, we investigated the role of CTSS in lung disease, exploring recent studies that have indicated that CTSS mediates fibrosis in unique ways, along with its structure, substrates, and distinct regulation. We also outlined examples of CTSS inhibitors in clinical and preclinical development and proposed CTSS as a potential therapeutic target for pulmonary fibrosis.
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Affiliation(s)
- YoungJo Yoo
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Eun Choi
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Yejin Kim
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Yunyoung Cha
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Eunhye Um
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Younghwa Kim
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Yunji Kim
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea
| | - Yun-Sil Lee
- Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-720, Republic of Korea.
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Fois SS, Canu S, Fois AG. The Role of Oxidative Stress in Sarcoidosis. Int J Mol Sci 2021; 22:ijms222111712. [PMID: 34769145 PMCID: PMC8584035 DOI: 10.3390/ijms222111712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 01/15/2023] Open
Abstract
Sarcoidosis is a rare, systemic inflammatory disease whose diagnosis and management can pose a challenge for clinicians and specialists. Scientific knowledge on the molecular pathways that drive its development is still lacking, with no standardized therapies available and insufficient strategies to predict patient outcome. In recent years, oxidative stress has been highlighted as an important factor in the pathogenesis of sarcoidosis, involving several enzymes and molecules in the mechanism of the disease. This review presents current data on the role of oxidative stress in sarcoidosis and its interaction with inflammation, as well as the application of antioxidative therapy in the disease.
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Affiliation(s)
- Sara Solveig Fois
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy;
- Correspondence:
| | - Sara Canu
- Respiratory Diseases Operative Unit, University Hospital of Sassari, 07100 Sassari, Italy;
| | - Alessandro Giuseppe Fois
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy;
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Shifera AS, Pockrandt C, Rincon N, Ge Y, Lu J, Varabyou A, Jedlicka AE, Sun K, Scott AL, Eberhart C, Thorne JE, Salzberg SL. Identification of microbial agents in tissue specimens of ocular and periocular sarcoidosis using a metagenomics approach. F1000Res 2021; 10:820. [PMID: 36212901 PMCID: PMC9515606 DOI: 10.12688/f1000research.55090.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/09/2021] [Indexed: 11/20/2022] Open
Abstract
Background: Metagenomic sequencing has the potential to identify a wide range of pathogens in human tissue samples. Sarcoidosis is a complex disorder whose etiology remains unknown and for which a variety of infectious causes have been hypothesized. We sought to conduct metagenomic sequencing on cases of ocular and periocular sarcoidosis, none of them with previously identified infectious causes. Methods: Archival tissue specimens of 16 subjects with biopsies of ocular and periocular tissues that were positive for non-caseating granulomas were used as cases. Four archival tissue specimens that did not demonstrate non-caseating granulomas were also included as controls. Genomic DNA was extracted from tissue sections. DNA libraries were generated from the extracted genomic DNA and the libraries underwent next-generation sequencing. Results: We generated between 4.8 and 20.7 million reads for each of the 16 cases plus four control samples. For eight of the cases, we identified microbial pathogens that were present well above the background, with one potential pathogen identified for seven of the cases and two possible pathogens for one of the cases. Five of the eight cases were associated with bacteria ( Campylobacter concisus, Neisseria elongata, Streptococcus salivarius, Pseudopropionibacterium propionicum, and Paracoccus yeei), two cases with fungi ( Exophiala oligosperma, Lomentospora prolificans and Aspergillus versicolor) and one case with a virus (Mupapillomavirus 1). Interestingly, four of the five bacterial species are also part of the human oral microbiome. Conclusions: Using a metagenomic sequencing we identified possible infectious causes in half of the ocular and periocular sarcoidosis cases analyzed. Our findings support the proposition that sarcoidosis could be an etiologically heterogenous disease. Because these are previously banked samples, direct follow-up in the respective patients is impossible, but these results suggest that sequencing may be a valuable tool in better understanding the etiopathogenesis of sarcoidosis and in diagnosing and treating this disease.
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Affiliation(s)
| | - Christopher Pockrandt
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Natalia Rincon
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Yuchen Ge
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jennifer Lu
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ales Varabyou
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
| | - Anne E. Jedlicka
- Genomic Analysis and Sequencing Core Facility, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Karen Sun
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Alan L. Scott
- Department of Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Charles Eberhart
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Jennifer E. Thorne
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Steven L. Salzberg
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
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Hysa E, Cutolo CA, Gotelli E, Pacini G, Schenone C, Kreps EO, Smith V, Cutolo M. Immunopathophysiology and clinical impact of uveitis in inflammatory rheumatic diseases: An update. Eur J Clin Invest 2021; 51:e13572. [PMID: 33851422 PMCID: PMC8365741 DOI: 10.1111/eci.13572] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/08/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Uveitis is one of the most frequent ophthalmologic manifestations in rheumatology. Uveal inflammation can underlie a systemic inflammatory rheumatic disease (SIRD) in approximately 30% of cases with a significant burden on the quality of life since it represents a cause of blindness in up to 20% of cases in Western countries. METHODS In this review, we provide a comprehensive overview of the pathophysiology of uveitis associated with SIRDs. According to our literature survey on the epidemiology of uveitis among SIRDs, spondyloarthritides, Behçet's disease and sarcoidosis get the major impact. RESULTS In Behçet's uveitis, the key players are highly polarized Th1 and Th17 lymphocytes, natural killer T cells and γδ T cells. All contribute to a great destructive inflammatory environment with the most serious visual damage resulting from the involvement of the posterior segment of the eye. In contrast, spondyloarthritides-related uveitis derives from a complex interaction between genetic background and extra-ocular inflammatory mediators originating from enthesitis, arthritis, psoriatic lesions and microbiome pro-inflammatory alterations. In such conditions, the immune infiltration of CD4+ T cells, Th17 and natural killer cells along with pro-inflammatory cytokines, TNF-α among all, leads to intraocular inflammation. Lastly, granuloma formation represents the primary hallmark lesion in sarcoid uveitis. This suggests a profound link between the innate system that mainly recruits activated macrophages and adaptive system involving by Th1, Th17 and Th17.1 cells. CONCLUSIONS Awareness among rheumatologists of a potential severe ocular involvement generates new insights into targeted therapeutic approaches and personalized treatments for each patient.
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Affiliation(s)
- Elvis Hysa
- Laboratory of Experimental Rheumatology and Academic Division of Clinical RheumatologyDepartment of Internal MedicineItaly – IRCCS Rheumatology UnitSan Martino PolyclinicUniversity of GenoaGenoaItaly
| | - Carlo Alberto Cutolo
- Ophthalmology Clinic DiNOGMIIRCCS Ophthalmology Unit San Martino PolyclinicUniversity of GenoaGenoaItaly
| | - Emanuele Gotelli
- Laboratory of Experimental Rheumatology and Academic Division of Clinical RheumatologyDepartment of Internal MedicineItaly – IRCCS Rheumatology UnitSan Martino PolyclinicUniversity of GenoaGenoaItaly
| | - Greta Pacini
- Laboratory of Experimental Rheumatology and Academic Division of Clinical RheumatologyDepartment of Internal MedicineItaly – IRCCS Rheumatology UnitSan Martino PolyclinicUniversity of GenoaGenoaItaly
| | - Carlotta Schenone
- Laboratory of Experimental Rheumatology and Academic Division of Clinical RheumatologyDepartment of Internal MedicineItaly – IRCCS Rheumatology UnitSan Martino PolyclinicUniversity of GenoaGenoaItaly
| | - Elke O Kreps
- Department of OphthalmologyGhent University HospitalGhentBelgium
| | - Vanessa Smith
- Department of Internal MedicineDepartment of RheumatologyGhent. University HospitalGhent UniversityGhentBelgium
- Unit for Molecular Immunology and InflammationVIB Inflammation Research Center (IRC)GhentBelgium
| | - Maurizio Cutolo
- Laboratory of Experimental Rheumatology and Academic Division of Clinical RheumatologyDepartment of Internal MedicineItaly – IRCCS Rheumatology UnitSan Martino PolyclinicUniversity of GenoaGenoaItaly
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Abstract
PURPOSE OF REVIEW The current review summarizes recent guidance in the diagnosis and management of sarcoidosis. Until recently, the main guidelines were the 1999 International Statement on Sarcoidosis. However, in 2020 two new guidelines were published by the American and British Thoracic Societies. They have a number of key updates and this review aims to summarize these. RECENT FINDINGS The key findings from 2020 revolve around several themes. First, the need for a histological diagnosis should be supported by a multidisciplinary team approach. When a histological biopsy is needed of the lungs, thought is given to the approach taken for this and to whether an endobronchial ultrasound, endoscopic ultrasound or transbronchial biopsy is needed. Second, information regarding supporting tests including blood biomarkers, lung function and imaging. Third, a section specific to cardiac sarcoidosis. Finally, a summary of guidance for treating sarcoidosis including the need to treat fatigue. SUMMARY The recent guidance suggests that a histological biopsy is only needed in cases of diagnostic uncertainty or in patients with typical long standing features on imaging. The guidelines also provide a clear pathway on the type of lung biopsy needed depending on the extent of mediastinal or parenchymal involvement. Support is given to steroid regimens and indication for second-line immunosuppression.
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Zhang C, Tian R, Dreifus EM, Hashemi Shahraki A, Holt G, Cai R, Griswold A, Bejarano P, Jackson R, V Schally A, Mirsaeidi M. Activity of the growth hormone-releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis-like granuloma. Clin Transl Immunology 2021; 10:e1310. [PMID: 34257968 PMCID: PMC8256670 DOI: 10.1002/cti2.1310] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/09/2021] [Accepted: 06/15/2021] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Growth hormone-releasing hormone (GHRH) is a potent stimulator of growth hormone (GH) secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remain unknown. METHODS Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti-inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model using different methods including ELISA, immunohistochemistry, RNA-seq analysis and flow cytometry. RESULTS MIA602 decreases the levels of IL-2, IL-2R, IL-7, IL-12, IL-17A and TNF-α in an in vitro granuloma model. Further, we show that the anti-inflammatory effect of MIA602 appears to be mediated by a reduction in CD45+CD68+ cells in granulomatous tissue and upregulation in PD-1 expression in macrophages. Analysis of the expression of proteins involved in the mitochondrial stage of apoptosis showed that MIA602 increases the levels of caspase-3, BCL-xL/BAK dimer and MCl-1/Bak dimer in the granuloma. These findings indicate that MIA602 may not induce apoptosis. CONCLUSIONS Our findings further suggest that GHRH-R is potentially a clinical target for the treatment of granulomatous disease and that MIA602 may be used as a novel therapeutic agent for sarcoidosis.
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Affiliation(s)
- Chongxu Zhang
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
| | - Runxia Tian
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
| | | | | | - Gregory Holt
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
- Division of Pulmonary and Critical CareUniversity of MiamiMiamiFLUSA
| | - Renzhi Cai
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
| | - Anthony Griswold
- School of MedicineJohn P. Hussman Institute for Human GenomicsUniversity of MiamiMiamiFLUSA
| | | | - Robert Jackson
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
- School of MedicineUniversity of MiamiMiamiFLUSA
| | - Andrew V Schally
- Polypeptide and Cancer InstituteVeterans Affairs Medical CenterMiamiFLUSA
- Department of PathologyUniversity of Miami Miller School of MedicineMiamiFLUSA
| | - Mehdi Mirsaeidi
- Section of PulmonaryMiami VA Healthcare SystemMiamiFLUSA
- Division of Pulmonary and Critical CareUniversity of MiamiMiamiFLUSA
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Ozbalci D. A tale of two diseases: Sarcoidosis, COVID-19 and new therapeutic options with dual RAS inhibition and tetanus-diphtheria vaccine. Med Hypotheses 2021; 152:110619. [PMID: 34102600 PMCID: PMC8168307 DOI: 10.1016/j.mehy.2021.110619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/25/2021] [Accepted: 05/30/2021] [Indexed: 01/08/2023]
Abstract
Sars Cov-2, the pathogen which belongs to the beta coronavirus family that is responsible for COVID-19, uses Angiotensin Converting Enzyme 2 (ACE2) as a receptor, which is responsible for controlling the actions of renin-angiotensin system (RAS). Sars Cov-2 - ACE2 binding leads to a RAS mediated immune response, which targets especially lungs to form ARDS, which in turn, is the most important cause of mortality in COVID-19. CD8+ T cell response dominates over CD4+ T cell response and natural killer cell dysfunction also leads to CD4+ cell dysfunction in COVID-19; this immune dysregulation leads to inappropriate (ARDS) and inadequate (low or quickly waning antibodies) responses to the disease and unfortunately, prepares the patients for re-infections. The peripheral anergy seen in chronic sarcoidosis has much resemblance to COVID-19; CD8+ T cell accumulation is also responsible for inadequate reaction to tuberculin and antigenic stimulus. This article, based on the similarity of COVID-19 and sarcoidosis, discusses a combination of the therapeutic strategy of the tetanus-diphtheria vaccine and dual RAS inhibition, alongside with hydroxychloroquine and antiviral agents, as a solution to overcome the problems described above.
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Affiliation(s)
- Demircan Ozbalci
- Suleyman Demirel University School of Medicine, Department of Hematology, Dogu Yerleskesi Cunur, Isparta, Turkey.
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Abstract
PURPOSE OF REVIEW The aim of this article is to describe the known health disparities that exist among patients with sarcoidosis by socioeconomic status, race, and gender, review potential contributors to health disparities in sarcoidosis, investigate the intersectionality among socioeconomic status, race, and gender in sarcoidosis, and outline a research agenda to address these disparities. RECENT FINDINGS Recent studies have reported the significant financial strain a diagnosis of sarcoidosis has on individuals and the disproportionate affect the strain has on low socioeconomic status individuals, Blacks, and females. Worse dyspnea, lower health-related quality of life, and higher rates of mortality and hospitalization are more common among those who are Black, female, or of low socioeconomic status. SUMMARY Health disparities in sarcoidosis by socioeconomic status, race, and gender have been described for decades. In this review, we describe potential contributors to health disparities including stress and propose interventions to address disparities including creating educational programs accessible for low-income patients and caregivers, targeting medication adherence and trust in physicians and the medical system, and ensuring access to high-quality care for all patients. As clinicians and researchers, we owe it to our patients to not only describe the health disparities that exist but also stimulate to achieve improvement in sarcoidosis.
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33
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Mertz P, Jeannel J, Guffroy A, Lescuyer S, Korganow AS, Rondeau-Lutz M, Weber JC. Granulomatous manifestations associated with COVID19 infection: Is there a link between these two diseases? Autoimmun Rev 2021; 20:102824. [PMID: 33864942 PMCID: PMC8056977 DOI: 10.1016/j.autrev.2021.102824] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 01/07/2021] [Indexed: 12/15/2022]
Affiliation(s)
- Philippe Mertz
- Internal Medicine department, Strasbourg University Hospital, Strasbourg, France.
| | - Juliette Jeannel
- Internal Medicine department, Strasbourg University Hospital, Strasbourg, France
| | - Aurélien Guffroy
- Clinical Immunology department, National Reference Center for Rare Autoimmune Diseases (RESO), ERN RITA, Strasbourg University Hospital, Strasbourg, France
| | - Sylvain Lescuyer
- Internal Medicine department, Strasbourg University Hospital, Strasbourg, France
| | - Anne Sophie Korganow
- Clinical Immunology department, National Reference Center for Rare Autoimmune Diseases (RESO), ERN RITA, Strasbourg University Hospital, Strasbourg, France
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Kim ST, Pundole X, Dadu R, Lambotte O, Ramos-Casals M, Suarez-Almazor ME. Use of immune checkpoint inhibitors in cancer patients with pre-existing sarcoidosis. Immunotherapy 2021; 13:465-475. [PMID: 33641345 DOI: 10.2217/imt-2020-0272] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim: To evaluate adverse events in cancer patients with pre-existing sarcoidosis receiving immune checkpoint inhibitors (ICIs). Patients & methods: We retrospectively reviewed cancer patients with sarcoidosis who underwent treatment with ICI to determine frequency of sarcoidosis flares. Results: 32 patients with sarcoidosis received ICIs The median time to ICI initiation was 7 years (range: 1 month to 51 years). One patient (3%) with a 20-year remote history of sarcoidosis developed a clinically symptomatic exacerbation after three doses of atezolizumab, with hilar lymphadenopathy, subcutaneous nodules, arthritis and uveitis. Atezolizumab was discontinued and prednisone initiated. She had a fluctuating course with two additional flares. Conclusion: Frequency of flares in patients with a remote history of sarcoidosis who receive ICIs is low.
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Affiliation(s)
- Sang T Kim
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xerxes Pundole
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ramona Dadu
- Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Olivier Lambotte
- AP-HP. Université Paris-Saclay, Hôpital Bicêtre Department of Internal Medicine & Clinical Immunology, Le Kremlin Bicêtre, France.,Université Paris-Saclay; INSERM; CEA, Centre Immunology of Viral Infections & Autoimmune Diseases, IDMIT Department, IBFJ, Le Kremlin-Bicêtre, France
| | - Manuel Ramos-Casals
- Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain.,Laboratory of Autoimmune Diseases Josep Font, IDIBAPS-CELLEX, Barcelona, Spain.,Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Maria E Suarez-Almazor
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Obi ON, Lower EE, Baughman RP. Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update. Expert Rev Clin Pharmacol 2021; 14:179-210. [PMID: 33487042 DOI: 10.1080/17512433.2021.1878024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Sarcoidosis is a multi-organ disease with a wide range of clinical manifestations and outcomes. A quarter of sarcoidosis patients require long-term treatment for chronic disease. In this group, corticosteroids and cytotoxic agents be insufficient to control diseaseAreas covered: Several biologic agents have been studied for treatment of chronic pulmonary and extra-pulmonary disease. A review of the available literature was performed searching PubMed and an expert opinion regarding specific therapy was developed.Expert opinion: These agents have the potential of treating patients who have progressive disease. Many of these agents have different mechanisms of action, response rates, and toxicity profiles.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Elyse E Lower
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Robert P Baughman
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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Casanova NG, Gonzalez-Garay ML, Sun B, Bime C, Sun X, Knox KS, Crouser ED, Sammani N, Gonzales T, Natt B, Chaudhary S, Lussier Y, Garcia JGN. Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Respir Res 2020; 21:321. [PMID: 33276795 PMCID: PMC7716494 DOI: 10.1186/s12931-020-01537-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/06/2020] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. OBJECTIVE To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). METHODS Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. RESULTS Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. CONCLUSION These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.
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Affiliation(s)
- Nancy G Casanova
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Manuel L Gonzalez-Garay
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Belinda Sun
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Christian Bime
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Xiaoguang Sun
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Kenneth S Knox
- Department of Medicine, College of Medicine, University of Arizona, Phoenix, AZ, USA
| | - Elliott D Crouser
- Division of Pulmonary and Critical Care Medicine, The Ohio State University, Columbus, OH, USA
| | - Nora Sammani
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Taylor Gonzales
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Bhupinder Natt
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Sachin Chaudhary
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Yves Lussier
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA
| | - Joe G N Garcia
- Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, AZ, USA.
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Isshiki T, Matsuyama H, Yamaguchi T, Morita T, Ono J, Nunomura S, Izuhara K, Sakamoto S, Homma S, Kishi K. Plasma matrix metalloproteinase 7, CC-chemokine ligand 18, and periostin as markers for pulmonary sarcoidosis. Respir Investig 2020; 58:479-487. [PMID: 32868264 DOI: 10.1016/j.resinv.2020.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/03/2020] [Accepted: 07/12/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Some patients with sarcoidosis experience worsening of pulmonary lesions. However, no biomarker has been identified that reflects pulmonary disease status in sarcoidosis. We investigated the usefulness of potential markers of pulmonary fibrosis in patients with sarcoidosis. METHODS Plasma matrix metalloproteinase 7 (MMP-7), CC-chemokine ligand 18 (CCL-18), and periostin levels were evaluated in 60 patients with sarcoidosis and 30 healthy controls; bronchoalveolar lavage fluid levels were analyzed in 22 patients with sarcoidosis. To determine the usefulness of these markers, we explored potential correlations between these markers and sarcoidosis clinical characteristics. RESULTS Plasma MMP-7, CCL-18, and periostin concentrations were significantly higher in patients with sarcoidosis than those in healthy controls. MMP-7 concentrations in plasma and bronchoalveolar lavage fluid were higher in patients with sarcoidosis with parenchymal infiltration than in those without lung lesions. Moreover, MMP-7 concentration was negatively correlated with pulmonary function. CONCLUSION Among these novel biomarkers, MMP-7 most precisely reflected pulmonary sarcoidosis disease status and thus, might be useful for diagnosing and evaluating sarcoidosis, particularly in patients with pulmonary parenchymal lesions.
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Affiliation(s)
- Takuma Isshiki
- Department of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
| | - Hisayo Matsuyama
- Department of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
| | | | - Toshisuke Morita
- Department of Laboratory Medicine, Toho University School of Medicine, Tokyo, Japan.
| | | | - Satoshi Nunomura
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.
| | - Kenji Izuhara
- Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.
| | - Susumu Sakamoto
- Department of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
| | - Sakae Homma
- Department of Advanced and Integrated Interstitial Lung Disease Research, School of Medicine, Toho University, Tokyo, Japan.
| | - Kazuma Kishi
- Department of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
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Hade EM, Smith RM, Culver DA, Crouser ED. Design, rationale, and baseline characteristics of a pilot randomized clinical trial of nicotine treatment for pulmonary sarcoidosis. Contemp Clin Trials Commun 2020; 20:100669. [PMID: 33089005 PMCID: PMC7567036 DOI: 10.1016/j.conctc.2020.100669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 09/22/2020] [Accepted: 10/03/2020] [Indexed: 11/27/2022] Open
Abstract
Introduction Sarcoidosis is a systemic granulomatous disease of unknown cause afflicting young to middle-aged adults. The majority of patients with active pulmonary sarcoidosis complain of overwhelming fatigue, which often persists despite administration of immune-modulating drugs typically used to treat sarcoidosis. Nicotine offers an alternative to conventional treatments, which are associated with a spectrum of serious untoward effects, including diabetes mellitus, osteoporosis, bone marrow suppression, severe infections, cirrhosis. The described pilot randomized trial aims to provide preliminary data required to design subsequent Phase II/III trials to formally evaluate nicotine as a novel low-cost and highly-effective, safe treatment option for patients with active pulmonary sarcoidosis. Methods and Design: This is a randomized double-blind controlled trial of adults with confirmed pulmonary sarcoidosis, allocated in equal proportion to sustained release transdermal nicotine or placebo patch. The primary objective outcome is the improvement in forced vital capacity at study week 26 from baseline measurement. Secondary measures include lung texture score, and self-reported outcomes including the Fatigue Assessment Scale, the St George's Respiratory Questionnaire, and the Sarcoidosis Assessment Tool. Discussion Current therapies for active pulmonary sarcoidosis, remain either expensive and often with numerous side-effects, as with novel industry developed therapies, or with reduced quality of life, as with corticosteroids. Nicotine therapy provides promise as a safe, available, and cost-effective intervention strategy, which we expect to be acceptable to patients. ClinicalTrials.gov NCT02265874.
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Affiliation(s)
- Erinn M Hade
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA.,Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH, 43210, USA
| | - Rachel M Smith
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA
| | - Daniel A Culver
- Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Elliott D Crouser
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA
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Dammacco R, Biswas J, Kivelä TT, Zito FA, Leone P, Mavilio A, Sisto D, Alessio G, Dammacco F. Ocular sarcoidosis: clinical experience and recent pathogenetic and therapeutic advancements. Int Ophthalmol 2020; 40:3453-3467. [PMID: 32740881 PMCID: PMC7669777 DOI: 10.1007/s10792-020-01531-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/21/2020] [Indexed: 12/16/2022]
Abstract
Purpose To describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed. Methods Data from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available. Results Ocular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Löfgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon’s injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-α is a central mediator of granuloma formation, adalimumab, targeting TNF-α, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis. Conclusion Uveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.
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Affiliation(s)
- Rosanna Dammacco
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Jyotirmay Biswas
- Department of Uveitis and Ocular Pathology, Sankara Nethralaya, Chennai, India
| | - Tero T Kivelä
- Department of Ophthalmology, University of Helsinki, Helsinki, Finland
| | | | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Medical School Polyclinic, Piazza Giulio Cesare, 11, 70124, Bari, Italy
| | - Alberto Mavilio
- Social Health District, Glaucoma Center, Azienda Sanitaria Locale, Brindisi, Italy
| | - Dario Sisto
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Giovanni Alessio
- Department of Ophthalmology and Neuroscience, University of Bari "Aldo Moro", Medical School, Bari, Italy
| | - Franco Dammacco
- Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Medical School Polyclinic, Piazza Giulio Cesare, 11, 70124, Bari, Italy.
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Peritoneal Sarcoidosis Mimicking Peritoneal Tuberculosis and Advanced Ovarian Carcinoma. Case Rep Obstet Gynecol 2020; 2020:1905649. [PMID: 32695535 PMCID: PMC7361883 DOI: 10.1155/2020/1905649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/05/2020] [Accepted: 06/18/2020] [Indexed: 11/18/2022] Open
Abstract
Sarcoidosis is an inflammatory disease that affects one or multiple organs, most commonly the lungs and lymph nodes. This disease can present in a variety of ways which often makes diagnosis difficult. A 54-year-old postmenopausal African American female with a history of omental carcinomatosis of unknown origin was referred to the gynecology-oncology service at a local community hospital following a laparoscopic incarcerated hernia repair where multiple abdominal lesions suspicious of ovarian carcinomatosis were visualized. She was brought to the operating room for a diagnostic laparoscopy at which point the intra-abdominal survey revealed white tubercle-like lesions that were consistent with peritoneal tuberculosis. The lesions were excised and sent to pathology. The omentum biopsy was originally reported as adipose tissue showing focal fibrosis, focal mild acute inflammation, few cyst formation, and multiple granulomatous chronic inflammation, with multinucleated giant cells. Periodic acid-Schiff stain and acid fast bacilli stain were negative, and a diagnosis of peritoneal tuberculosis was made. The patient was started on an antituberculosis treatment regimen; however, she was not improving. The pathology slides were reexamined and revealed nonnecrotizing granulomatous inflammation consistent with sarcoidosis. The patient was immediately referred to the department of pulmonology and rheumatology, at which point she was started on corticosteroids and had an improvement in her condition.
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Harding JS, Herbath M, Chen Y, Rayasam A, Ritter A, Csoka B, Hasko G, Michael IP, Fabry Z, Nagy A, Sandor M. VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection. Cell Rep 2020; 27:2119-2131.e6. [PMID: 31091450 DOI: 10.1016/j.celrep.2019.04.072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/11/2019] [Accepted: 04/16/2019] [Indexed: 12/22/2022] Open
Abstract
Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.
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Affiliation(s)
- Jeffrey S Harding
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada
| | - Melinda Herbath
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Yuli Chen
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Aditya Rayasam
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Anna Ritter
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Balazs Csoka
- Department of Anesthesiology, Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - George Hasko
- Department of Anesthesiology, Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Iacovos P Michael
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada
| | - Zsuzsanna Fabry
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Andras Nagy
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada; Department of Obstetrics and Gynecology, and Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Matyas Sandor
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
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Abstract
Sarcoidosis is a chronic, multisystem, inflammatory disorder of unknown etiology that is characterized by noncaseating granulomas that impair normal organ functioning. Sarcoidosis predominantly affects the lungs, but the skin is often cited as the second most frequently involved organ. Cutaneous manifestations of sarcoidosis are highly variable and ongoing research seeks to better understand the relationship between clinical morphology and disease prognosis. Skin findings in patients with sarcoidosis can be "specific," in which sarcoidal granulomas infiltrate the skin, or they can represent a "nonspecific" reactive inflammatory process, as is seen in calcinosis cutis and erythema nodosum. Cutaneous sarcoidosis can be the initial presenting sign or develop later in the course of the disease. In some patients, the skin will be the most involved and impactful organ system and will drive therapy. In other cases, the skin will be an incidental or minor finding, but may be easily accessible for biopsy to confirm the diagnosis. There are many potential therapies for sarcoidosis, though no one therapy is universally effective.
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Affiliation(s)
- Avrom Caplan
- Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York
| | - Misha Rosenbach
- Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sotonye Imadojemu
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Papiris SA, Manali ED, Papaioannou AI, Georgakopoulos A, Kolilekas L, Pianou NK, Kallergi M, Papaporfyriou A, Kallieri M, Apollonatou V, Papadaki G, Malagari K, Kelekis NL, Pneumatikos SG, Chatziioannou S. Prevalence, distribution and clinical significance of joints, muscles and bones in sarcoidosis: an 18F-FDG-PET/CT study. Expert Rev Respir Med 2020; 14:957-964. [PMID: 32460642 DOI: 10.1080/17476348.2020.1775587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVES In Sarcoidosis joints-muscles-bones (JMBs) localizations are of the least common. 18F-FDG-PET/CT imaging revolutionized detection of JMBs involvement by adding metabolic activity information and allowing for a comprehensive, whole-body mapping of the disease. AIM AND METHODS This study investigated prevalence, distribution, and clinical significance of JMBs sarcoidosis in 195 consecutive patients that underwent 18F-FDG PET/CT examination. RESULTS Joint and bone involvement were encountered in 15% of patients with a mean of the maximum-standardized-uptake-value (SUVmax) of 6.1. Most common location was the axial skeleton. Hypercalciuria was significantly more frequent in patients with osseous involvement (p = 0.003). Muscle activity (SUVmax = 2.4) was encountered in 20% of the patients, most frequently in treatment-naïve (p = 0.02). The muscles of the lower extremities were affected the most. Muscle and bone localization coexist in 50% of the cases. JMBs disease was almost asymptomatic, not related to chronicity but to pulmonary, nodal, and systemic disease. Long-term follow-up and treatment response of affected patients confirmed sarcoidosis. CONCLUSION 18F-FDG-PET/CT revealed JMBs localizations and coexistence with other organ sites supporting the concept that sarcoidosis is a systemic disease. By allowing an integrative interpretation of multi-organ involvement in the context of a pattern highly suggestive of sarcoidosis, it strongly keeps-off the diagnosis of malignancy.
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Affiliation(s)
- Spyros A Papiris
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Effrosyni D Manali
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Andriana I Papaioannou
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Alexandros Georgakopoulos
- 2nd Department of Radiology, Division of Nuclear Medicine, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece.,Nuclear Medicine Division, Biomedical Research Foundation of the Academy of Athens , Athens, Greece
| | | | - Nikoletta K Pianou
- Nuclear Medicine Division, Biomedical Research Foundation of the Academy of Athens , Athens, Greece.,Departments of Nuclear Medicine, Evangelismos General Hospital , Athens, Greece
| | - Maria Kallergi
- Nuclear Medicine Division, Biomedical Research Foundation of the Academy of Athens , Athens, Greece.,Department of Biomedical Engineering, University of West Attika , Athens, Greece
| | - Anastasia Papaporfyriou
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Maria Kallieri
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Vasiliki Apollonatou
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Georgia Papadaki
- 2nd Pulmonary Medicine Department, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Katerina Malagari
- 2nd Department of Radiology, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Nikolaos L Kelekis
- 2nd Department of Radiology, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Spyros G Pneumatikos
- 3rd Orthopaedic Department, KAT General Hospital, Medical School, National and Kapodistrian University of Athens , Athens, Greece
| | - Sofia Chatziioannou
- 2nd Department of Radiology, Division of Nuclear Medicine, General University Hospital "Attikon", Medical School, National and Kapodistrian University of Athens , Athens, Greece.,Nuclear Medicine Division, Biomedical Research Foundation of the Academy of Athens , Athens, Greece
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Zhang C, Chery S, Lazerson A, Altman NH, Jackson R, Holt G, Campos M, Schally AV, Mirsaeidi M. Anti-inflammatory effects of α-MSH through p-CREB expression in sarcoidosis like granuloma model. Sci Rep 2020; 10:7277. [PMID: 32350353 PMCID: PMC7190699 DOI: 10.1038/s41598-020-64305-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 04/08/2020] [Indexed: 12/11/2022] Open
Abstract
Lung inflammation due to sarcoidosis is characterized by a complex cascade of immunopathologic events, including leukocyte recruitment and granuloma formation. α-melanocyte stimulating hormone (α-MSH) is a melanocortin signaling peptide with anti-inflammatory properties. We aimed to evaluate the effects of α-MSH in a novel in vitro sarcoidosis model. An in vitro sarcoidosis-like granuloma model was developed by challenging peripheral blood mononuclear cells (PBMCs) derived from patients with confirmed treatment-naïve sarcoidosis with microparticles generated from Mycobacterium abscessus cell walls. Unchallenged PBMCsand developed granulomas were treated daily with 10 μM α-MSH or saline as control. Cytokine concentrations in supernatants of culture and in cell extracts were measured using Illumina multiplex Elisa and western blot, respectively. Gene expression was analyzed using RNA-Seq and RT-PCR. Protein secretion and gene expression of IL-7, IL-7R, IFN-γ, MC1R, NF-κB, phosphorylated NF-κB (p-NF-κB), MARCO, and p-CREB were measured with western blot and RNAseq. A significant increase in IL-7, IL-7R, and IFN-γ protein expression was found in developed granulomas comparing to microparticle unchallenged PBMCs. IL-7, IL-7R, and IFN-γ protein expression was significantly reduced in developed granulomas after exposure to α-MSH compared with saline treated granulomas. Compared with microparticle unchallenged PBMCs, total NF-κB and p-NF-κB were significantly increased in developed granulomas, while expression of p-CREB was not changed. Treatment with α-MSH promoted a significantly higher concentration of p-CREB in granulomas. The anti-inflammatory effects of α-MSH were blocked by specific p-CREB inhibition. α-MSH has anti-inflammatory properties in this in vitro granuloma model, which is an effect mediated by induction of phosphorylation of CREB.
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Affiliation(s)
- Chongxu Zhang
- Section of Pulmonary, Miami VA Health System, Miami, FL, USA
| | - Stephanie Chery
- Departments of Medicine University of Miami Miller School of Medicine, Miami, FL, USA
| | - Aaron Lazerson
- Comparative Pathology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Norman H Altman
- Comparative Pathology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Robert Jackson
- Section of Pulmonary, Miami VA Health System, Miami, FL, USA
- Division of Pulmonary and Critical Care, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Greg Holt
- Section of Pulmonary, Miami VA Health System, Miami, FL, USA
- Division of Pulmonary and Critical Care, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michael Campos
- Section of Pulmonary, Miami VA Health System, Miami, FL, USA
- Division of Pulmonary and Critical Care, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andrew V Schally
- Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA
| | - Mehdi Mirsaeidi
- Section of Pulmonary, Miami VA Health System, Miami, FL, USA.
- Division of Pulmonary and Critical Care, University of Miami Miller School of Medicine, Miami, FL, USA.
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Greaves SA, Atif SM, Fontenot AP. Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease. Front Immunol 2020; 11:474. [PMID: 32256501 PMCID: PMC7093490 DOI: 10.3389/fimmu.2020.00474] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 02/28/2020] [Indexed: 12/11/2022] Open
Abstract
Pulmonary sarcoidosis and chronic beryllium disease (CBD) are inflammatory granulomatous lung diseases defined by the presence of non-caseating granulomas in the lung. CBD results from beryllium exposure in the workplace, while the cause of sarcoidosis remains unknown. CBD and sarcoidosis are both immune-mediated diseases that involve Th1-polarized inflammation in the lung. Beryllium exposure induces trafficking of dendritic cells to the lung in a mechanism dependent on MyD88 and IL-1α. B cells are also recruited to the lung in a MyD88 dependent manner after beryllium exposure in order to protect the lung from beryllium-induced injury. Similar to most immune-mediated diseases, disease susceptibility in CBD and sarcoidosis is driven by the expression of certain MHCII molecules, primarily HLA-DPB1 in CBD and several HLA-DRB1 alleles in sarcoidosis. One of the defining features of both CBD and sarcoidosis is an infiltration of activated CD4+ T cells in the lung. CD4+ T cells in the bronchoalveolar lavage (BAL) of CBD and sarcoidosis patients are highly Th1 polarized, and there is a significant increase in inflammatory Th1 cytokines present in the BAL fluid. In sarcoidosis, there is also a significant population of Th17 cells in the lungs that is not present in CBD. Due to persistent antigen exposure and chronic inflammation in the lung, these activated CD4+ T cells often display either an exhausted or anergic phenotype. Evidence suggests that these T cells are responding to common antigens in the lung. In CBD there is an expansion of beryllium-responsive TRBV5.1+ TCRs expressed on pathogenic CD4+ T cells derived from the BAL of CBD patients that react with endogenous human peptides derived from the plexin A protein. In an acute form of sarcoidosis, there are expansions of specific TRAV12-1/TRBV2 T cell receptors expressed on BAL CD4+ T cells, indicating that these T cells are trafficking to and expanding in the lung in response to common antigens. The specificity of these pathogenic CD4+T cells in sarcoidosis are currently unknown.
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Affiliation(s)
- Sarah A Greaves
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Shaikh M Atif
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Andrew P Fontenot
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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D'Argenio V, Casaburi G, Precone V, Gioacchino Moccia L, Postiglione I, Bocchino M, Sanduzzi A. A common microbial signature is present in the lower airways of interstitial lung diseases including sarcoidosis. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2020; 35:354-362. [PMID: 32476923 PMCID: PMC7170129 DOI: 10.36141/svdld.v35i4.7061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/06/2018] [Indexed: 12/14/2022]
Abstract
Background: The etiology of pulmonary sarcoidosis is not well established. Although the mechanism triggering pulmonary sarcoidosis remains to be established, inflammatory reactions seem to play an important role in this process. Objectives: The aim of this study was to define the composition of the lower airway microbiota in the bronchoalveolar lavage (BAL) of patients affected by interstitial lung diseases, including sarcoidosis, to determine whether the bacterial signature differs among these diseases. Methods: Ten patients affected by pulmonary sarcoidosis and 9 patients affected by other interstitial lung diseases were enrolled. 16S rRNA next-generation sequencing was used to study BAL microbial composition of these patients, and were also compared with already published microbial content in higher airways of such diseases. Results: Four phyla dominated the lower airway microbiota, Bacteroidetes being the most abundant phylum in both groups (56.9%). Diversity analysis showed no significant differences between the various diseases, particularly between pulmonary sarcoidosis and other interstitial lung diseases affecting lower airways. Conclusions: Our data indicate that the bacterial lower airways microbiota share the same signature and, therefore, cannot be used as a diagnostic tool to discriminate among different interstitial lung diseases, including sarcoidosis, while microbial diversity is present when considering lower or higher respiratory airways. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 354-362).
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Affiliation(s)
- Valeria D'Argenio
- CEINGE-Biotecnologie Avanzate s.c.a r.l. Naples, Italy.,Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Italy.,Task Force on Microbiome Studies, University of Naples Federico II, Naples, Italy
| | - Giorgio Casaburi
- CEINGE-Biotecnologie Avanzate s.c.a r.l. Naples, Italy.,Evolve Biosystems, Inc. Davis, CA, USA
| | - Vincenza Precone
- CEINGE-Biotecnologie Avanzate s.c.a r.l. Naples, Italy.,Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Italy
| | - Livio Gioacchino Moccia
- Department of Clinical Medicine and Surgery, Respiratory Medicine Section, University of Naples Federico II, Italy
| | | | - Marialuisa Bocchino
- Department of Clinical Medicine and Surgery, Respiratory Medicine Section, University of Naples Federico II, Italy
| | - Alessandro Sanduzzi
- Department of Clinical Medicine and Surgery, Respiratory Medicine Section, University of Naples Federico II, Italy
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Sharp M, Brown T, Chen ES, Rand CS, Moller DR, Eakin MN. Association of Medication Adherence and Clinical Outcomes in Sarcoidosis. Chest 2020; 158:226-233. [PMID: 32032588 DOI: 10.1016/j.chest.2020.01.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 12/16/2019] [Accepted: 01/03/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Sarcoidosis, one of the most common interstitial lung diseases, has significant health disparities. Approximately 50% of individuals affected with sarcoidosis will undergo spontaneous remission, but those who do not undergo remission often require long-term or lifelong treatment to prevent disease progression. We sought to assess the association between medication adherence and clinical outcomes in sarcoidosis. METHODS Adult patients in the Johns Hopkins Sarcoidosis Clinic diagnosed with pulmonary sarcoidosis on treatment were eligible for enrollment. Questionnaires were administered to assess medication adherence, health-related quality of life (HRQoL), health-care utilization, and sociodemographic information. Clinical information was abstracted from medical charts including lung function, disease duration, comorbidities, and sarcoidosis organ involvement. RESULTS A total of 117 participants were enrolled (57% women; 55% black; median age, 57 years). Within the cohort, 66% of individuals reported at least one nonadherent behavior. Higher medication adherence was associated with better HRQoL (P < .05). There was no association between medication adherence and the odds of health-care utilization, FVC % predicted, FEV1 % predicted, or diffusion capacity of the lungs for carbon monoxide % predicted. Black participants reported lower medication adherence than white participants (P < .05). CONCLUSIONS This is the first observational study of medication adherence in sarcoidosis. We found that higher medication adherence was associated with better HRQoL, with blacks more likely to report nonadherence. Medication adherence may be an important target to improve patient-reported outcomes and health disparities in sarcoidosis.
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Affiliation(s)
- Michelle Sharp
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
| | - Taylor Brown
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Edward S Chen
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Cynthia S Rand
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - David R Moller
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michelle N Eakin
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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Heming M, Lohmann L, Schulte-Mecklenbeck A, Brix T, Gross CC, Wiendl H, Klotz L, Meyer Zu Hörste G. Leukocyte profiles in blood and CSF distinguish neurosarcoidosis from multiple sclerosis. J Neuroimmunol 2020; 341:577171. [PMID: 32007787 DOI: 10.1016/j.jneuroim.2020.577171] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/13/2020] [Accepted: 01/25/2020] [Indexed: 12/26/2022]
Abstract
Distinguishing neurosarcoidosis (NS) from multiple sclerosis (MS) remains challenging and available parameters lack discriminatory power. Comprehensive flow cytometry data of blood and CSF leukocytes of patients with NS (n = 24), MS (n = 49) and idiopathic intracranial hypertension (IIH, n = 52) were analyzed by machine learning algorithms. NS featured a specific immune cell pattern with increased activated CD4+ T cells in CSF and increased plasma cells in blood. Combining blood and CSF parameters improved the differentiation. We thereby identify and independently validate a multi-dimensional model of blood and CSF supporting the difficult differential diagnosis between NS and MS.
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Affiliation(s)
- Michael Heming
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Lisa Lohmann
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | | | - Tobias Brix
- Institute of Medical Informatics, University of Münster, Münster, Germany
| | - Catharina C Gross
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Heinz Wiendl
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Luisa Klotz
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Gerd Meyer Zu Hörste
- Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
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Huppertz C, Jäger B, Wieczorek G, Engelhard P, Oliver SJ, Bauernfeind FG, Littlewood-Evans A, Welte T, Hornung V, Prasse A. The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation. Eur Respir J 2020; 55:13993003.00119-2019. [DOI: 10.1183/13993003.00119-2019] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 12/18/2019] [Indexed: 12/21/2022]
Abstract
Sarcoidosis is a disease characterised by granuloma formation. There is an unmet need for new treatment strategies beyond corticosteroids. The NLRP3 inflammasome pathway is expressed in innate immune cells and senses danger signals to elicit inflammatory interleukin (IL)-1β; it has recently become a druggable target. This prompted us to test the role of the NLRP3 inflammasome and IL-1β pathway in granuloma formation and sarcoidosis.19 sarcoid patients and 19 healthy volunteers were recruited into this pilot study. NLRP3 inflammasome activity was measured in bronchoalveolar lavage (BAL) cells and lung and skin biopsies using immunohistochemistry, Western blot, reverse-transcriptase PCR and ELISA. For in vivo experiments we used the trehalose 6,6′-dimycolate-granuloma mouse model and evaluated lung granuloma burden in miR-223 knockout and NLRP3 knockout mice, as well as the treatment effects of MCC950 and anti-IL-1β antibody therapy.We found strong upregulation of the NLRP3 inflammasome pathway, evidenced by expression of activated NLRP3 inflammasome components, including cleaved caspase-1 and IL-1β in lung granuloma, and increased IL-1β release of BAL cells from sarcoid patients compared to healthy volunteers (p=0.006). mRNA levels of miR-223, a micro-RNA downregulating NLRP3, were decreased and NLRP3 mRNA correspondingly increased in alveolar macrophages from sarcoid patients (p<0.005). NLRP3 knockout mice showed decreased and miR-223 knockout mice increased granuloma formation compared to wild-type mice. Pharmacological interference using NLRP3 pathway inhibitor MCC950 or an anti-IL-1β antibody resulted in reduced granuloma formation (p<0.02).In conclusion, our data provide evidence of upregulated inflammasome and IL-1β pathway activation in sarcoidosis and suggest both as valid therapeutic targets.
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Chronic Inflammatory Arthropathy Preceding Acute Systemic Manifestations of Sarcoidosis: A Possible Overlap of Idiopathic Juvenile Arthritis and Sarcoidosis. Case Rep Rheumatol 2019; 2019:6483245. [PMID: 31886005 PMCID: PMC6925795 DOI: 10.1155/2019/6483245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/14/2019] [Accepted: 11/18/2019] [Indexed: 12/17/2022] Open
Abstract
Sarcoidosis is a multisystem disease with unknown etiology, marked by T lymphocytes and macrophages agglomeration, which leads to the formation of noncaseating granulomas in the affected tissues. We describe a case of a 40-year-old black patient referred to our service for evaluation of nephrolithiasis and persistent elevation of plasma creatinine. He reported important weight loss, fever episodes, and abdominal and low back intermittent pain in the past 6 months. The investigation revealed elevated serum calcium level, hepatosplenomegaly, retroperitoneal lymphadenopathy, anemia, thrombocytopenia, and nephrolithiasis. The initial diagnostic hypothesis was lymphoproliferative disease, but the laparoscopic propaedeutic showed multiple white lesions on the liver surface, which biopsy identified as noncaseating granulomas with asteroid corpuscles, suggestive of sarcoidosis. He was treated with corticosteroids with significant improvement in symptoms and in calcium and creatinine levels. Besides, the patient presented a long-term large joints arthropathy, especially on the knees (with bilateral prosthesis), wrists, and ankles, of unknown etiology. We discuss the systemic manifestations of sarcoidosis related to the reported case, as well as the possible overlapping of idiopathic juvenile arthritis with sarcoidosis.
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