Potential therapeutic targets to prevent organ damage in chronic pulmonary sarcoidosis.

INTRODUCTION: Sarcoidosis is a granulomatous inflammatory disease with high chances of reduced quality of life, irreversible organ damage, and reduced life expectancy when vital organs are involved. Any organ system can be affected, and the lungs are most often affected. There is no preventive strategy as the exact etiology is unknown, and complex immunogenetic and environmental factors determine disease susceptibility and phenotype. Present-day treatment options originated from clinical practice and are effective in many patients. However, a substantial percentage of patients suffer from unacceptable side effects or still develop refractory, threatening pulmonary or extrapulmonary disease. AREAS COVERED: As non-caseating granulomas, the pathological hallmark of disease, are assigned to divergent activation and regulation of the immune system, targets in relation to the possible triggers of granuloma formation and their sequelae were reviewed. EXPERT OPINION: The immunopathogenesis underlying sarcoidosis has been a dynamic field of study. Several recent new insights give way to promising new therapeutic targets, such as certain antigenic triggers (e.g. from Aspergillus nidulans), mTOR, JAK-STAT and PPARγ pathways, the NRP2 receptor and MMP-12, which await further exploration. Clinical and trigger related phenotyping, and molecular endotyping will likely hold the key for precision medicine in the future.

Hypoxia Promotes a Mixed Inflammatory-Fibrotic Macrophages Phenotype in Active Sarcoidosis.

Background: Macrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis. Methods: We studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O2) or hypoxia (1.5% O2). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response. Results: We observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls. Conclusions: Hypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.

Associations between occupational and environmental exposures and organ involvement in sarcoidosis: a retrospective case-case analysis.

BACKGROUND: Sarcoidosis most commonly affects lungs and intrathoracic lymph nodes, but any other organ can be involved. In epidemiological studies, many occupational and environmental exposures have been linked to sarcoidosis but their relationship with the disease phenotype has barely been studied. OBJECTIVE: To investigate how occupational and environmental exposures prior to diagnosis relate to organ involvement in patients with sarcoidosis METHODS: We retrospectively studied patients seen at a sarcoidosis clinic between 2017 and 2020. Patients were included if they had a clinical presentation consistent with sarcoidosis and histologically confirmed epithelioid granulomas or had Löfgren syndrome. In a case-case analysis using multivariable logistic regression we calculated odds ratios (OR) of prespecified exposure categories (based on expert ascertainment) for cases with a given organ involvement versus cases without this organ involvement. RESULTS: We included 238 sarcoidosis patients. Sarcoidosis limited to pulmonary involvement was associated with exposure to inorganic dust prior to diagnosis (OR 2.11; 95% confidence interval [CI] 1.11-4.17). Patients with liver involvement had higher odds of contact with livestock (OR 3.68; 95% CI 0.91-12.7) or having jobs with close human contact (OR 4.33; 95% CI 1.57-11.3) than patients without liver involvement. Similar associations were found for splenic involvement (livestock: OR 4.94, 95% CI 1.46-16.1; close human contact: OR 3.78; 95% CI 1.47-9.46). Cardiac sarcoidosis was associated with exposure to reactive chemicals (OR 5.08; 95% CI 1.28-19.2) or livestock (OR 9.86; 95% CI 1.95-49.0). Active smokers had more ocular sarcoidosis (OR 3.26; 95% CI 1.33-7.79). CONCLUSIONS: Our study indicates that, in sarcoidosis patients, different exposures might be related to different organ involvements-hereby providing support for the hypothesis that sarcoidosis has more than one cause, each of which may promote a different disease phenotype.

Sarcoidosis: An Occupational Disease?

Sarcoidosis is an important member of the family of granulomatous lung diseases. Since its recognition in the late 19th century, sarcoidosis has been thought of as a disease of unknown cause. Over the past 20 years, this paradigm has been shifting, more rapidly in the past 10 years. Epidemiologic studies, bolstered by case reports, have provided evidence of causal associations between occupational exposure to specific agents and sarcoidosis. Pathogenesis has been more clearly defined, including the role of gene-exposure interactions. The use of in vitro lymphocyte proliferation testing to detect sensitization to inorganic antigens is being examined in patients with sarcoidosis. These antigens include silica and certain metals. Results of studies to date show differences in immunoreactivity of occupationally exposed sarcoidosis cases compared with control cases, suggesting that lymphocyte proliferation testing may prove useful in diagnosing work-related disease. This review discusses recently published findings regarding associations between occupational exposure to silica and silicates, World Trade Center dust, and metals and risk for sarcoidosis, as well as advances in the development of diagnostic tools. Not all cases of sarcoidosis have an identified cause, but some do. Where the cause is occupational, its recognition is critical to enable effective treatment through removal of the affected worker from exposure and to inform intervention aimed at primary prevention.

Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis.

BACKGROUND: Glomerular involvement in rheumatoid arthritis has been known to be associated with treatment side effects from medications and secondary amyloidosis. However, limited basic science and clinical studies have been performed to address the potential disease specific immune-mediated mechanisms causing secondary glomerular pathology, its various types of presentation, and the potential treatments. CASE PRESENTATION: A 41-year-old man with chronic active rheumatoid arthritis presented with nephrotic syndrome and was found to have membranous nephropathy with eosinophilic intracapillary thrombi on renal biopsy. Proteinuria persisted despite complete withdrawal from non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Throughout the disease course, he developed cryoglobulinemic vasculitis and pulmonary sarcoidosis, both of which achieved clinical resolution with glucocorticoids. However, only partial improvement was observed in proteinuria with treatment of steroids and Rituximab. CONCLUSION: Our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous and cryoglobulinemic nephropathy in the absence of DMARDs use, as well as pulmonary sarcoidosis. We speculate that there is a wider spectrum of glomerular disease in patients with untreated rheumatoid arthritis. In addition, the potential association between rheumatoid arthritis and cryoglobulinemic vasculitis should probably be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.

Granulomatous lung disease in two workers making light bulbs.

BACKGROUND: Associations between sarcoidosis or sarcoid-like granulomatous lung disease and exposure to silica and other inorganic agents have been suggested in several studies. CASES: We describe granulomatous lung disease in two workers of a small production unit making metal-halide lamps. Initially, both were diagnosed with sarcoidosis. However, in both men, birefringent particles were observed in the lung or mediastinal lymph node biopsies. Clipping of glass tubes led to moderate exposure to dust, consisting mainly of amorphous fused silica, with some cristobalite. After removal from exposure, both subjects improved clinically, radiologically, and functionally. CONCLUSION: The present cases support the hypothesis that silica might be a trigger for sarcoid-like granulomatous lung disease. Sarcoidosis should be considered a diagnosis of exclusion and clinicians should carefully collect occupational and environmental exposure histories to identify workplace triggers.

Host-microbe interactions in the pathogenesis and clinical course of sarcoidosis.

Sarcoidosis is a rare inflammatory disease characterized by the development of granulomas in various organs, especially in the lungs and lymph nodes. Clinics of the disease largely depends on the organ involved and may range from mild symptoms to life threatening manifestations. Over the last two decades, significant advances in the diagnosis, clinical assessment and treatment of sarcoidosis have been achieved, however, the precise etiology of this disease remains unknown. Current evidence suggests that, in genetically predisposed individuals, an excessive immune response to unknown antigen/s is crucial for the development of sarcoidosis. Epidemiological and microbiological studies suggest that, at least in a fraction of patients, microbes or their products may trigger the immune response leading to sarcoid granuloma formation. In this article, we discuss the scientific evidence on the interaction of microbes with immune cells that may be implicated in the immunopathogenesis of sarcoidosis, and highlight recent studies exploring potential implications of human microbiota in the pathogenesis and the clinical course of sarcoidosis.

Musculoskeletal and pulmonary outcomes of sarcoidosis after initial presentation of osseous involvement.

OBJECTIVE: We aimed to investigate the musculoskeletal and pulmonary outcomes of patients with osseous sarcoidosis. METHODS: We identified 24 patients with osseous sarcoidosis and at least one year of follow-up after diagnosis (baseline). We collected outcome data at 1-year follow-up and last follow-up. We defined a composite outcome measure; worsening considered as worsening in any of the following 4 components compared to baseline: 1) osseous sarcoidosis symptoms, 2) musculoskeletal imaging of affected bone, 3) chest imaging, or 4) pulmonary function testing (PFT). RESULTS: A minority of patients had a worsening composite outcome at 1-year (9/24, 38%) and last follow-up (5/24, 21%). When only considering musculoskeletal symptoms and imaging, only 25% (6/24) and 13% (3/24) of patients worsened compared to baseline at 1-year and last follow-up, respectively. Patients with a worsening composite overall outcome tended to be older at baseline than those without the outcome for both 1-year (54.3 years vs. 47.5 years, p=0.11) and last follow-up (55.0 years vs. 48.7 years; p=0.23), although these differences were non-significant. Treatment was not associated with worsening composite overall outcome at 1-year follow-up (p=0.40), but was significantly associated with decreased risk for worsening at last follow-up (p=0.05). CONCLUSIONS: In this retrospective cohort study of osseous sarcoidosis, most patients had a favorable outcome according to symptoms, musculoskeletal/chest imaging, and PFTs, even though only a minority were treated with glucocorticoids or DMARDs. These results suggest that the natural history of osseous sarcoidosis is often benign, although some patients experience clinical progression.

The natural history of cutaneous sarcoidosis. Clinical spectrum and histological analysis of 40 cases.

BACKGROUND: Cutaneous lesions of sarcoidosis can allow physicians to establish the diagnosis of a systemic disease, but the need of monitoring patients presenting skin limited sarcoidosis in order to detect further extracutaneous involvement has rarely been evaluated. OBJECTIVES: To review clinical and histological features of patients with cutaneous sarcoidosis and the risk of progression to systemic disease. To characterize the phenotype of patients with isolated cutaneous sarcoidosis and to assess the temporal relationship between cutaneous and systemic disease. METHODS: Retrospective review of a series of patients with cutaneous sarcoidosis. Clinical, histopathological, and evolutive features were reviewed. RESULTS: Forty patients were included in the study. Systemic disease was present in 82.5% of patients. Previous or concurrent cutaneous involvement occurred in 81.8% of them. Seven out of 14 patients with cutaneous lesions evolved to a systemic sarcoidosis in a mean time of 6 years, with a range between 4 and 9 years. No clinical or histological differences were found between patients with systemic sarcoidosis and those who showed persistent isolated cutaneous lesions. CONCLUSIONS: Sarcoidosis may be manifested as an isolated cutaneous disorder. No clinical or histopathological features seem to be helpful to discriminate cases of a persistent isolated cutaneous disease from those that will develop systemic involvement. Since the development of systemic involvement in cases of isolated cutaneous sarcoidosis can occur many years afterward, careful monitoring seems advisable, and a long follow-up is recommended.

Small Cell Lung Cancer with Sarcoidosis in Spontaneous Remission: A Case Report.

A 69-year-old woman was diagnosed with sarcoidosis, which was not treated with corticosteroid therapy. Her levels of angiotensin converting enzyme decreased significantly over 4 years and a mass lesion was detected near the lower part of her left main bronchus, and diagnosed as small cell lung cancer (SCLC). Treatment of the SCLC with a series of chemotherapeutic agents produced excellent results. The pulmonary sarcoidosis did not show any deterioration despite the frequent use of amrubicin, which is known to be a cause of interstitial pneumonia. This is a case report of SCLC complicated with sarcoidosis in a stage of spontaneous remission, possibly suggesting an association between sarcoidosis and tumor immunity, since recent reports have suggested that immune checkpoint inhibitors might be involved in the development of sarcoidosis.

Atezolizumab-induced sarcoid-like granulomatous reaction in a patient with urothelial cell carcinoma.

A 61-year-old woman with locally advanced, high-grade urothelial cell carcinoma was treated with the anti-programmed death-ligand 1 antibody atezolizumab. She initially received neoadjuvant chemotherapy and surgery that led to clinical and radiographic remission at the time of atezolizumab initiation. Within 3 months she developed new mediastinal and hilar lymphadenopathy as well as pulmonary nodules in a pattern characteristic of pulmonary sarcoidosis. Mediastinal lymph node biopsy by endobronchial ultrasound demonstrated noncaseating granulomas without evidence of malignancy or infection. Within 4 weeks of initiation of prednisone and cessation of atezolizumab there was marked reduction in intrathoracic lymphadenopathy and perilymphatic nodules. This is the first reported case of atezolizumab-induced sarcoid-like granulomatous reaction.

Clinical features of sarcoidosis associated pulmonary hypertension: Results of a multi-national registry.

BACKGROUND: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality in sarcoidosis. We established a multi-national registry of sarcoidosis associated PH (SAPH) patients. METHODS: Sarcoidosis patients with PH confirmed by right heart catheterization (RHC) were studied. Patients with pulmonary artery wedge pressure (PAWP) of 15 mmHg or less and a mean pulmonary artery pressure (mPAP) ≥ 25 Hg were subsequently analyzed. Data collected included hemodynamics, forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO), chest x-ray, and 6-min walk distance (6MWD). RESULTS: A total of 176 patients were analyzed. This included 84 (48%) cases identified within a year of entry into the registry and 94 (53%) with moderate to severe PH. There was a significant correlation between DLCO percent predicted (% pred) andmPAP (Rho = -0.228, p = 0.0068) and pulmonary vascular resistance (PVR) (Rho = -0.362, p < 0.0001). PVR was significantly higher in stage 4 disease than in stage 0 or 1 disease (p < 0.05 for both comparisons). About two-thirds of the SAPH patients came from the United States (US). There was a significant difference in the rate of treatment between US (67.5%) versus non-US (86%) (Chi Square 11.26, p = 0.0008) sites. CONCLUSIONS: The clinical features of SAPH were similar across multiple centers in the US, Europe, and the Middle East. The severity of SAPH was related to reduced DLCO. There were treatment differences between the US and non-US centers.

[socioecological features of the epidemiology of sarcoidosis in the poltava region, Ukraine].

OBJECTIVE: Introduction: Lung sarcoidosis is a systemic granulomatous disease that can affect various organs and systems of a person. Due to the lack of a uniform standardized approach to the diagnosis of sarcoidosis, the epidemiological pattern is heterogeneous and depends on many factors. The aim: To investigate the correlation between the number of patients with sarcoidosis among the population of the Poltava region (Ukraine) and the ecological characteristics of the industrial activity of the region in comparison with the data on the availability of subspecialists in respiratory diseases. PATIENTS AND METHODS: Materials and methods: The study is based on a retrospective analysis of patients with sarcoidosis living in the Poltava region (Ukraine) for the period from 2008 to 2018. RESULTS: Results: The analysis of the correlation between the intensity of environmental impacts on the region and the number of patients with sarcoidosis did not reveal statistically significant changes. An odds ratio (OR) of the occurrence of sarcoidosis among the urban population has not experienced significant dynamics (OR 1,337, 95% CI: 0.96-1.86) compared with those living in rural areas. The number of specialists performing the duties of a pulmonologist in the region is associated with a significantly higher number of registered patients with various forms of sarcoidosis (r=0.27, p=0.04). CONCLUSION: Conclusions: There was no reliable relationship between the risk of sarcoidosis and habitat in areas with increased ecological and industrial load in the Poltava region. The uneven distribution of specialized medical care reduces the patient's odds of establishing a diagnosis of sarcoidosis in the countryside.

Sarcoid-Like Granulomatosis of the Lung Related to Immune-Checkpoint Inhibitors: Distinct Clinical and Imaging Features of a Unique Immune-Related Adverse Event.

With the rapidly expanding role of immune-checkpoint inhibitor therapy in advanced cancer treatment, an increasing number of new immune-related adverse events (irAEs) are being reported. The present report describes sarcoid-like granulomatosis of the lung as a distinct type of irAE with characteristic clinical, imaging, and histologic features. In patients treated with immune-checkpoint inhibitors, sarcoid-like granulomatosis of the lung presented with a focal area of consolidation in the lung, which was often nodular or round, in the absence of new or enlarging lymphadenopathy on imaging. Histologic examination demonstrated nonnecrotizing granulomas and an absence of malignant cells. The patients were free of new or worsening respiratory symptoms, despite the development of lung parenchymal consolidations. Holding the immune-checkpoint inhibitors led to the spontaneous resolution of the findings, without any specific treatment for the abnormality. Awareness of the manifestations of sarcoid-like granulomatosis of the lung as a distinct type of irAE will improve management of patients treated with immune-checkpoint inhibitors. Cancer Immunol Res; 6(6); 630-5. ©2018 AACR.

[The diagnostic algorithm of practice in pulmonary and extrapulmonary sarcoidosis]. / Diagnostyczny algorytm postepowania w sarkoidozie plucnej i pozaplucnej.

Sarcoidosis (SA) is a granulomatous multisystem disease of unknown ethiology. Pulmonary, lymphadenopathy, liver, spleen, skin, and bone sarcoidosis are more frequent but also SA of the heart, central nervous system, eye, and hypercalcemia with following kidney failure also occur. Sarcoidosis may co-exist with extrapulmonary forms, which may overtake or precede each other. SA may occur as acute or chronic with the possibility of complete remission in the early stages of disease. Due to frequent occurrence of asymptomatic SA in threatening vital organs a diagnostic algorithm of practice in pulmonary and extrapulmonary sarcoidosis has been proposed by the author of the article. Diagnosis of SA is based on a correlation of clinical, radiological and histopathological pictures with the presence of non-caseating granuloma in material from the biopsy from at least one organ and having excluded tuberculosis. In all forms of SA, USG abdomen, ECG, ECHO heart, blood tests (blood count, calcium, creatinine, transaminases), level of calcium in a 24-hour urine samples, ophtalmoscopic examinations and lung function tests in pulmonary sarcoidosis should be undertaken to avoid overlooking any form of SA, especially in threatened vital organs. For this purpose, the multidisciplinary team providing an adequate care to the patient with SA has been created by the author of the article has been created by the author of the article in the University Clinical Center in Gdansk providing comprehensive care to patients with sarcoidosis.

Pulmonary Sarcoidosis in a patient with Multiple Sclerosis on daclizumab monotherapy.

As new immunomodulatory therapies continue to be licensed for use in Multiple Sclerosis, it is important to remain vigilant for new, unexpected associations relating to these medications. We highlight this by reporting on a case of a 45-year-old man who developed systemic, non-specific symptoms following long term use of daclizumab and was subsequently diagnosed with sarcoidosis. We go on to briefly discuss the action of daclizumab, in particular the effect it has on CD56bright natural killer cells, a cell type that has been investigated in relation to sarcoidosis.

Sarcoidosis with fever and a splenic infarct due to CMV or lymphoma?

We present a case of an adult female with a past history of pulmonary sarcoidosis who presented with fever, night sweats, profound fatigue, and LUQ abdominal pain. Sarcoidosis is an afebrile disorder (excluding Lofgren's syndrome, Heerfordt's syndrome or neurosarcoidosis). Therefore, the presence of fever with sarcoidosis should suggest infection, usually viral, or lymphoma. Sarcoidosis-lymphoma syndrome describes the evolution of a lymphoma in long standing sarcoidosis. Fever aside, possible lymphoma is suggested by otherwise unexplained fever, pleural unilateral effusion, highly elevated ESR or ferritin levels. In this case, a viral etiology was suggested because of atypical lymphocytosis and mildly elevated transaminases. In this patient, CMV IgM titers and elevated CMV PCR viral load confirmed the diagnosis of CMV infectious mononucleosis with lung and liver involvement. In this case CMV infectious mononucleosis was accompanied by procoagulant activity which resulted a DVT, pulmonary emboli and splenic infarct. We believe this to be the first reported case of CMV infectious mononucleosis splenic infarct in a patient with a history of sarcoidosis.

Pulmonary manifestations of urothelial carcinoma of the bladder.

Urothelial carcinoma (Transitional cell carcinoma) of the bladder is the pre-dominant histological type of bladder cancer in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. In some patients, the metastatic lesions will cause the initial presenting symptoms. We conducted a MedLine/PubMED search identifying all relevant articles with "pulmonary manifestations", "urothelial bladder cancer", "manifestations of bladder cancer" or a combination of these terms in the title. The pulmonary manifestations of urothelial carcinoma of the bladder include metastatic disease including cavitary lesions, endobronchial, pleural, or lymph node metastasis pleural effusion and chylothorax. Pulmonary embolism and tumor embolism is another manifestation of this cancer. Intravesical Bacillus Calmette-Gurin therapy for bladder cancer has been associated with a range of adverse effects including the systemic spread of Bacilli Calmette-Guérin immunotherapy affecting the lungs. Other drugs used to treat bladder cancer can be associated with drug-related pneumonitis. Other rare manifestations include a sarcoid like reaction and systemic granulomatous disease to Bacilli Calmette-Guérin therapy. In this review we discuss the various pulmonary manifestations of urothelial carcinoma of the bladder. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention.