Pulmonary sarcoidosis-like reactions induced by sintilimab in esophageal cancer: A case report.

RATIONALE: Esophageal cancer is one of the deadliest cancers in the world, with high incidence and mortality rates ranking among the top ten in China. The efficacy of conventional treatments is limited and often accompanied by severe adverse reactions, which results in unsatisfactory outcomes. The mechanism of immune checkpoint inhibitors (ICIs) is to activate cytotoxic T cells to kill tumor cells expressing tumor antigens. The application of ICIs has profoundly changed the mode of cancer treatment. However, the use of ICIs also induces a series of adverse reactions similar to autoimmune reactions, called immune-related adverse events (irAEs). Some ICIs can cause manifestations similar to those in the development of sarcoidosis, which are called sarcoidosis-like reactions or granulomatosis. PATIENT CONCERNS: We report a 50-year-old Chinese male patient. DIAGNOSES: The patient had been diagnosed with advanced esophageal squamous cell carcinoma , and was confirmed to have pulmonary sarcoidosis-like reactions associated with sintilimab, a human programmed cell death protein 1 (PD-1) inhibitor. INTERVENTIONS: The patient was administered corticosteroid treatment. OUTCOMES: After receiving steroid treatment, the patient's systemic and pulmonary symptoms improved rapidly. To our knowledge, this is the first report of pulmonary sarcoidosis-like reaction in a patient with esophageal squamous cell carcinoma. The patient then continued to receive 1 year of follow-up antitumor treatment after the appearance of lung pulmonary sarcoidosis-like reactions. The prognosis was good and the patient's condition is currently stable. LESSONS: The diagnosis of ICI-induced sarcoidosis often requires comprehensive evaluation through clinical, pathological, and radiological assessment. A subset of patients with sarcoidosis-like reactions may not require treatment unless there is organ dysfunction or severe clinical symptoms, and these reactions generally respond well to treatment. The occurrence of sarcoidosis-like reactions after immunotherapy is positively correlated with the long-term prognosis of cancer patients. However, this hypothesis requires larger prospective studies for validation.

Pembrolizumab-Associated Cutaneous and Pulmonary Sarcoidosis in Non-Small Cell Lung Cancer Treatment.

Immune checkpoint inhibitor (ICI) therapy has reshaped the treatment landscape in many cancers including non-small cell lung cancer (NSCLC). ICI-therapy can lead to a diverse array of immune-related adverse effects (irAEs), and prompt recognition and management are key to successful treatment. With wide-spread use of ICI therapy in clinical practice, rare irAEs are being increasingly recognized. This report documents a patient with advanced NSCLC who developed pembrolizumab-associated sarcoidosis with multiorgan involvement. Multidisciplinary management led to timely diagnosis and treatment, leading to improvement in symptoms. This case raises awareness of sarcoidosis as a rare side effect of pembrolizumab.

COVID-19-induced pulmonary sarcoid: A case report and review of the literature.

BACKGROUND: The COVID-19 pandemic has resulted in dramatic loss of life worldwide, but as the large number of acutely ill patients subsides, the emerging group of "COVID-19 long-haulers" present a clinical challenge. Studies have shown that many of these patients suffer long-term pulmonary disease related to residual fibrosis. Prior studies have shown that while many patients have non-specific findings of fibrotic-like changes, others develop specific patterns of interstitial lung disease. CASE REPORT: Here, we present the first case of a patient developing pulmonary sarcoidosis one year after critical illness from COVID-19. He developed numerous non-necrotizing and well-formed granulomas in mediastinal lymph nodes and pulmonary nodules, compatible radiographically and pathologically with sarcoid. CONCLUSIONS: While the pathophysiology of sarcoid is incompletely understood, inflammation is mediated through the dysregulation of a number of different cytokines (IFNγ, IL-2, IL-12, IL-17, IL-22). This case provides valuable clues for better understanding of the shared pathophysiology of cytokine dysregulation seen in COVID-19 and other interstitial lung diseases such as sarcoidosis.

Development of pulmonary sarcoidosis in Crohn's disease patient under infliximab biosimilar treatment after long-term original infliximab treatment: a case report and literature review.

BACKGROUND: Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn's disease (CD) patient developed after a long period administration (15 years) of TNF-I. CASE PRESENTATIONS: A 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission. CONCLUSIONS: To our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.

Systemic sarcoidosis reactions as a result of tumour necrosis factor-alpha treatment for patients with psoriasis.

The high efficacy and tolerability of biological therapies such as anti-tumour necrosis factor-alpha (TNF-α) have transformed outcomes for many inflammatory conditions. Conversely, a wide range of paradoxical reactions, including pulmonary, renal and ocular sarcoidosis secondary to TNF-α blocking agents in patients with severe psoriasis, has been reported. Sarcoid-like granulomatosis is one of these reactions, which may affect the pulmonary and cutaneous systems. Renal and ocular sarcoidosis, however, are less frequent and have unknown consequences. In this report, we present two cases of anti-TNF-α-induced sarcoidosis involving the pulmonary and renal systems.

Propionibacterium acnes-associated Sarcoidosis Possibly Initially Triggered by Interferon-alpha Therapy.

A 46-year-old woman with uveitis was referred to our respiratory diseases department in July 2018. Her medical history included transient bilateral hilar mediastinal lymphadenopathy (BHL) and multiple pulmonary nodules in May 2013 during pegylated interferon-alpha and ribavirin treatment for chronic hepatitis C infection. Five years post-treatment, chest X-ray revealed BHL and nodular recurrence. A biopsy of the subcutaneous buttock nodules revealed scattered non-caseating epithelioid granulomas with positive PAB immunohistochemical staining. This seem to be the first report of Propionibacterium acnes-associated sarcoidosis possibly initially triggered by interferon-alpha therapy. Understanding the mechanisms underlying interferon-triggered P. acnes-associated sarcoidosis may clarify the sarcoidosis immunopathogenesis.

Matrix Metalloproteinase-12 Is Required for Granuloma Progression.

Background: Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation. Methods: C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1). Results: Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days. Conclusions: The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

Pirfenidone-Induced Sarcoid-Like Reaction: A Novel Complication.

Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia. Prognosis is poor with a median survival <3 years. Pirfenidone is one of two US Food and Drug Administration-approved medications that slow disease progression. We describe the development of lymphadenopathy or a sarcoid-like reaction following initiation of pirfenidone, a complication not previously reported.

[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.

EBUS-TBNA Can Distinguish Sarcoid-Like Side Effect of Nivolumab Treatment from Tumor Progression in Non-Small Cell Lung Cancer.

With the expansion of immunotherapy in the treatment of lung cancer, clinicians have to face new clinical pictures and adapt their practice. We report the case of a 69-year-old man diagnosed with non-small cell lung cancer using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and treated with nivolumab as second-line therapy. After 8 injections of nivolumab, a new CT and PET scan revealed massive growth and increase in metabolism of hilar and mediastinal lymph nodes, whereas the size and metabolism of the left upper lobe lesion were reduced. A new EBUS-TBNA was thus performed and showed an epithelioid cell reaction compatible with sarcoidosis in the 3 punctured lymph nodes (stations 4R, 11L, 7). In the absence of cancer evolution, nivolumab was continued, and the CT after the twelfth injection showed stability.

Nivolumab-Induced Development of Pulmonary Sarcoidosis in Renal Cell Carcinoma.

A 64-year-old woman with metastatic clear cell renal carcinoma who had been on nivolumab immunotherapy for 10 months was referred for a FDG PET scan to monitor disease progress. New bilateral mediastinal and hilar FDG-avid lymphadenopathy was noted. Pathology on subsequent mediastinal nodal biopsy showed well-formed epithelioid granulomas with no evidence of malignancy consistent with sarcoidosis. This case illustrates that pulmonary sarcoidosis can be induced by immunotherapy in the treatment of renal cell carcinoma.

Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1 checkpoint inhibitors: Case series and immunophenotypic analysis.

AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a documented association with the diagnosis of melanoma and can be induced in melanoma patients receiving anti-neoplastic therapy. We evaluated a case series of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS: Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated with anti-programmed cell death (PD)-1 antibody therapy at two institutions developed biopsy-proven sarcoidosis. We used mass cytometry to determine expression of the relevant chemokine receptors (CR) by peripheral blood mononuclear cells for two of the three patients who developed sarcoidosis and 13 melanoma patients who did not. Blood samples were collected before receiving PD-1 checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated abnormally high numbers of circulating Th17.1 (CCR6+ CCR4- CXCR3+ CCR10- ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15 melanoma patients, including both the patients who developed sarcoidosis during the course of therapy. CONCLUSION: Our findings support prior literature implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we demonstrate these findings in patients with melanoma prior to administration of checkpoint therapy and before the onset of clinically symptomatic sarcoidosis. The identification of elevated Th17.1 cells in melanoma patients who have not developed sarcoidosis may reflect the established association between melanoma and sarcoidosis. With some patients receiving these agents over a prolonged period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.

Adalimumab-induced pulmonary sarcoidosis not progressing upon treatment with etanercept.

Tumor necrosis factor alpha (TNF-α) inhibitors effectively treat sarcoidosis, but can, paradoxically, induce sarcoidosis. The TNF-α inhibitor etanercept is most commonly associated with paradoxical sarcoidosis, which has previously been reported to be resolved by adalimumab. However, we describe the case of a patient with ankylosing spondylitis and adalimumab-induced sarcoidosis not aggravated by switching to etanercept, thus indicating that etanercept could be a treatment option for patients who develop paradoxical sarcoid-like reactions after treatment with other TNF-α inhibitors.

Polishing surgical metal pieces, granulomatosis and mineralogical analysis.

This report describes the case of a 44-year-old man with pulmonary nodules whose histological analysis initially suggested tuberculosis. The Mycobacterium tuberculosis (MT) culture was negative and a questionnaire revealed a professional activity of brushing and polishing surgical instruments without any protection for 7 years.  A mineralogical analysis by optical and electron microscopy was performed on both a healthy lung tissue biopsy and a lung nodule in a paraffin block. Electron microscopy analysis revealed the presence of metal particles (iron oxide, titanium oxide, aluminum oxide and steel) in both samples. This study suggests that mineralogical analysis combined with a questionnaire on dust exposure could help redirect the diagnosis of a dust-related disease.

[Sarcoid-like granulomatosis in patients treated with anti-TNFα]. / LE CAS CLINIQUE DU MOIS. Granulomatose sarcoïdose-like chez les patients traités par anti-TNFα.

Over recent years, anti-TNFα have been used to treat rheumatoid arthritis. The principal secondary effect of anti-TNFα is tuberculosis infections. Another paradoxical effect, previously less well understood, is the development of sarcoid-like granulomatous reactions. We report the case of a 36 year old woman who had been treated for 9 years with anti-TNF alpha. She developed a pulmonary sarcoid-like gra-nulomatosis, complication that is rare but not exceptional in patients treated with TNF-blockers. Discontinuation of anti TNF usually led to recovery. It has been suggested that these reactions mainly occur with etanercept, but this requires further confirmation.