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Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.

ABSTRACT: Pulmonary sarcoidosis is characterized by an exaggerated CD4+ T cell response and formation of non-necrotizing granulomas. Tumour necrosis factor ? (TNF-?) is regarded as crucial for granuloma formation and TNF-? inhibitors offer a third-line treatment option for patients not responding to conventional treatment. However, not all patients benefit from treatment, and an optimal dose and treatment duration have not been established. Insight into the influence of TNF-? inhibitors on lung immune cells may provide clues as to what drives inflammation in sarcoidosis and improve our understanding of treatment outcomes. To evaluate the effects of treatment with the TNF-? inhibitor infliximab on lung immune cells and clinical features of the patients, 13 patients with sarcoidosis refractory to conventional treatment were assessed with bronchoalveolar lavage (BAL), spirometry and computerized tomography (CT) scan closely adjacent to the start of infliximab treatment. These investigations were repeated after 6 months of treatment. Treatment with TNF-? inhibitor infliximab was well tolerated with no adverse events, except for one patient who developed a probable adverse event with liver toxicity. Ten patients were classified as responders, having a reduced CD4/CD8 ratio, a decreased percentage of CD4+ T cells expressing the activation marker CD69 and number of mast cells (P < 0·05 for all). The percentage of T regulatory cells (Tregs ), defined as forkhead box P3+ CD4+ T cells decreased in most patients. In conclusion, six months of infliximab treatment in patients with sarcoidosis led to signs of decreased CD4+ T cell alveolitis and decreased mastocytosis in the lungs of responders.

SUBMITTER: Kullberg S

PROVIDER: S-EPMC7290087 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.

Kullberg S S Rivera N V NV Abo Al Hayja M M Grunewald J J Eklund A A

Clinical and experimental immunology 20200422 1

Pulmonary sarcoidosis is characterized by an exaggerated CD4<sup>+</sup> T cell response and formation of non-necrotizing granulomas. Tumour necrosis factor α (TNF-α) is regarded as crucial for granuloma formation and TNF-α inhibitors offer a third-line treatment option for patients not responding to conventional treatment. However, not all patients benefit from treatment, and an optimal dose and treatment duration have not been established. Insight into the influence of TNF-α inhibitors on lung ...[more]

PMID: 32275772

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Project description:Background & aimsClinical manifestation of hepatic involvement in sarcoidosis can vary from asymptomatic disease to severe complications such as cirrhosis and portal hypertension. However, data on hepatic sarcoidosis are limited, and evidence-based recommendations are lacking. Our study aimed to assess the features and clinical course of hepatic sarcoidosis in a predominantly Caucasian cohort.MethodsWe performed a retrospective study including all patients with hepatic sarcoidosis between 2004 and 2020 in 5 German centres. The median follow-up time was 36 months (range 0.0-195). Data on demographic parameters, clinical manifestations, diagnostic test results, treatment, and outcome were collected.ResultsA total of 1,476 patients with sarcoidosis and 62 patients with hepatic involvement (4.2%) were identified. Of the patients, 51.6% were female, and 80.6% were Caucasian. Most patients were asymptomatic and were observed to have a cholestatic pattern of liver enzyme elevations. Cirrhosis was detected in 9 patients (14.5%), of whom 6 developed clinical manifestations of portal hypertension. Fifty-four patients were medically treated, most commonly with glucocorticoids (69.4%) or ursodeoxycholic acid (UDCA) (40.3%). Levels of alkaline phosphatase (ALP) decreased by 60.8% on average from baseline in patients treated with glucocorticoids and by 59.9% in patients treated with UDCA. Seventeen patients received treatment augmentation with a second line agent, of whom 8 patients normalised ALP levels during follow-up. None of the patients underwent liver transplantation or developed hepatocellular carcinoma (HCC). Three of the patients died during follow-up owing to liver-related complications.ConclusionsHepatic involvement in sarcoidosis was found in 4.2% of patients with sarcoidosis and was clinically significant in 14.5% of those. These findings highlight the importance of early identifying, monitoring, and treating hepatic sarcoidosis, given its increased mortality when associated with end-stage liver disease.Lay summaryClinical diagnostic and surveillance of hepatic involvement in sarcoidosis has not been standardised, and management of hepatic involvement is a clinical challenge, since it remains poorly characterised in many ways. Our results show that one-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, 14.5% suffered from cirrhosis, and 3 patients died owing to liver-related complications. Regarding pharmacological treatment options, corticosteroids and UDCA were the medical agents most frequently used, and both of them have been shown to induce biochemical response in the majority of patients. These findings highlight the importance of correctly and early identifying hepatic involvement in sarcoidosis, because of the potentially progressive course of disease.

Project description:BackgroundInflammatory 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 presentationsA 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.ConclusionsTo 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.

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Project description:Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.

Project description:Lung adenocarcinoma (LUAD) is one of the leading fatal malignancy with high morbidity and mortality worldwide. However, due to its complicated mechanism and lack of effective clinical therapeutics, early diagnosis and prognosis are still unsatisfactory. Most of the previous studies focused on cancer stem cells (CSCs), the relationship between cancer stemness (stem-like characteristics) and anti-tumor immunity has not been clearly revealed. Therefore, this study aimed to comprehensively analyze the role of cancer stemness and tumor microenvironment (TME) in LUAD using weighted gene co-expression network analysis (WGCNA). We constructed a gene co-expression network, identified key modules, and hub genes, and further explored the relationship between hub gene expression and cancer immunological characteristics through a variety of algorithms, including Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) and Gene Set Enrichment Analysis (GSEA). The hub genes were renamed stemness related genes (SRGs), whose functions were examined at the transcription and protein levels through survival analysis with additional samples, Oncomine database, immunohistochemistry, single cell RNA sequencing (scRNA-seq) and single-sample Gene Set Enrichment Analysis (ssGSEA). Subsequently, Tumor Immune Dysfunction and Exclusion (TIDE) and Connectivity Map (CMap) were implemented for treatment and prognosis analyses. As a result, 15 co-expressed SRGs (CCNA2, CCNB1, CDC20, CDCA5, CDCA8, FEN1, KIF2C, KPNA2, MCM6, NUSAP1, RACGAP1, RRM2, SPAG5, TOP2A, and TPX2) were identified. The overexpression of which was discovered to be associated with reduced immune infiltration in LUAD. It was discovered that there was a general negative correlation between cancer stemness and immunity. The expression of SRGs could probably affect our tumor occurrence, progression, the efficacy of chemotherapy and immunotherapy, and clinical outcomes. In conclusion, the 15 SRGs reported in our study may be used as potential candidate biomarkers for prognostic indicators and therapeutic targets after further validation.

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Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.

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Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.

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