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Yousef Abuamer - One of the best experts on this subject based on the ideXlab platform.
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the iκb kinase ikk inhibitor nemo binding domain peptide blocks osteoclastogenesis and bone erosion in Inflammatory Arthritis
Journal of Biological Chemistry, 2004Co-Authors: Simon Dai, Teruhisa Hirayama, Sabiha Abbas, Yousef AbuamerAbstract:Activation of NF-kappaB leads to expression of ample genes that regulate Inflammatory and osteoclastogenic responses. The process is facilitated by induction of IkappaB kinase (IKK) complex that phosphorylates IkappaB and leads to its dissociation from the NF-kappaB complex, thus permitting activation of NF-kappaB. The IKK complex contains primarily IKKalpha, IKKbeta, and the regulatory kinase IKKgamma, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKKalpha and IKKbeta, termed NEMO-binding domain (NBD). In this regard, a cell-permeable NBD peptide has been shown to block association of NEMO with the IKK complex and inhibit activation of NF-kappaB. Given the pivotal role of cytokine-induced NF-kappaB in osteoclastogenesis and Inflammatory bone loss, we deduced that cell-permeable TAT-NBD peptide may hinder osteoclastogenesis and bone erosion in Inflammatory Arthritis. Using NBD peptides, we show that wild type, but not mutant, NBD blocks IKK activation and reduces cytokine-induced promoter and DNA binding activities of NF-kappaB and inhibits cytokine-induced osteoclast formation by osteoclast precursors. Consistent with the key role of NF-kappaB in osteoInflammatory responses in vivo, wild type TAT-NBD administered into mice prior to induction of Inflammatory Arthritis efficiently block in vivo osteoclastogenesis, inhibits focal bone erosion, and ameliorates Inflammatory responses in the joints of arthritic mice. The mutant NBD peptide fails to exert these functions. These results provide strong evidence that IKKs are potent regulators of cytokine-induced osteoclastogenesis and Inflammatory Arthritis. More importantly, blockade of NEMO assembly with the IKK complex is a viable strategy to avert Inflammatory osteolysis.
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the iκb kinase ikk inhibitor nemo binding domain peptide blocks osteoclastogenesis and bone erosion in Inflammatory Arthritis
Journal of Biological Chemistry, 2004Co-Authors: Teruhisa Hirayama, Sabiha Abbas, Yousef AbuamerAbstract:Abstract Activation of NF-κB leads to expression of ample genes that regulate Inflammatory and osteoclastogenic responses. The process is facilitated by induction of IκB kinase (IKK) complex that phosphorylates IκB and leads to its dissociation from the NF-κB complex, thus permitting activation of NF-κB. The IKK complex contains primarily IKKα, IKKβ, and the regulatory kinase IKKγ, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKKα and IKKβ, termed NEMO-binding domain (NBD). In this regard, a cell-permeable NBD peptide has been shown to block association of NEMO with the IKK complex and inhibit activation of NF-κB. Given the pivotal role of cytokine-induced NF-κB in osteoclastogenesis and Inflammatory bone loss, we deduced that cell-permeable TAT-NBD peptide may hinder osteoclastogenesis and bone erosion in Inflammatory Arthritis. Using NBD peptides, we show that wild type, but not mutant, NBD blocks IKK activation and reduces cytokine-induced promoter and DNA binding activities of NF-κB and inhibits cytokine-induced osteoclast formation by osteoclast precursors. Consistent with the key role of NF-κB in osteoInflammatory responses in vivo, wild type TAT-NBD administered into mice prior to induction of Inflammatory Arthritis efficiently block in vivo osteoclastogenesis, inhibits focal bone erosion, and ameliorates Inflammatory responses in the joints of arthritic mice. The mutant NBD peptide fails to exert these functions. These results provide strong evidence that IKKs are potent regulators of cytokine-induced osteoclastogenesis and Inflammatory Arthritis. More importantly, blockade of NEMO assembly with the IKK complex is a viable strategy to avert Inflammatory osteolysis.
Auli Toivanen - One of the best experts on this subject based on the ideXlab platform.
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British Journal of Rheumatology 1994^3:1127-1130 SYNOVIAL FLUID MURAMIC ACID IN ACUTE Inflammatory Arthritis
2016Co-Authors: Auli ToivanenAbstract:Presence of muramic acid, a bacterial cell wall component, was analysed by gas chromatography-mass spectrometry in synovial fluid (SF) of 40 patients with acute Inflammatory Arthritis. SF muramic acid was observed in 4/14 patients with acute, culture negative Inflammatory Arthritis of unclear origin. Each of these four patients had a history of a recent bacterial disease (pansinuitis, purulent leg ulcer, erysipelas, unexplained fever with suspicion of cholecystitis and urinary tract infection). In the bacterial Arthritis, SF muramic acid was detected in 6/12 patients (in 2/6 culture negative cases). In the reactive Arthritis due to Salmonella or Yersinia, the rate of positivity was 2/14. Nineteen samples of traumatic SF effusion were muramic acid negative. These findings indicate that several cases of undefined acute Inflammatory Arthritis are of bacterial origin. KEY WORDS: Arthritis, Mass spectrometry, Peptidoglycan. OFTEN, in the absence of any indication for microbial or other cause, the aetiology of an acute Inflammatory Arthritis remains undefined [1]. The differential diag-nosis between bacterial Arthritis and reactive Arthritis is a well known clinical problem. The only definitive test for bacterial Arthritis is the demonstration of bacteri
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synovial fluid muramic acid in acute Inflammatory Arthritis
Rheumatology, 1994Co-Authors: L Lehtonen, P Kortekangas, P Oksman, Erkki Eerola, Hannu T Aro, Auli ToivanenAbstract:Presence of muramic acid, a bacterial cell wall component, was analysed by gas chromatography-mass spectrometry in synovial fluid (SF) of 40 patients with acute Inflammatory Arthritis. SF muramic acid was observed in 4/14 patients with acute, culture negative Inflammatory Arthritis of unclear origin. Each of these four patients had a history of a recent bacterial disease (pansinuitis, purulent leg ulcer, erysipelas, unexplained fever with suspicion of cholecystitis and urinary tract infection). In the bacterial Arthritis, SF muramic acid was detected in 6/12 patients (in 2/6 culture negative cases). In the reactive Arthritis due to Salmonella or Yersinia, the rate of positivity was 2/14. Nineteen samples of traumatic SF effusion were muramic acid negative. These findings indicate that several cases of undefined acute Inflammatory Arthritis are of bacterial origin.
P Pentony - One of the best experts on this subject based on the ideXlab platform.
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comorbidities in anti cyclic citrullinated peptide positive at risk individuals do not differ from those patients with early Inflammatory Arthritis
Frontiers in Medicine, 2018Co-Authors: Sarah Twigg, Elena Nikiphorou, Jackie L Nam, L Hunt, Kulveer Mankia, P PentonyAbstract:Objectives: To compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of Inflammatory Arthritis (IA), to those in patients with early IA. Methods: Baseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n=296). The second cohort (the Inflammatory Arthritis CONtinuum study, IACON) recruited patients with early IA (n=725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status and body mass index. Results: Patients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid lowering agent, ischaemic heart disease, cerebrovascular disease, lung disease and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p=0.037). Conclusion: There was no significant difference in comorbidities amongst people with CCP antibodies but without Inflammatory Arthritis, compared to those of patients with established Inflammatory Arthritis.
Jemima Albayda - One of the best experts on this subject based on the ideXlab platform.
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Inflammatory Arthritis a newly recognized adverse event of immune checkpoint blockade
Oncologist, 2017Co-Authors: Jarushka Naidoo, Laura C Cappelli, Patrick M Forde, Kristen A Marrone, Evan J Lipson, Hans J Hammers, William H Sharfman, Alan N Baer, Ami A Shah, Jemima AlbaydaAbstract:This commentary summarizes current knowledge on the clinical presentation, management, and outcomes of the Inflammatory Arthritis which may occur as an immune‐related adverse evet of immune checkpoint inhibitor therapy. Herein, we propose a new algorithm aimed at assisting oncologists in the diagnosis and management of this immune‐related adverse event.
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Inflammatory Arthritis and sicca syndrome induced by nivolumab and ipilimumab
Annals of the Rheumatic Diseases, 2017Co-Authors: Laura C Cappelli, Evan J Lipson, Alan N Baer, Ami A Shah, Jemima Albayda, Anna Kristina Gutierrez, Rebecca L Manno, Uzma Haque, Karen B Bleich, Jarushka NaidooAbstract:Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with Inflammatory Arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an Inflammatory Arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with Inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for Inflammatory Arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
Jarushka Naidoo - One of the best experts on this subject based on the ideXlab platform.
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Inflammatory Arthritis a newly recognized adverse event of immune checkpoint blockade
Oncologist, 2017Co-Authors: Jarushka Naidoo, Laura C Cappelli, Patrick M Forde, Kristen A Marrone, Evan J Lipson, Hans J Hammers, William H Sharfman, Alan N Baer, Ami A Shah, Jemima AlbaydaAbstract:This commentary summarizes current knowledge on the clinical presentation, management, and outcomes of the Inflammatory Arthritis which may occur as an immune‐related adverse evet of immune checkpoint inhibitor therapy. Herein, we propose a new algorithm aimed at assisting oncologists in the diagnosis and management of this immune‐related adverse event.
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Inflammatory Arthritis and sicca syndrome induced by nivolumab and ipilimumab
Annals of the Rheumatic Diseases, 2017Co-Authors: Laura C Cappelli, Evan J Lipson, Alan N Baer, Ami A Shah, Jemima Albayda, Anna Kristina Gutierrez, Rebecca L Manno, Uzma Haque, Karen B Bleich, Jarushka NaidooAbstract:Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with Inflammatory Arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an Inflammatory Arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with Inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for Inflammatory Arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.