Treatment: Immunomodulatory Drugs

2018 ◽  
pp. 109-112
Author(s):  
Kazushige Uchida ◽  
Kazuichi Okazaki
Keyword(s):  
Immunomodulatory Drugs

Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs

2019 ◽  
Vol 19 (1) ◽  
pp. 51-78 ◽  
Author(s):  
Ota Fuchs
Keyword(s):  
Clinical Trials ◽  
Transcription Factors ◽  
Ubiquitin Ligase ◽  
Mononuclear Cells ◽  
E3 Ubiquitin Ligase ◽  
Lymphocytic Leukemia ◽  
Monocarboxylate Transporter ◽  
Immunomodulatory Drugs ◽  
Monocarboxylate Transporter 1 ◽  
Argonaute 2

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

scholarly journals JC Virus Seroprevalence and JCVAb Index in Polish Multiple Sclerosis Patients Treated with Immunomodulating or Immunosuppressive Therapies

2021 ◽  
Vol 10 (9) ◽  
pp. 1998
Author(s):  
Robert Bonek ◽  
Wojciech Guenter ◽  
Robert Jałowiński ◽  
Anna Karbicka ◽  
Anna Litwin ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Jc Virus ◽  
Dimethyl Fumarate ◽  
Risk Category ◽  
Seroprevalence Rate ◽  
Immunomodulatory Drugs ◽  
Cross Sectional ◽  
Treatment Type ◽  
Multiple Sclerosis Patients ◽  
The Impact

The use of a highly-effective treatment for multiple sclerosis (MS) is associated with a severe risk of developing complications, such as progressive multifocal leukoencephalopathy (PML) caused by the John Cunningham virus (JCV). The aim of this study was to evaluate the correlation between anti-JCV Ab seroprevalence, anti-JCV AI, demographic and clinical factors as well as the type of therapy used in the Polish MS population. This is a multicentre, prospective and cross-sectional study involving 1405 MS patients. The seroprevalence of anti-JCV Ab and anti-JCV AI levels as well as AI categories were analysed with the use of a second-generation two-step ELISA test (STRATIFY JCV DxSelect). The overall prevalence of anti-JCV Ab was 65.8%. It was shown that seroprevalence increases with the patient’s age. The seroprevalence was significantly associated with the treatment type, and the highest values (76%) were obtained from immunosuppressant-treated patients. Overall, 63.3% of seropositive patients had an antibody index (AI) level of >1.5. In the seropositive patient group, the mean AI level amounted to 2.09. Similarly to the seroprevalence, AI levels correlated with the patient’s age; AI level for patients above 40 years old and from subsequent age quintiles plateaued, amounting to at least 1.55. Patients treated with immunosuppressants and immunomodulatory drugs obtained the highest (1.67) and lowest (1.35) AI levels, respectively. Of the immunosuppressants used, the highest mean AI levels were observed in mitoxantrone and cladribine groups, amounting to 1.75 and 1.69, respectively. In patients treated with immunomodulatory drugs, the lowest AI levels were observed in the dimethyl fumarate (DMF) group (1.11). The seroprevalence rate in the Polish MS population is one of the highest in Europe. The majority of seropositive patients had an anti-JCV Ab level qualifying them for a high-risk category. The highest mean AI levels are observed in patients receiving immunosuppressants, especially mitoxantrone and cladribine. Patients receiving immunomodulatory drugs have lower AI levels compared to treatment-naïve subjects, especially when treated with DMF. Further studies, especially longitudinal studies, are required to determine the impact of MS drugs on the seroprevalence of anti-JCV Ab and AI levels.

scholarly journals The Rheumatology Drugs for COVID-19 Management: Which and When?

2021 ◽  
Vol 10 (4) ◽  
pp. 783
Author(s):  
Fabiola Atzeni ◽  
Ignazio Francesco Masala ◽  
Javier Rodríguez-Carrio ◽  
Roberto Ríos-Garcés ◽  
Elisabetta Gerratana ◽  
...  
Keyword(s):  
English Language ◽  
Multidisciplinary Approach ◽  
Intravenous Immunoglobulins ◽  
Cochrane Library ◽  
Immunomodulatory Drugs ◽  
Antiviral Therapies ◽  
Tnf Α ◽  
Large Heterogeneity ◽  
Necrosis Factor ◽  
Game Changer

Introduction: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. ‘Repurposing’ immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

Pomalidomide experience: an effective therapeutic approach with immunomodulatory drugs in a patient with relapsed-refractory multiple myeloma

2017 ◽  
Vol 13 (5s) ◽  
pp. 3-6 ◽  
Author(s):  
Concetta Conticello ◽  
Marina Parisi ◽  
Alessandra Romano ◽  
Valeria Calafiore ◽  
Flavia Ancora ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Therapeutic Approach ◽  
Immunomodulatory Drugs ◽  
Refractory Multiple Myeloma

scholarly journals Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 436
Author(s):  
Ali A. Rabaan ◽  
Shamsah H. Al-Ahmed ◽  
Javed Muhammad ◽  
Amjad Khan ◽  
Anupam A Sule ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Therapeutic Drug ◽  
Molecular Pathways ◽  
Cytokine Storm ◽  
Immunomodulatory Drugs ◽  
Alveolar Cells ◽  
Systemic Complications ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

Influence of immunomodulatory drugs on the gut microbiota

2021 ◽  
Author(s):  
Inessa Cohen ◽  
William E. Ruff ◽  
Erin E. Longbrake
Keyword(s):  
Gut Microbiota ◽  
Immunomodulatory Drugs

scholarly journals Immunomodulatory drugs for psoriasis

BMJ ◽  
2003 ◽  
Vol 327 (7416) ◽  
pp. 634-635 ◽  
Author(s):  
W.-H. Boehncke
Keyword(s):  
Immunomodulatory Drugs

scholarly journals ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment

2021 ◽  
Vol 7 (23) ◽  
pp. eabg2697
Author(s):  
Jiye Liu ◽  
Teru Hideshima ◽  
Lijie Xing ◽  
Su Wang ◽  
Wenrong Zhou ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Bone Marrow ◽  
Nuclear Factor Κb ◽  
Mek Inhibitor ◽  
Erk Signaling ◽  
Immunomodulatory Drugs ◽  
Pathway Activation ◽  
Extracellular Signal

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal–regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

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