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Eldew H, Soldera J. Evaluation of biological therapies in autoimmune hepatitis: A case-based systematic review. World J Gastrointest Pathophysiol 2025; 16:101481. [PMID: 40123748 PMCID: PMC11923927 DOI: 10.4291/wjgp.v16.i1.101481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is typically treated with immunomodulators and steroids. However, some patients are refractory to these treatments, necessitating alternative approaches. Biological therapies have recently been explored for these difficult cases. AIM To assess the efficacy and safety of biologics in AIH, focusing on patients unresponsive to standard treatments and evaluating outcomes such as serological markers and histological remission. METHODS A case-based systematic review was performed following the PRISMA protocol to evaluate the efficacy and safety of biological therapies in AIH. The primary focus was on serological improvement and histological remission. The secondary focus was on assessing therapy safety and additional outcomes. A standardized search command was applied to MEDLINE, EMBASE, and Cochrane Library databases to identify relevant studies. Inclusion criteria encompassed adult AIH patients treated with biologics. Data were analyzed based on demographics, prior treatments, and therapy-related outcomes. A narrative synthesis was employed to address biases and provide a comprehensive overview of the evidence. RESULTS A total of 352 studies were reviewed, with 30 selected for detailed analysis. Key findings revealed that Belimumab led to a favourable response in five out of eight AIH patients across two studies. Rituximab demonstrated high efficacy, with 41 out of 45 patients showing significant improvement across six studies. Basiliximab was assessed in a single study, where the sole patient treated experienced a beneficial outcome. Additionally, a notable number of AIH cases were induced by anti-tumor necrosis factor (TNF) medications, including 16 cases associated with infliximab and four cases with adalimumab. All these cases showed improvement upon withdrawal of the biologic agent. CONCLUSION Belimumab and Rituximab show promise as effective alternatives for managing refractory AIH, demonstrating significant improvements in clinical outcomes and liver function. However, the variability in patient responses to different therapies highlights the need for personalized treatment strategies. The risk of AIH induced by anti-TNF therapies underscores the need for vigilant monitoring and prompt symptom recognition. These findings support the incorporation of biologic agents into AIH treatment protocols, particularly for patients who do not respond to conventional therapies.
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Affiliation(s)
- Haifa Eldew
- Consultant in Acute Internal Medicine with Specialist Interest in Hepatology, Princess Royal University Hospital, Kings College Hospital Foundation Trust, Orpington Kent BR6 8ND, United Kingdom
| | - Jonathan Soldera
- Acute Medicine and Gastroenterology, University of South Wales, Cardiff CF37 1DL, United Kingdom
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Kao S, Liu X, Jin J, Zhang L, Shen T, Wu J, Qin Y, Zhou X, Zhao X, Wang L, He Q, Huang B. Development of a time-resolved fluoroimmunoassay for rituximab and its application to therapeutic drug monitoring. Clin Chim Acta 2025; 568:120142. [PMID: 39842652 DOI: 10.1016/j.cca.2025.120142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/26/2024] [Accepted: 01/13/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND Rituximab pharmacokinetics in patients with membranous nephropathy (MN) exhibit significant interindividual variability. Accurate measurement of serum rituximab concentrations is essential for effective therapeutic monitoring. This study develops a highly sensitive time-resolved fluoroimmunoassay (TRFIA) for rituximab (rituximab-TRFIA) with a wide detection range, aimed at enhancing therapeutic drug monitoring in MN treatment. METHODS A capture -type rituximab-TRFIA was developed using streptavidin-coated microplates, biotinylated anti-rituximab idiotypic antibodies, and Eu3+-labeled mouse anti-human IgG targeting the Fc fragment of rituximab. The assay was used to measure rituximab serum concentrations in MN patients treated with rituximab. RESULTS The linear range of rituximab-TRFIA is 0.50 to 2500 ng/mL, with a limit of detection (LOD) of 0.062 ng/mL. The intra-assay coefficient of variation (CV) ranges from 1.97 % to 9.50 %, while the inter-assay CV ranges from 7.44 % to 9.99 %. The recovery rate ranges from 99.14 % to 107.75 %. No cross-reactivity was observed with other monoclonal antibody drugs (mAbs). The detection range is two orders of magnitude higher, and the sensitivity is six times greater than that of the enzyme-linked immunosorbent assay (ELISA). Rituximab-TRFIA showed strong consistency within the same measurement range compared to ELISA (P < 0.0001). The serum rituximab levels in MN patients were significantly higher than those in the control group (P < 0.0001). Among patients who did not achieve remission, 60 % to 70 % had insufficient drug concentrations, and rituximab pharmacokinetics followed the expected trends. CONCLUSIONS The rituximab-TRFIA provides high sensitivity, a wide detection range, and reliable performance for monitoring serum rituximab concentrations in MN patients, supporting personalized treatment strategies.
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Affiliation(s)
- Shangbin Kao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Xiaobin Liu
- Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
| | - Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, 310006, China.
| | - Lin Zhang
- Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China.
| | - Ting Shen
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Jialong Wu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Yuan Qin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Xiumei Zhou
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Xueqin Zhao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
| | - Liang Wang
- Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, 310006, China.
| | - Biao Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China.
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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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Kulbay M, Tanya SM, Tuli N, Dahoud J, Dahoud A, Alsaleh F, Arthurs B, El-Hadad C. A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches. Int J Mol Sci 2024; 25:11628. [PMID: 39519180 PMCID: PMC11546489 DOI: 10.3390/ijms252111628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/21/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence).
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Affiliation(s)
- Merve Kulbay
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
| | - Stuti M. Tanya
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
| | - Nicolas Tuli
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada;
| | - Jade Dahoud
- Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada;
| | - Andrea Dahoud
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
| | - Fares Alsaleh
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
| | - Bryan Arthurs
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
| | - Christian El-Hadad
- Department of Ophthalmology & Visual Sciences, McGill University, Montreal, QC H4A 0A4, Canada; (M.K.); (S.M.T.); (A.D.); (F.A.); (B.A.)
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Costaguta GA, Álvarez F. B cell depletion for autoimmune liver diseases: A retrospective review of indications and outcomes. JPGN REPORTS 2024; 5:326-333. [PMID: 39149184 PMCID: PMC11322033 DOI: 10.1002/jpr3.12098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 04/08/2024] [Accepted: 05/19/2024] [Indexed: 08/17/2024]
Abstract
Objectives Pediatric autoimmune hepatitis has an incidence of 0.23/100.000 children in North America, with a bleak prognosis if left untreated. Steroids are the therapy of choice but are not always effective. B cell depletion is a safe and effective therapy that allows for a steroid-sparing protocol, especially in patients who do not tolerate side effects. Methods We retrospectively reviewed rituximab-treated patients between 2017 and 2022. Demographics, previous treatments, reasons for B cell depletion, response, and adverse effects were noted. Results Six patients with a mean age of 10.2 years were included. All patients had comorbidities that rendered treatment with steroids unsuccessful or undesirable. Rituximab was started at a mean follow-up of 8 months. After 6 months, the mean alanine transaminase and aspartate transaminase levels decreased from 575 IU/L and 342 IU/L, respectively, to 28 IU/L (p = 0.02) and 36 IU/L (p = 0.008), respectively. Mean γ-glutamyl transpeptidase decreased from 105 to 25 IU/L (p = 0.01). Immunoglobulin G levels were normalized in all patients (p = 0.01). No severe adverse events were observed. One patient had persistent hypogammaglobulinemia, and another had lymphopenia. Conclusion B-cell depletion is an effective and safe treatment for autoimmune liver diseases and should be included as an option, particularly for relapsing patients in whom steroids are undesirable or have shown nonadherence.
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Affiliation(s)
| | - Fernando Álvarez
- Gastroenterology, Hepatology and NutritionCHU Sainte‐JustineMontrealQuebecCanada
- Department of PediatricsUniversity of MontrealMontrealQuebecCanada
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Gheisari M, Safari Giv T, Pourgholi E, Zaresharifi S. Rituximab-induced serum sickness in immunobullous disorders: A case series. Clin Case Rep 2024; 12:e9152. [PMID: 38979086 PMCID: PMC11228350 DOI: 10.1002/ccr3.9152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/11/2024] [Accepted: 06/20/2024] [Indexed: 07/10/2024] Open
Abstract
Key Clinical Message Rituximab-induced serum sickness (RISS) is a rare complication of Rituximab (RTX) in immunobullous disorders. Clinicians should be aware of the occurrence of serum sickness symptoms during RTX administration, and prompt initiation of corticosteroid therapy is crucial in these patients. Additionally, RISS may occur with subsequent RTX doses and patients should be counseled accordingly. Abstract Rituximab (RTX) is a chimeric monoclonal anti-CD20 antibody which has gained approval for the treatment of various autoimmune and lymphoproliferative disorders. While RTX-induced minor reactions, including immediate infusion-related reactions, are common, serum sickness is rare. Limited data exist regarding rituximab-induced serum sickness (RISS) in pemphigus vulgaris (PV) and mucous membrane pemphigoid (MMP). We report two cases of RISS following RTX administration in PV and MMP patients. Both patients presented with typical symptoms of serum sickness after RTX infusion, necessitating drug cessation and corticosteroid therapy for resolution. RISS represents a rare complication of RTX therapy. Clinicians should maintain awareness of serum sickness presentations during and post-RTX administration.
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Affiliation(s)
- Mehdi Gheisari
- Skin Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Dermatology, Loghman‐Hakim Hospital, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Toktam Safari Giv
- Skin Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Dermatology, Loghman‐Hakim Hospital, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Elnaz Pourgholi
- Skin Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Dermatology, Loghman‐Hakim Hospital, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Shirin Zaresharifi
- Skin Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Dermatology, Loghman‐Hakim Hospital, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
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Hamzavi SS, Bahrololoom R, Saeb S, Marandi NH, Hosseini M, Hesam Abadi AK, Jamalidoust M. Humoral immune response and safety of Sars-Cov-2 vaccine in people with multiple sclerosis. BMC Immunol 2024; 25:35. [PMID: 38898409 PMCID: PMC11186195 DOI: 10.1186/s12865-024-00628-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/07/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND For the past three years, the pandemic has had a major effect on global public health, mainly on those with underlying medical conditions, such as people living with Multiple Sclerosis. Vaccination among this group is of great importance, and the long-term impacts of vaccination and its safety on the health of these patients will continue to be revealed. Therefore, risks related to vaccination and immune response need to be assessed. The objective here was to characterize the immune response, short-term safety, and the effects of multiple variables on these factors after COVID-19 vaccination (mainly Sinopharm) among people with Multiple Sclerosis. We assessed the short-term safety and humoral SARS-COV-2 anti-RBD IgG response using a data collection form and Immunoassay, respectively. RESULTS No severe adverse events or MS relapse was observed. Myalgia/body pain (26.7%), low-grade fever (22.2%), and mild headache (15.6%) were the most common adverse events. The use and type of vaccine influenced the frequency of side effects with a p-value < 0.0001. Regarding immune response, patients on rituximab and fingolimod had a lower antibody titer compared to other medications. With a significant difference, hybrid immunity (p-value: 0.047) and type of DMTs (p-value: 0.017) affected the humoral response. CONCLUSION There is a low incidence of serious adverse effects, MS worsening or relapse after COVID-19 vaccination, and mainly, side effects are similar to that of the general population. It appears that treatment with various disease-modifying therapies does not induce or worsen the post-vaccination side effects, although some, including Rituximab and fingolimod, may affect the immunity induced after vaccination.
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Affiliation(s)
- Seyedeh Sadigheh Hamzavi
- Department of Pediatrics, Namazi Teaching Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
- Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, 71936-13311, Iran
| | - Rosemina Bahrololoom
- Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, 71936-13311, Iran.
| | - Sepideh Saeb
- Department of Virology, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Nahid Heydari Marandi
- Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, 71936-13311, Iran
| | - Marzieh Hosseini
- Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, 71936-13311, Iran
| | | | - Marzieh Jamalidoust
- Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, 71936-13311, Iran.
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Moledina M, Damato EM, Lee V. The changing landscape of thyroid eye disease: current clinical advances and future outlook. Eye (Lond) 2024; 38:1425-1437. [PMID: 38374366 PMCID: PMC11126416 DOI: 10.1038/s41433-024-02967-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 01/07/2024] [Accepted: 01/26/2024] [Indexed: 02/21/2024] Open
Abstract
AIMS This review aims to provide an overview of the current understanding of TED and its pathophysiology. To describe the evidence base for current consensus treatment recommendations and newer biological therapies available as well as to present future therapeutic research. METHODS We reviewed and assessed the peer-reviewed literature placing particular emphasis on recent studies evaluating the pathophysiology of TED, landmark trials forming the basis of current management and recent clinical trials informing future therapeutics. Searched were made in MEDLINE Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register and EU Clinical Trials Register. Keywords included: "Thyroid Eye Disease", "Graves Orbitopathy", "Thyroid Orbitopathy" and "Graves' Ophthalmopathy". RESULTS AND CONCLUSIONS The pathophysiology of TED involves a complex array of cellular and humoral based autoimmune dysfunction. Previous therapies have been broad-based acting as a blunt instrument on this mechanism with varying efficacy but often accompanied with a significant side effect profile. The recent development of targeted therapy, spearheaded by Teprotumumab has led to an array of treatments focusing on specific components of the molecular pathway optimising their impact whilst possibly minimising their side effect profile. Future challenges involve identifying the most effective target for each patient rather than any single agent being a panacea. Long-term safety profiles will require clarification as unintended immunological consequence downstream may become manifest as seen in other diseases. Finally, future novel therapeutics will entail significant expenditure and may lead to a divergence of available treatment modalities between healthcare systems due to funding disparities.
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Affiliation(s)
- Malik Moledina
- Oculoplastics Service, Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Erika M Damato
- Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Vickie Lee
- Oculoplastics Service, Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK.
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Nilforoushzadeh MA, Heidari N, Heidari A, Ghane Y, Lotfi Z, Jaffary F, Najar Nobari M, Najar Nobari N. The role of BAFF and BAFF-R inhibitors in the treatment of immune thrombocytopenia; a focused review. Int Immunopharmacol 2024; 131:111827. [PMID: 38460303 DOI: 10.1016/j.intimp.2024.111827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune-driven disease characterized by increased destruction and impaired platelet production resulting in an enhanced risk of bleeding. Immunosuppressant agents are the most common treatment strategies for ITP. Despite their efficacy, these medications often cause unpredictable side effects. Recent investigations revealed that patients with ITP exhibit elevated B-cell activating factor (BAFF) levels in both their spleens and serum. Belimumab, a BAFF inhibitor, illustrated a promising therapeutic avenue for managing ITP by interfering with BAFF activity and long-lived plasma cell production. Both clinical and experimental studies have yielded positive outcomes when combining rituximab with an anti-BAFF monoclonal antibody in treating ITP. In addition, ianalumab, a monoclonal antibody with a dual mechanism that targets BAFF-R and deletes peripheral BAFF-R+ B cells, is currently being used for ITP treatment [NCT05885555]. The upcoming results from novel BAFF inhibitors, such as ianalumab, could offer clinicians an additional therapeutic option for treating ITP.
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Affiliation(s)
- Mohammad Ali Nilforoushzadeh
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Nazila Heidari
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Amirhossein Heidari
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Yekta Ghane
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zahra Lotfi
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Fariba Jaffary
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Minou Najar Nobari
- Department of Orofacial Pain and Dysfunction, UCLA School of Dentistry, Los Angeles, CA, USA.
| | - Niloufar Najar Nobari
- Skin Repair Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Thatte AS, Billingsley MM, Weissman D, Melamed JR, Mitchell MJ. Emerging strategies for nanomedicine in autoimmunity. Adv Drug Deliv Rev 2024; 207:115194. [PMID: 38342243 PMCID: PMC11015430 DOI: 10.1016/j.addr.2024.115194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune disorders have risen to be among the most prevalent chronic diseases across the globe, affecting approximately 5-7% of the population. As autoimmune diseases steadily rise in prevalence, so do the number of potential therapeutic strategies to combat them. In recent years, fundamental research investigating autoimmune pathologies has led to the emergence of several cellular targets that provide new therapeutic opportunities. However, key challenges persist in terms of accessing and specifically combating the dysregulated, self-reactive cells while avoiding systemic immune suppression and other off-target effects. Fortunately, the continued advancement of nanomedicines may provide strategies to address these challenges and bring innovative autoimmunity therapies to the clinic. Through precise engineering and rational design, nanomedicines can possess a variety of physicochemical properties, surface modifications, and cargoes, allowing for specific targeting of therapeutics to pathological cell and organ types. These advances in nanomedicine have been demonstrated in cancer therapies and have the broad potential to advance applications in autoimmunity therapies as well. In this review, we focus on leveraging the power of nanomedicine for prevalent autoimmune disorders throughout the body. We expand on three key areas for the development of autoimmunity therapies - avoiding systemic immunosuppression, balancing interactions with the immune system, and elevating current platforms for delivering complex cargoes - and emphasize how nanomedicine-based strategies can overcome these barriers and enable the development of next-generation, clinically relevant autoimmunity therapies.
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Affiliation(s)
- Ajay S Thatte
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Drew Weissman
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jilian R Melamed
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Malakar S, Gontor EN, Dugbaye MY, Shah K, Sinha S, Sutaoney P, Chauhan NS. Cancer treatment with biosimilar drugs: A review. CANCER INNOVATION 2024; 3:e115. [PMID: 38946928 PMCID: PMC11212292 DOI: 10.1002/cai2.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/04/2023] [Accepted: 12/11/2023] [Indexed: 07/02/2024]
Abstract
Biosimilars are biological drugs created from living organisms or that contain living components. They share an identical amino-acid sequence and immunogenicity. These drugs are considered to be cost-effective and are utilized in the treatment of cancer and other endocrine disorders. The primary aim of biosimilars is to predict biosimilarity, efficacy, and treatment costs; they are approved by the Food and Drug Administration (FDA) and have no clinical implications. They involve analytical studies to understand the similarities and dissimilarities. A biosimilar manufacturer sets up FDA-approved reference products to evaluate biosimilarity. The contribution of next-generation sequencing is evolving to study the organ tumor and its progression with its impactful therapeutic approach on cancer patients to showcase and target rare mutations. The study shall help to understand the future perspectives of biosimilars for use in gastro-entero-logic diseases, colorectal cancer, and thyroid cancer. They also help target specific organs with essential mutational categories and drug prototypes in clinical practices with blood and liquid biopsy, cell treatment, gene therapy, recombinant therapeutic proteins, and personalized medications. Biosimilar derivatives such as monoclonal antibodies like trastuzumab and rituximab are common drugs used in cancer therapy. Escherichia coli produces more than six antibodies or antibody-derived proteins to treat cancer such as filgrastim, epoetin alfa, and so on.
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Affiliation(s)
- Shilpa Malakar
- Department of MicrobiologyKalinga UniversityRaipurChhattisgarhIndia
| | | | - Moses Y. Dugbaye
- Department of MicrobiologyKalinga UniversityRaipurChhattisgarhIndia
| | - Kamal Shah
- Institute of Pharmaceutical ResearchGLA UniversityMathuraUttar PradeshIndia
| | - Sakshi Sinha
- Department of MicrobiologyKalinga UniversityRaipurChhattisgarhIndia
| | - Priya Sutaoney
- Department of MicrobiologyKalinga UniversityRaipurChhattisgarhIndia
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12
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Mostkowska A, Rousseau G, Raynal NJM. Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases. FASEB J 2024; 38:e23536. [PMID: 38470360 DOI: 10.1096/fj.202302259rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/13/2024]
Abstract
Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases.
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Affiliation(s)
- Agata Mostkowska
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Guy Rousseau
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Noël J-M Raynal
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
- Centre de recherche du CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
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13
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Oakman G, Bach CA, Ong C. Incidence of anti-neutrophil cytoplasmic antibody-associated renal vasculitis: a retrospective study in rural and regional Victoria, Australia. Intern Med J 2024; 54:461-466. [PMID: 37183767 DOI: 10.1111/imj.16127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/11/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND The epidemiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) varies worldwide. Previous Australian studies described a higher incidence of AAV in rural areas; however, this has not yet been investigated in Victoria. AIMS To calculate the incidence of AAV in rural and regional Victoria and characterise the demographics and clinical outcomes of this cohort. METHODS We performed a retrospective review of patients with newly diagnosed AAV confirmed on renal biopsy at Bendigo Health between 2013 and 2021. Cases were classified according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria. Local disease incidence was calculated using Estimated Resident Population data for our catchment, the Loddon Mallee region. RESULTS Twenty-eight cases of new AAV were identified; 17 were classified as microscopic polyangiitis (MPA) and the remainder as granulomatosis with polyangiitis (GPA). The median age at diagnosis was 68 years (interquartile range (IQR): 59-77). The incidence per million person-years was 9.3 for AAV overall (95% CI: 6.2-13.5), 5.7 for MPA (95% CI: 3.3-9.1) and 3.7 for GPA (95% CI: 1.8-6.6). With a median follow-up time of 3.3 years (IQR: 1.9-5.6), one-quarter of patients relapsed (n = 7, 25%), and six required ongoing renal-replacement therapy (21%). CONCLUSIONS The calculated incidence of AAV in rural and regional Victoria is not higher than the reported incidence in most urban Australian cohorts. This study may underestimate the true local disease incidence as only patients with renal vasculitis were included.
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Affiliation(s)
- Georgina Oakman
- Department of Renal Medicine, Bendigo Health, Victoria, Bendigo, Australia
- Department of Medicine, Austin Health, Victoria, Heidelberg, Australia
| | - Cindy-Anne Bach
- Department of Renal Medicine, Bendigo Health, Victoria, Bendigo, Australia
- Department of Medicine, Austin Health, Victoria, Heidelberg, Australia
| | - Cindy Ong
- Department of Renal Medicine, Bendigo Health, Victoria, Bendigo, Australia
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14
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Atschekzei F, Fedchenko M, Elsayed A, Dubrowinskaja N, Graalmann T, Ringshausen FC, Witte T, Sogkas G. Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD. RMD Open 2023; 9:e003507. [PMID: 38088248 PMCID: PMC10711922 DOI: 10.1136/rmdopen-2023-003507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023] Open
Abstract
Prolidase deficiency (PD) is a rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD, the gene that encodes prolidase. PD typically manifests with variable dysmorphic features, chronic cutaneous ulcers, recurrent infections and autoimmune features, including systemic lupus erythematosus. So far, there is no consensus regarding treatment of PD and its autoimmune manifestations. Here, we present a 28-year-old female patient with PD due to a novel homozygous intragenic deletion in PEPD, diagnosed at the age of 6 years and 7 months with an undifferentiated connective tissue disease that, apart from its very early onset, would be consistent with the diagnosis of Sjögren's syndrome. Steroids and diverse conventional synthetic disease-modifying antirheumatic drugs failed to control PD-associated vasculitis and mucocutaneous ulcerations and led to infectious complications, including cytomegalovirus colitis. Introduction of rituximab (RTX) treatment in this patient led to sustained recession of mucocutaneous ulceration, enabling tapering of steroids. High interleukin-1β (IL-1β) production by this patient's monocytes, together with the detection of both IL-1β and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD, whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD.
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Affiliation(s)
- Faranaz Atschekzei
- Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Mykola Fedchenko
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Abdulwahab Elsayed
- Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | | | - Theresa Graalmann
- Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Junior Research Group for Translational Immunology, TWINCORE, Center for Infection Research and the Hannover Medical School, Hannover, Germany
- Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Felix C Ringshausen
- Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
- Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
- European Reference Network on Rare and Complex Respiratory Diseases (ERN-LUNG), Frankfurt, Germany
| | - Torsten Witte
- Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Georgios Sogkas
- Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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15
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Vesperinas-Castro A, Cortés-Vicente E. Rituximab treatment in myasthenia gravis. Front Neurol 2023; 14:1275533. [PMID: 37849836 PMCID: PMC10577386 DOI: 10.3389/fneur.2023.1275533] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
Myasthenia gravis (MG) is a chronic autoimmune disease mediated by antibodies against post-synaptic proteins of the neuromuscular junction. Up to 10%-30% of patients are refractory to conventional treatments. For these patients, rituximab has been used off-label in the recent decades. Rituximab is a monoclonal antibody against the CD20 protein that leads to B cell depletion and to the synthesis of new antibody-secreting plasma cells. Although rituximab was created to treat B-cell lymphoma, its use has widely increased to treat autoimmune diseases. In MG, the benefit of rituximab treatment in MuSK-positive patients seems clear, but a high variability in the results of observational studies and even clinical trials has been reported for AChR-positive patients. Moreover, few evidence has been reported in seronegative MG and juvenile MG and some questions about regimen of administration or monitoring strategies, remains open. In this review, we intend to revise the available literature on this topic and resume the current evidence of effectiveness of Rituximab in MG, with special attention to results on every MG subtype, as well as the administration protocols, monitoring strategies and safety profile of the drug.
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Affiliation(s)
- Ana Vesperinas-Castro
- Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Cortés-Vicente
- Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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16
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Bader A, Begemann M, Al-Obaidi A, Habib MH, Anwer F, Raza S. Ocular complications of antineoplastic therapies. Future Sci OA 2023; 9:FSO871. [PMID: 37485446 PMCID: PMC10357395 DOI: 10.2144/fsoa-2022-0081] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/15/2023] [Indexed: 07/25/2023] Open
Abstract
Ocular complications of antineoplastic agents can have a profound effect on the quality of life of cancer patients. New oncologic treatments like monoclonal antibodies, immunotherapies, antibody-drug conjugates, checkpoint inhibitors and growth factor receptors have resulted in increased ocular complications. These ocular complications differs in respect to distinct mechanisms of actions and lead to significant challenges in the management of cancer patients. In this review, we reviewed literature, clinical studies and cases detailing ocular complications due to administration of antineoplastic agents and emphasized the need for communication between oncologists and ophthalmologists toward early detection and management of ocular complications.
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Affiliation(s)
- Abbas Bader
- University of Missouri Kansas City School of Medicine, 5000 Holmes St, Kansas City, MO 64110, USA
| | - Madeline Begemann
- Saint Luke's Hospital of Kansas City, 4401 Wornall Rd, Kansas City, MO 64111, USA
| | - Ammar Al-Obaidi
- Saint Luke's Hospital of Kansas City, 4401 Wornall Rd, Kansas City, MO 64111, USA
| | - Muhammad Hamza Habib
- Rutgers Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901, USA
| | - Faiz Anwer
- Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Shahzad Raza
- Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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17
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Xiao Z, Murakhovskaya I. Rituximab resistance in ITP and beyond. Front Immunol 2023; 14:1215216. [PMID: 37575230 PMCID: PMC10422042 DOI: 10.3389/fimmu.2023.1215216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
The pathophysiology of immune thrombocytopenia (ITP) is complex and encompasses innate and adaptive immune responses, as well as megakaryocyte dysfunction. Rituximab is administered in relapsed cases and has the added benefit of inducing treatment-free remission in over 50% of patients. Nevertheless, the responses to this therapy are not long-lasting, and resistance development is frequent. B cells, T cells, and plasma cells play a role in developing resistance. To overcome this resistance, targeting these pathways through splenectomy and novel therapies that target FcγR pathway, FcRn, complement, B cells, plasma cells, and T cells can be useful. This review will summarize the pathogenetic mechanisms implicated in rituximab resistance and examine the potential therapeutic interventions to overcome it. This review will explore the efficacy of established therapies, as well as novel therapeutic approaches and agents currently in development.
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Affiliation(s)
| | - Irina Murakhovskaya
- Division of Hematology, Department of Hematology-Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, New York City, NY, United States
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18
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Apivatthakakul A, Liu R, Sobrin L. Successful treatment of idiopathic retinal vasculitis with rituximab in two patients. Am J Ophthalmol Case Rep 2023; 30:101844. [PMID: 37124152 PMCID: PMC10133649 DOI: 10.1016/j.ajoc.2023.101844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/23/2023] [Accepted: 04/08/2023] [Indexed: 05/02/2023] Open
Abstract
Purpose To describe results of treatment of idiopathic retinal vasculitis with intravenous rituximab. Observations We present two patients with idiopathic retinal vasculitis who required steroid-sparing therapy and achieved steroid-free remission with intravenous rituximab. Rituximab was used as a first-line steroid-sparing agent after steroids in one patient and as a second-line steroid-sparing agent in the other patient. Both patients achieved steroid-free remission of disease with follow up of at least one year after rituximab initiation. Conclusions and importance Rituximab achieved steroid-free remission in two patients with idiopathic retinal vasculitis. It should be considered as a treatment option in these patients.
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Affiliation(s)
- Atitaya Apivatthakakul
- Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology, Faculty of Medicine, Chiangmai University, Chiangmai, Thailand
| | - Renee Liu
- Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Lucia Sobrin
- Department of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
- Corresponding author.
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19
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Brzezicka KA, Paulson JC. Impact of Siglecs on autoimmune diseases. Mol Aspects Med 2023; 90:101140. [PMID: 36055802 PMCID: PMC9905255 DOI: 10.1016/j.mam.2022.101140] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/19/2022] [Accepted: 08/21/2022] [Indexed: 02/08/2023]
Abstract
Autoimmune diseases affect tens of millions of people just in the United States alone. Most of the available treatment options are aimed at reducing symptoms but do not lead to cures. Individuals affected with autoimmune diseases suffer from the imbalance between tolerogenic and immunogenic functions of their immune system. Often pathogenesis is mediated by autoreactive B and T cells that escape central tolerance and react against self-antigens attacking healthy tissues in the body. In recent years Siglecs, sialic-acid-binding immunoglobulin (Ig)-like lectins, have gained attention as immune checkpoints for therapeutic interventions to dampen excessive immune responses and to restore immune tolerance in autoimmune diseases. Many Siglecs function as inhibitory receptors suppressing activation signals in various immune cells through binding to sialic acid ligands as signatures of self. In this review, we highlight potential of Siglecs in suppressing immune responses causing autoimmune diseases. In particular, we cover the roles of CD22 and Siglec-G/Siglec-10 in regulating autoreactive B cell responses. We discuss several functions of Siglec-10 in the immune modulation of other immune cells, and the potential of therapeutic strategies for restoring immune tolerance by targeting Siglecs and expanding regulatory T cells. Finally, we briefly review efforts evaluating Siglec-based biomarkers to monitor autoimmune diseases.
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Affiliation(s)
- Katarzyna Alicja Brzezicka
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - James C Paulson
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
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20
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Carnero Contentti E, López PA, Pettinicchi JP, Tkachuk V, Daccach Marques V, de Castillo IS, Cristiano E, Patrucco L, Caride A, Rojas JI. Neuromyelitis optica spectrum disorders with and without associated autoimmune diseases. Neurol Sci 2023; 44:1731-1737. [PMID: 36645533 DOI: 10.1007/s10072-023-06611-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 01/06/2023] [Indexed: 01/17/2023]
Abstract
OBJECTIVES We aimed to determinate the frequency of this association and compare the features of neuromyelitis optica spectrum disorder (NMOSD) with and without associated autoimmune diseases (AD) in a Latin American (LATAM) population in clinical practice. METHODS We retrospectively reviewed the medical records of patients with NMOSD according to the 2015 diagnostic criteria. Patients from Argentina (n=77), Brazil (n=46), and Venezuela (n=17) were enrolled and classified into two groups as follows: with AD or without AD. Clinical, paraclinical (including aquaporin-4 antibodies (AQP4-ab) status), magnetic resonance imaging (MRI), and prognosis data were analyzed and compared. Kaplan-Meier (KM) and the Nelson-Aalen estimator analyses were performed to estimate both time and the cumulative hazard risk of disability reaching an EDSS≥4; and time for the first recurrence. RESULTS Out of 140 patients, 33 (23.5%) patients had associated an AD at presentation. The most frequent associated AD was Hashimoto disease (n=10) followed by lupus (n=7) and Sjogren's syndrome (n=6). However, rituximab use (42.4% vs. 21.5%, p=0.02), female gender (82.2% vs. 100%, p=0.006), corticospinal lesions on MRI (0% vs. 12.5%, p=0.01) at onset, and positivity for antinuclear antibodies (21.2% vs. 48.4%, p=0.03) were significantly associated with NMOSD patients with AD in comparison to NMOSD patients without AD. No differences were found in other clinical and paraclinical aspects between groups. KM and Nelson-Aalen estimator analyses did not show differences between groups. CONCLUSION NMOSD patients associated with AD were observed in 23.5%. In addition, NMOSD patients with and without associated AD were similar in most evaluated features.
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Affiliation(s)
| | - Pablo A López
- Neuroimmunology Unit, Department of Neuroscience, Hospital Alemán, Buenos Aires, Argentina
| | - Juan Pablo Pettinicchi
- Neuroimmunology Unit, Department of Neuroscience, Hospital Alemán, Buenos Aires, Argentina
| | - Verónica Tkachuk
- Seccion de Neuroinmunologia y Enfermedades Desmielinizantes, Servicio de Neurología, Hospital de Clínicas José de San Martin, Buenos Aires, Argentina
| | - Vanessa Daccach Marques
- Department of Neurosciences and Behavioral Sciences, Hospital das Clínicas, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Ibis Soto de Castillo
- Neurology Department, Hospital Universitario de Maracaibo, Maracaibo, Bolivarian Republic of Venezuela
| | - Edgardo Cristiano
- Centro de esclerosis múltiple de Buenos Aires (CEMBA), Buenos Aires, Argentina
| | - Liliana Patrucco
- Centro de esclerosis múltiple de Buenos Aires (CEMBA), Buenos Aires, Argentina
| | - Alejandro Caride
- Neuroimmunology Unit, Department of Neuroscience, Hospital Alemán, Buenos Aires, Argentina
| | - Juan Ignacio Rojas
- Centro de esclerosis múltiple de Buenos Aires (CEMBA), Buenos Aires, Argentina
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Advancing Biologic Therapy for Refractory Autoimmune Hepatitis. Dig Dis Sci 2022; 67:4979-5005. [PMID: 35147819 DOI: 10.1007/s10620-021-07378-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
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22
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Bennett B, Tahir H, Ganguly S, Moorthy A. An update on the considerations for patients with rheumatic disease being treated with rituximab during the COVID-19 pandemic and the potential drug treatment strategies. Expert Opin Pharmacother 2022; 23:1695-1700. [PMID: 36180063 DOI: 10.1080/14656566.2022.2131395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Over the last two decades, rituximab has become an increasingly popular drug in the treatment of a wide range of rheumatic diseases. However, with the advent of the COVID-19 pandemic, clinicians face challenges in weighing risk against benefit in its use. AREAS COVERED A review of existing data was performed to examine the relationship between rituximab use, morbidity and mortality from COVID-19, and vaccine efficacy in patients with rheumatic diseases, aiming to guide clinicians in continued use of the medication and consider the direction of future research. A literature review was performed through a search of the PubMed database, using the terms ((SARS-CoV-2) OR (COVID-19)) AND (rituximab) AND (rheumatic), which generated an initial 55 results, with relevant articles then selected for inclusion. EXPERT OPINION In order to safeguard patients with an ongoing need for rituximab therapy, vaccination remains the primary concern. A target of performing booster doses 6 months after last rituximab dose is a reasonable estimate, which may be made more precise by use of B cell counts, although primary immunization should not be delayed. In those patients who remain seronegative, the use of newer antivirals and broadly neutralizing antibody infusions may help provide further safeguards.
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Affiliation(s)
- Benjamin Bennett
- Department of Rheumatology, Barnet Hospital, Royal Free London NHS Foundation Trust, London, UK
| | - Hasan Tahir
- Department of Rheumatology, Barnet Hospital, Royal Free London NHS Foundation Trust, London, UK.,Division of Medicine, University College London, London, UK
| | - Sujata Ganguly
- University Hospitals of Leicester NHS Foundation Trust, Leicester, UK
| | - Arumugam Moorthy
- University Hospitals of Leicester NHS Foundation Trust, Leicester, UK
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23
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Rizzi L, Sabbà C, Suppressa P. Sarcoidosis and autoimmunity: In the depth of a complex relationship. Front Med (Lausanne) 2022; 9:991394. [PMID: 36148452 PMCID: PMC9485866 DOI: 10.3389/fmed.2022.991394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/01/2022] [Indexed: 11/25/2022] Open
Abstract
Sarcoidosis is a chronic granulomatous disease that can virtually affect any organ. Its etiology is unknown, although it has been proposed that environmental or biological agents can act as triggers, ultimately leading to chronic inflammation in genetically predisposed individuals. The main component of sarcoid inflammation is represented by an exaggerated T- lymphocytic cellular response to a putative antigen that could not be efficiently cleared in the patient. However, several clinical and immunological observations, such as the association of sarcoidosis to autoimmune diseases or the presence of autoantibodies in the serum of patients with sarcoidosis, suggest that humoral-mediated immune response might also play a role in the pathogenesis of sarcoidosis. The aim of this review is to deepen the relationship between sarcoidosis and autoimmunity, by analyzing the most recent advances and proposing new fields of research.
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Hillen JB, Stanford T, Ward M, Roughead EE, Kalisch Ellett L, Pratt N. Rituximab and Pyoderma Gangrenosum: An Investigation of Disproportionality Using a Systems Biology-Informed Approach in the FAERS Database. Drugs Real World Outcomes 2022; 9:639-647. [PMID: 35933497 DOI: 10.1007/s40801-022-00322-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Studies have found an increased risk of pyoderma gangrenosum associated with rituximab. The structural properties and pharmacological action of rituximab may affect the risk of pyoderma gangrenosum. Additionally, pyoderma gangrenosum is associated with autoimmune disorders for which rituximab is indicated. OBJECTIVE We aimed to determine whether rituximab is disproportionally associated with pyoderma gangrenosum using a systems biology-informed approach. METHODS Adverse event reports were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS, 2013-20). The Bayesian Confidence Propagation Neural Network Information Component was used to test for disproportionality. Comparators used to determine potential causal pathways included all other medicines, all medicines with a similar structure (monoclonal antibodies), all medicines with the same pharmacological target (CD20 antagonists) and all medicines used for the same indication(s) as rituximab. RESULTS Thirty-two pyoderma gangrenosum cases were identified, 62.5% were female, with a median age of 48 years. There was an increased association of pyoderma gangrenosum with rituximab compared with all other medicines (exponentiated Information Component 6.75, 95% confidence interval (CI) 4.66-9.23). No association was observed when the comparator was either monoclonal antibodies or CD20 antagonists. Conditions for which an association of pyoderma gangrenosum with rituximab was observed were multiple sclerosis (6.68, 95% CI 1.63-15.15), rheumatoid arthritis (2.67, 95% CI 1.14-4.80) and non-Hodgkin's lymphoma (2.94, 95% CI 1.80-3.73). CONCLUSIONS Pyoderma gangrenosum was reported more frequently with rituximab compared with all other medicines. The varying results when restricting medicines for the same condition suggest the potential for confounding by indication. Post-market surveillance of biologic medicines in FAERS should consider a multi-faceted approach, particularly when the outcome of interest is associated with the underlying immune condition being treated by the medicine of interest.
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Affiliation(s)
- Jodie Belinda Hillen
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia
| | - Ty Stanford
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia
| | - Michael Ward
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia.,Pharmacy Education, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - E E Roughead
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia
| | - Lisa Kalisch Ellett
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia
| | - Nicole Pratt
- Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Playford Building Level 6, Frome Rd, Adelaide, SA, 5000, Australia.
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Kahn C, Singh S, Mathew R, Ramrattan LA, Mohammed IJ, Omman R. Rituximab Used for the Treatment of Nonuremic Calciphylaxis: A Complication of Prolonged Steroid Use in Lupus Nephritis. Cureus 2022; 14:e26516. [PMID: 35795578 PMCID: PMC9250422 DOI: 10.7759/cureus.26516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2022] [Indexed: 11/05/2022] Open
Abstract
Nonuremic calciphylaxis (NUC) is a rare and debilitating form of panniculitis. NUC is associated with a high mortality rate within the first year of diagnosis. Connective tissue diseases account for a small fraction of the reported cases. However, there have also been reported cases of patients developing NUC while on treatment with chronic corticosteroid immunosuppressive therapy. The pathophysiology of NUC is still not fully established. Several risk factors including underlying diseases, obesity, female gender, and medications have been associated with the development of NUC. The diagnosis remains challenging due to the condition's similarities with other forms of panniculitis. The gold standard for diagnosis is a tissue biopsy showing calcifications within the medial layer of arterioles and the presence of microthrombi with surrounding necrosis. The treatment for NUC has not advanced much in recent years and focuses on the management of the underlying condition, wound care, and treating any superimposed infection. Treating superimposed infections remains important as most of the associated mortality from NUC occurs due to sepsis. We describe a case of a young woman with lupus nephritis who developed NUC while on prolonged corticosteroid therapy. She did not respond to several immunosuppressive agents and was ultimately treated with rituximab, a monoclonal antibody against CD20 antigen, as salvage therapy.
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Menon D, Bril V. Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals. Drugs 2022; 82:865-887. [PMID: 35639288 PMCID: PMC9152838 DOI: 10.1007/s40265-022-01726-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 11/20/2022]
Abstract
Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.
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Affiliation(s)
- Deepak Menon
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Vera Bril
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, University Health Network, 5EC-309, Toronto General Hospital, University of Toronto, 200 Elizabeth St, Toronto, M5G 2C4, Canada.
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27
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Tsai YJ, Cho YT, Chu CY. Clinical Effectiveness and Safety of Initial Combination Therapy with Corticosteroids and Rituximab in Bullous Pemphigoid: A Retrospective Cohort Study. Am J Clin Dermatol 2022; 23:571-585. [PMID: 35579853 DOI: 10.1007/s40257-022-00688-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Rituximab is a potential initial adjuvant therapy for bullous pemphigoid, yet clinical experience is scarce. OBJECTIVE We aimed to examine the clinical outcomes and safety of initial combination therapy with systemic corticosteroids and adjuvant rituximab for the treatment of bullous pemphigoid. METHODS A retrospective cohort study was performed on 84 patients with bullous pemphigoid, who received systemic corticosteroids with or without initial adjuvant rituximab therapy (defined as rituximab use within 12 weeks after initiation of systemic corticosteroids). RESULTS Among the 84 patients included (37 received systemic corticosteroids with rituximab and 47 were treated with systemic corticosteroids without rituximab), the median time to complete remission on minimal therapy or off therapy was 215 days (95% confidence interval 176.9-253.1) in patients receiving rituximab vs 529 days (95% confidence interval 338.6-719.4) in those not receiving rituximab. A Cox regression analysis showed an increased probability of reaching complete remission on minimal therapy or off therapy with the combined therapy (hazard ratio = 2.28 [1.28-4.07], p = 0.005) after age, Bullous Pemphigoid Disease Activity Index score, and underlying diseases were controlled. In multivariate logistic/linear regressions, initial adjuvant rituximab therapy was associated with a higher complete remission rate (odds ratio = 6.63 [2.09-21.03]) and lower cumulative prednisolone (mg)/body weight (kg) (B = -24.86 [-44.06 to -8.29]) within 48 weeks. Risk of hospitalization for infection was not elevated in the group treated with adjuvant rituximab. CONCLUSIONS Rituximab use as adjuvant therapy within 12 weeks after initiation of systemic corticosteroids was associated with a faster and higher rate of achieving complete remission on minimal therapy or off therapy, as well as a significant corticosteroid-sparing effect and a comparable safety profile in this retrospective study. Hence, initial combination therapy with corticosteroids and adjuvant rituximab could serve as an effective treatment option for bullous pemphigoid, but this requires confirmation in randomized controlled studies.
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Affiliation(s)
- Yun-Ju Tsai
- Department of Dermatology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 15F, No. 7, Chung-Shan South Road, Taipei, Taiwan
| | - Yung-Tsu Cho
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 15F, No. 7, Chung-Shan South Road, Taipei, Taiwan
| | - Chia-Yu Chu
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 15F, No. 7, Chung-Shan South Road, Taipei, Taiwan.
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28
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Weng X, Iwata D, Namba K, Suzuki K, Mizuuchi K, Nakamura H, Atsumi T, Ishida S. Posterior scleritis with anti-neutrophil cytoplasmic antibody-associated vasculitis utilizing rituximab therapy to maintain remission: A case report. Am J Ophthalmol Case Rep 2022; 25:101333. [PMID: 35128165 PMCID: PMC8802867 DOI: 10.1016/j.ajoc.2022.101333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 09/28/2021] [Accepted: 01/20/2022] [Indexed: 01/01/2023] Open
Affiliation(s)
- Xinyu Weng
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Daiju Iwata
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Corresponding author. Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University; N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan.
| | - Kenichi Namba
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kayo Suzuki
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuomi Mizuuchi
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroyuki Nakamura
- Internal Medicine II, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Internal Medicine II, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Susumu Ishida
- Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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29
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Fukasawa T, Yoshizaki A, Ebata S, Yoshizaki-Ogawa A, Asano Y, Enomoto A, Miyagawa K, Kazoe Y, Mawatari K, Kitamori T, Sato S. Single-cell-level protein analysis revealing the roles of autoantigen-reactive B lymphocytes in autoimmune disease and the murine model. eLife 2021; 10:e67209. [PMID: 34854378 PMCID: PMC8639144 DOI: 10.7554/elife.67209] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 11/21/2021] [Indexed: 12/21/2022] Open
Abstract
Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.
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Affiliation(s)
- Takemichi Fukasawa
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Ayumi Yoshizaki
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Satoshi Ebata
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Asako Yoshizaki-Ogawa
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Yoshihide Asano
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Atsushi Enomoto
- Laboratory of Radiology and Biomedical Engineering, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Kiyoshi Miyagawa
- Laboratory of Radiology and Biomedical Engineering, The University of Tokyo Graduate School of MedicineTokyoJapan
| | - Yutaka Kazoe
- Department of System Design Engineering, Keio university, Faculty of Science and technologyTokyoJapan
| | - Kazuma Mawatari
- Department of Applied Chemistry, The University of Tokyo Graduate School of EngineeringTokyoJapan
| | - Takehiko Kitamori
- Department of Mechanical Engineering, The University of Tokyo Graduate School of EngineeringTokyoJapan
| | - Shinichi Sato
- Department of Dermatology, The University of Tokyo Graduate School of MedicineTokyoJapan
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30
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Harada S, Ando J, Ando M, Nitta H, Inano T, Hirasawa Y, Furukawa Y, Kinoshita S, Kondo A, Ohshima K, Komatsu N. High-grade Primary Central Nervous System Lymphomatoid Granulomatosis: Successful Rituximab Monotherapy. Intern Med 2021; 60:3795-3799. [PMID: 34121006 PMCID: PMC8710380 DOI: 10.2169/internalmedicine.7232-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The primary central nervous system (CNS) presentation of lymphomatoid granulomatosis (LYG) is rare, and no standard therapy for LYG with primary CNS symptoms exists. CNS-LYG patients usually survive for only less than a year from diagnosis. This is the first report of high-grade primary CNS-LYG with monoclonality that was successfully treated with rituximab monotherapy, resulting in a durable remission for more than 1 year in a 66-year-old woman with pemphigus vulgaris who was also on immunosuppressive therapy.
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Affiliation(s)
- Sakiko Harada
- Department of Hematology, Juntendo University School of Medicine, Japan
| | - Jun Ando
- Department of Hematology, Juntendo University School of Medicine, Japan
- Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of Medicine, Japan
| | - Miki Ando
- Department of Hematology, Juntendo University School of Medicine, Japan
| | - Hideaki Nitta
- Department of Hematology, Juntendo University School of Medicine, Japan
| | - Tadaaki Inano
- Department of Hematology, Juntendo University School of Medicine, Japan
| | - Yusuke Hirasawa
- Department of Dermatology, Juntendo University School of Medicine, Japan
| | - Yoshiki Furukawa
- Department of Hematology, Juntendo University School of Medicine, Japan
| | | | - Akihide Kondo
- Department of Neurosurgery, Juntendo University School of Medicine, Japan
| | - Koichi Ohshima
- Department of Pathology, School of Medicine, Kurume University, Japan
| | - Norio Komatsu
- Department of Hematology, Juntendo University School of Medicine, Japan
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31
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van Dijk WEM, van Es RJJ, Correa MEP, Schutgens REG, van Galen KPM. Dentoalveolar Procedures in Immune Thrombocytopenia; Systematic Review and an Institutional Guideline. TH OPEN 2021; 5:e489-e502. [PMID: 34805736 PMCID: PMC8595053 DOI: 10.1055/a-1641-7770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 09/07/2021] [Indexed: 11/10/2022] Open
Abstract
Background
Dentoalveolar procedures in immune thrombocytopenia (ITP) pose a risk of bleeding due to thrombocytopenia and infection due to immunosuppressive treatments. We aimed to systematically review the safety and management of dentoalveolar procedures in ITP patients to create practical recommendations.
Methods
PubMed, Embase, Cochrane, and Cinahl were searched for original studies on dentoalveolar procedures in primary ITP patients. We recorded bleeding- and infection-related outcomes and therapeutic strategies. Clinically relevant bleeding was defined as needing medical attention.
Results
Seventeen articles were included, of which 12 case reports/series. Overall, the quality of the available evidence was poor. Outcomes and administered therapies (including hemostatic therapies and prophylactic antibiotics) were not systematically reported. At least 73 dentoalveolar procedures in 49 ITP patients were described. The range of the preoperative platelet count was 2 to 412 × 10
9
/L. Two clinically relevant bleedings (2%) were reported in the same patient of which one was life-threatening. Strategies used to minimize the risk of bleeding were heterogeneous and included therapies to increase platelet count, antifibrinolytics, local measures, and minimally invasive techniques. Reports on the occurrence of bleedings due to anesthetics or infection were lacking.
Conclusion
Based on alarmingly limited data, clinically relevant bleedings and infections after dentoalveolar procedures in ITP patients seem rare. Awaiting prospective and controlled studies to further evaluate these risks and the efficacy of therapeutic interventions, we provided our institutional guideline to guide the management of dentoalveolar procedures in ITP patients.
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Affiliation(s)
- Wobke E M van Dijk
- Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Robert J J van Es
- Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Maria E P Correa
- Oral Medicine Ambulatory, Hematology and Hemotherapy Center, University of Campinas, Campinas, Sao Paulo, Brazil
| | - Roger E G Schutgens
- Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Karin P M van Galen
- Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
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32
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Hu J, Sun C, Lu J, Zhao C, Lin J. Efficacy of rituximab treatment in chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis. J Neurol 2021; 269:1250-1263. [PMID: 34120208 DOI: 10.1007/s00415-021-10646-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Current standard treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been proved effective, but it is poorly effective in refractory patients and unclear for anti-IgG4 antibody-associated CIDP. Rituximab is a B cell-depleting monoclonal antibody. It has been applied as one of the management strategies in CIDP, but its efficacy is unknown. OBJECTIVE To perform a systematic review and a meta-analysis of the efficacy of rituximab treatment in CIDP patients. METHODS Through searches in MEDLINE, PubMed, EMBASE, BIOSOS, Web of Science, and Cochrane library on March 31st, 2021, 15 studies were identified. Patients' characteristics, treatment regime and outcome measure were extracted. RESULTS Ninety-six patients in 15 studies were included. The pooled estimate of responsiveness was 75% (95% CI 72-78%). The standard mean difference (SMD) of Inflammatory Neuropathy Cause and Treatment (INCAT) disability score improvement was 1.7 (95% CI 1.0-2.3, p value < 0.0001) and the Medical Research Council (MRC) score for muscle power is 1.3 (95% CI - 2.6 to - 0.1, p value 0.04). All of the anti-IgG4 antibody-positive patients showed excellent responses to rituximab treatment. CONCLUSION Rituximab was effective in the treatment in CIDP patients, especially in anti-IgG4 antibody-positive patients. Randomized clinical trials are needed to determine the effectiveness and safety of rituximab in CIDP patients.
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Affiliation(s)
- Jianian Hu
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Chong Sun
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jiahong Lu
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Chongbo Zhao
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China
| | - Jie Lin
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, China.
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Stasi C, Tiengo G, Sadalla S, Zignego AL. Treatment or Prophylaxis against Hepatitis B Virus Infection in Patients with Rheumatic Disease Undergoing Immunosuppressive Therapy: An Update. J Clin Med 2021; 10:2564. [PMID: 34200522 PMCID: PMC8227638 DOI: 10.3390/jcm10122564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/31/2021] [Accepted: 06/07/2021] [Indexed: 12/20/2022] Open
Abstract
Chronic hepatitis B virus (HBV) flares or reactivations are serious causes of morbidity or mortality in rheumatologic patients undergoing immunosuppressive therapy. The recent insights in the pathogenesis of rheumatic diseases led to the use of new immunosuppressive therapies indicated in case of failure, partial response, or intolerance of conventional synthetic disease-modifying anti-rheumatic drugs. Based on these premises, this review examines and discusses the main rheumatologic treatments that could require the initiation of prophylactic treatment or close monitoring of occult HBV infection in patients beginning antiviral therapy at the first signs of HBV reactivation, or antiviral treatment in chronic HBV-infected patients. We searched for relevant studies published in the last five years. Studies suggested that the presence of HBV infection is common in rheumatic patients and HBV reactivation during these immunosuppressant treatments is quite frequent in these kinds of patients. Therefore, before starting an immunosuppressive therapy, patients should be screened for HBsAg, anti-HBs, and anti-HBc and, on the basis of markers positivity, they should be carefully characterized for HBV infection phases. In conclusion, screening of HBV infection in patients undergoing immunosuppressive therapy with subsequent HBV monitoring, prophylaxis or treatment consistently reduces the risk of clinical consequences.
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Affiliation(s)
- Cristina Stasi
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence and CRIA-MASVE Center for Research and Innovation, Careggi University Hospital, 50134 Florence, Italy; (G.T.); (A.L.Z.)
- Epidemiology Unit, Regional Health Agency of Tuscany, 50141 Florence, Italy
| | - Giacomo Tiengo
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence and CRIA-MASVE Center for Research and Innovation, Careggi University Hospital, 50134 Florence, Italy; (G.T.); (A.L.Z.)
| | - Sinan Sadalla
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Anna Linda Zignego
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence and CRIA-MASVE Center for Research and Innovation, Careggi University Hospital, 50134 Florence, Italy; (G.T.); (A.L.Z.)
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34
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Tugizova M, Vlahovic L, Tomczak A, Wetzel NS, Han MH. New Therapeutic Landscape in Neuromyelitis Optica. Curr Treat Options Neurol 2021; 23:13. [PMID: 33814893 PMCID: PMC8008025 DOI: 10.1007/s11940-021-00667-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2021] [Indexed: 12/11/2022]
Abstract
Purpose of review This review discusses the current treatment trends and emerging therapeutic landscape for patients with neuromyelitis optica spectrum disorder (NMOSD). Recent findings Conventional immune suppressive therapies, such as B cell depletion, have been used for long-term treatment. However, the availability of recent FDA-approved and investigational drugs has made therapeutic choices for NMOSD more complex. Summary Recent randomized clinical trials have shown that eculizumab, inebilizumab, and satralizumab are efficacious therapies for AQP4 seropositive NMOSD. These therapies may not have the same benefit in patients with seronegative NMOSD, including MOG-associated disease, and further investigation is required in this population. Reliable biomarkers to guide therapy decisions are urgently needed. There is a plethora of promising investigational therapies currently in the pipeline with exciting and novel mechanisms of action.
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Affiliation(s)
- Madina Tugizova
- Department of Neurology, Division of Neuroimmunology, Stanford University, 1201 Welch Road, MSLS p212, Stanford, CA 94305 USA.,Multiple Sclerosis Center, Stanford Hospital and Clinics, Palo Alto, CA USA
| | - Luka Vlahovic
- Department of Neurology, Creighton University School of Medicine, Omaha, NE USA
| | - Anna Tomczak
- Department of Neurology, Division of Neuroimmunology, Stanford University, 1201 Welch Road, MSLS p212, Stanford, CA 94305 USA.,Multiple Sclerosis Center, Stanford Hospital and Clinics, Palo Alto, CA USA
| | - Nora Sandrine Wetzel
- Department of Neurology, Division of Neuroimmunology, Stanford University, 1201 Welch Road, MSLS p212, Stanford, CA 94305 USA.,Faculty of Medicine, University of Zurich, Zürich, Switzerland
| | - May Htwe Han
- Department of Neurology, Division of Neuroimmunology, Stanford University, 1201 Welch Road, MSLS p212, Stanford, CA 94305 USA.,Multiple Sclerosis Center, Stanford Hospital and Clinics, Palo Alto, CA USA
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Zian Z, Berry SPDG, Bahmaie N, Ghotbi D, Kashif A, Madkaikar M, Bargir UA, Abdullahi H, Khan H, Azizi G. The clinical efficacy of Rituximab administration in autoimmunity disorders, primary immunodeficiency diseases and malignancies. Int Immunopharmacol 2021; 95:107565. [PMID: 33773205 DOI: 10.1016/j.intimp.2021.107565] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Rituximab (RTX), as a monoclonal antibody-based immunotherapeutic intervention targeting CD20 on B cells, has proven efficacy in the treatment of patients with some immune-mediated diseases. In the present review, we provided information on the immunobiological mechanisms of signaling for RTX and its clinical applications, according to the immune-pathophysiology involved in the microenvironment of multiple diseases. We highlighted combination therapy, dose schedules, and laboratory monitoring, as well as the associated common and rare side effects to avoid. We also discussed the efficacy and safety of RTX-based therapeutic strategies and whether RTX therapy can be used as a promising treatment regimen for autoimmune diseases, primary immunodeficiency diseases, and malignancies. Our review highlights and supports the importance of collaboration between basic medical researchers and clinical specialists when considering the use of RTX in the treatment of various immune-mediated disorders.
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Affiliation(s)
- Zeineb Zian
- Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, P.B. 416, Abdelmalek Essaadi University, Tetouan, Morocco
| | - S P Déo-Gracias Berry
- Centre de Recherches Médicales (CERMEL) de Lambaréné, B.P: 242, Gabon; Technical University of Munich, 80333, Germany
| | - Nazila Bahmaie
- Department of Allergy and Immunology, Faculty of Medicine, Graduate School of Health Science, Near East University (NEU), Nicosia, 99138, Northern Cyprus, Cyprus
| | - Dana Ghotbi
- Faculty of Biological Sciences, University of Kharazmi, Tehran 14911-15719, Iran
| | - Ali Kashif
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology, Mumbai 400070, India
| | - Umair Ahmed Bargir
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohaematology, Mumbai 400070, India
| | - Hamisu Abdullahi
- Department of Immunology, School of Medical Laboratory Sciences, Usmanu Danfodiyo University Sokoto, 840232, Nigeria
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj 3149779453, Iran.
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Wyckoff SL, Hudson KE. Targeting the neonatal Fc receptor (FcRn) to treat autoimmune diseases and maternal-fetal immune cytopenias. Transfusion 2021; 61:1350-1354. [PMID: 33650699 DOI: 10.1111/trf.16341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/21/2022]
Abstract
FcRn, a non-classical Fc gamma (γ) receptor (FcγR) with near ubiquitous expression, plays key roles in disease pathogenesis and progression though immunoglobulin G (IgG) transport, IgG recycling, and IgG-immune complex clearance. FcRn function can be inhibited using IgG-based and non-IgG-based antagonists, by exploiting the pH-dependent binding affinity of FcRn for the IgG Fc region. FcRn therapeutics have shown promise in murine models and human clinical trials for autoimmune diseases and maternal-fetal immune cytopenias; they appear safe, well-tolerated, and reduce circulating IgG levels. Compared to traditional therapeutics, inhibiting FcRn has fewer adverse side effects and represents a new approach that is less invasive, time-consuming, and costly.
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Affiliation(s)
- Sarah L Wyckoff
- Columbia University Irving Medical Center, New York, New York, USA
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LeValley PJ, Sutherland BP, Jaje J, Gibbs S, Jones M, Gala R, Kloxin CJ, Kiick KL, Kloxin AM. On-demand and tunable dual wavelength release of antibody using light-responsive hydrogels. ACS APPLIED BIO MATERIALS 2020; 3:6944-6958. [PMID: 34327309 PMCID: PMC8315695 DOI: 10.1021/acsabm.0c00823] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
There has been an increased interest in the use of protein therapeutics, especially antibodies, for the treatment of a variety of diseases due to their high specificity to tissues and biological pathways of interest. However, the use of antibodies can be hindered by physical aggregation, degradation, and diffusion when injected in vivo leading to the need for antibody-releasing depots for the controlled and localized delivery within tissues of interest. Here, we investigated photolabile hydrogel chemistries for creating on-demand and tunable antibody release profiles. Innovative, scalable synthetic procedures were established and applied for fabricating hydrogels with nitrobenzyl (NB) and coumarin (CMR) photolabile crosslinks that responded to clinically relevant doses of long-wavelength UV and short-wavelength visible light. This synthetic procedure includes a route to make a CMR linker possessing two functional handles at the same ring position with water-stable bonds. The photocleavage properties of NB and CMR crosslinked hydrogels were characterized, as well as their potential for translational studies by degradation through pig skin, a good human skin mimic. The mechanism of hydrogel degradation, bulk versus surface eroding, was determined to be dependent on the wavelength of light utilized and the molar absorptivity of the different photolabile linkers, providing a facile means for altering protein release upon hydrogel degradation. Further, the encapsulation and on-demand release of a model monoclonal antibody was demonstrated, highlighting the ability to control antibody release from these hydrogels through the application of light while retaining its bioactivity. In particular, the newly designed CMR hydrogels undergo surface erosion-based protein release using visible light, which is more commonly used clinically. Overall, this work establishes scalable syntheses and relevant pairings of formulation-irradiation conditions for designing on-demand and light-responsive material systems that provide controlled, tunable release of bioactive proteins toward addressing barriers to preclinical translation of light-based materials and ultimately improving therapeutic regimens.
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Affiliation(s)
- Paige J. LeValley
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, United States
| | - Bryan P. Sutherland
- Department of Material Science and Engineering, University of Delaware, Newark, DE, United States
| | - Jennifer Jaje
- Fraunhofer USA Center for Molecular Biotechnology (CMB), Newark, DE, United States
| | - Sandra Gibbs
- Fraunhofer USA Center for Molecular Biotechnology (CMB), Newark, DE, United States
| | - Mark Jones
- Fraunhofer USA Center for Molecular Biotechnology (CMB), Newark, DE, United States
| | - Rikhav Gala
- Fraunhofer USA Center for Molecular Biotechnology (CMB), Newark, DE, United States
| | - Christopher J. Kloxin
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, United States
- Department of Material Science and Engineering, University of Delaware, Newark, DE, United States
| | - Kristi L. Kiick
- Department of Material Science and Engineering, University of Delaware, Newark, DE, United States
| | - April M. Kloxin
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, United States
- Department of Material Science and Engineering, University of Delaware, Newark, DE, United States
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Low class–switched memory B cells predict the need for continued immunoglobulin replacement following B cell reconstitution after rituximab: a case series and review of the literature. J Hematop 2020. [DOI: 10.1007/s12308-020-00415-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Whiting ZG, Doerre T. Diagnosis of Culture-Negative Septic Arthritis with Polymerase Chain Reaction in an Immunosuppressed Patient: A Case Report. JBJS Case Connect 2020; 10:e2000057. [PMID: 32910594 DOI: 10.2106/jbjs.cc.20.00057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
CASE We present a 23-year-old woman on immunosuppressive therapy with polyarticular, culture-negative septic arthritis. She underwent irrigation and debridement with empiric antibiotic therapy but had recurrence of septic arthritis despite treatment. Polymerase chain reaction testing eventually identified Ureaplasma as the causative organism. She was successfully treated with an extended course of organism-specific antibiotics. CONCLUSION More patients are being treated with immune modulating therapies. Immunosuppressed patients are at risk for atypical infections and may have different presentations than immunocompetent patients. Newer diagnostic modalities can help identify causative organisms and direct treatment in the case of negative cultures.
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Affiliation(s)
- Zachariah G Whiting
- 1The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia 2Department of Orthopedic Surgery, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
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Luciani L, Ninove L, Zandotti C, Chalvignac V, Lagier D, Baume J, Mélade J, Piorkowski G, Coutard B, Lepidi H, Pelletier J, Audoin B, Rico-Lamy A, Nougairède A. Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease. Mult Scler 2020; 27:320-323. [DOI: 10.1177/1352458520923978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
We report a fatal case of coxsackievirus B4 chronic infection in a 30-year-old woman with a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disorder controlled by rituximab monotherapy for 3 years. Initially presenting as self-limited meningitis, the infection remained silent for 8 months before the sudden onset of fulminant myocarditis. Analysis of the complete genome showed that the same virus was responsible for both episodes.
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Affiliation(s)
- Léa Luciani
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France; Laboratoire de microbiologie (Assistance Publique – Hôpitaux de Marseille; IHU Méditerranée Infection) Marseille, France
| | - Laetitia Ninove
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France; Laboratoire de microbiologie (Assistance Publique – Hôpitaux de Marseille; IHU Méditerranée Infection) Marseille, France
| | - Christine Zandotti
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France; Laboratoire de microbiologie (Assistance Publique – Hôpitaux de Marseille; IHU Méditerranée Infection) Marseille, France
| | - Virginie Chalvignac
- Assistance publique–hôpitaux de Marseille (AP-HM), Centre Hospitalo-Universitaire Timone, Service de chirurgie cardio-thoracique, Marseille, France
| | - David Lagier
- Aix-Marseille University, APHM, Hôpital de la Timone, Service d’Anesthésie et de Réanimation, Marseille, France
| | - Julien Baume
- Laboratoire de microbiologie (Assistance Publique – Hôpitaux de Marseille; IHU Méditerranée Infection), Marseille, France
| | - Julien Mélade
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France
| | - Géraldine Piorkowski
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France
| | - Bruno Coutard
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France
| | - Hubert Lepidi
- Laboratoire d’anatomo-pathologie, APHM, Aix Marseille Univ, IRD, MEPHI, IHU Méditerranée Infection, Marseille, France
| | - Jean Pelletier
- Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France
| | - Bertrand Audoin
- Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France
| | - Audrey Rico-Lamy
- Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France/CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France
| | - Antoine Nougairède
- Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille, France; Laboratoire de microbiologie (Assistance Publique – Hôpitaux de Marseille; IHU Méditerranée Infection) Marseille, France
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41
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Black LA, Zorina T. Genetic profile considerations for induction of allogeneic chimerism as a therapeutic approach for type 1 diabetes mellitus. Drug Discov Today 2020; 25:1293-1297. [PMID: 32445668 DOI: 10.1016/j.drudis.2020.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/26/2020] [Accepted: 05/05/2020] [Indexed: 11/28/2022]
Abstract
The major therapeutic modality for type 1 diabetes mellitus (T1DM) remains sustaining euglycemia by exogenous administration of insulin. Based on a new understanding of bone marrow structural and functional dynamics, a conditioning-free bone marrow transplantation (BMT), with reduced adverse effects, opens the possibility for evaluating β cell regeneration and restoration of euglycemia by induction of allogeneic chimerism in patients T1DM, as shown in a mouse model. With this therapeutic modality, donor bone marrow (BM) selection based on T1DM-predisposing and preventive phenotypes will improve treatment outcomes by limiting the risk of exacerbating the autoimmune processes in the BM recipient.
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Affiliation(s)
- Labe A Black
- Thomas Jefferson University, Jefferson College of Health Professions, Department of Medical Laboratory Science and Biotechnology, Philadelphia, PA, USA.
| | - Tatiana Zorina
- Thomas Jefferson University, Jefferson College of Health Professions, Department of Medical Laboratory Science and Biotechnology, Philadelphia, PA, USA.
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Abstract
Rituximab (MabThera®, Rituxan®), a chimeric murine/human anti-CD20 monoclonal antibody administered by intravenous infusion, is indicated for the treatment of moderate to severe pemphigus vulgaris (PV), in combination with a tapering course of corticosteroids. Approval in the EU and USA was based on data for the subset of patients with newly-diagnosed, previously untreated PV participating in the randomized, controlled RITUX 3 study; rituximab plus short-course prednisone resulted in a > 3-fold higher rate of complete remission off prednisone therapy and a > 2-fold decrease in the rate of moderate/severe relapse compared with standard-dose prednisone in this patient subpopulation. In addition, rituximab plus short-term prednisone was steroid-sparing and resulted in fewer patients experiencing grade 3 or 4 corticosteroid-related adverse events compared with standard-dose prednisone. The adverse event profile of rituximab in patients with PV was consistent with that observed for the drug in other approved autoimmune disorders; no new safety concerns were identified. Notwithstanding there is some uncertainty over the optimum dosing schedule to achieve and maintain disease control, rituximab is a highly effective and generally well tolerated, steroid-sparing treatment for moderate to severe PV.
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Affiliation(s)
- James E Frampton
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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Lunge S, Patil V, Doshi B. Cardiac side effect of rituximab. INDIAN JOURNAL OF DRUGS IN DERMATOLOGY 2020. [DOI: 10.4103/ijdd.ijdd_64_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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44
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Than NN, Hodson J, Schmidt-Martin D, Taubert R, Wawman RE, Botter M, Gautam N, Bock K, Jones R, Appanna GD, Godkin A, Montano-Loza AJ, Lammert F, Schramm C, Manns MP, Swain M, Burak KW, Adams DH, Hirschfield GM, Oo YH. Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group. JHEP Rep 2019; 1:437-445. [PMID: 32039395 PMCID: PMC7005655 DOI: 10.1016/j.jhepr.2019.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. METHODS Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. RESULTS Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. CONCLUSION In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. LAY SUMMARY Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.
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Affiliation(s)
- Nwe Ni Than
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - James Hodson
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Daniel Schmidt-Martin
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca E. Wawman
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Imperial College, London
| | - Meemee Botter
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- University of Amsterdam, Netherland
| | - Nishant Gautam
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
| | - Kilian Bock
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- European Reference Network (ERN) Rare Liver
| | - Rebecca Jones
- Leeds Liver Transplant Unit, St James University Hospital, Leeds, United Kingdom
| | | | - Andrew Godkin
- University Hospital of Wales, Cardiff, United Kingdom
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Centre, Homburg
| | - Christoph Schramm
- University Medical Centre Hamburg-Eppendorf, Hamburg, I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
- European Reference Network (ERN) Rare Liver
| | - Mark Swain
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - Kelly W. Burak
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - David H. Adams
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Gideon M Hirschfield
- University of Toronto, Canada
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Ye Htun Oo
- Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, United Kingdom
- Centre for Liver and Gastroenterology Research & National Institute of Health Research Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
- Autoimmune Liver Diseases Clinic, Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
- European Reference Network (ERN) Rare Liver
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Karimi A, Esmaili N, Ranjkesh M, Zolfaghari MA. Expression of human endogenous retroviruses in pemphigus vulgaris patients. Mol Biol Rep 2019; 46:6181-6186. [PMID: 31473891 DOI: 10.1007/s11033-019-05053-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/28/2019] [Indexed: 01/09/2023]
Abstract
Pemphigus is a severe, potentially life-threatening autoimmune blistering mucocutaneous disease which establishes with autoreactive IgG antibodies that target cellular adhesions, precisely extracellular domains of keratinocyte proteins. Several genetic and environmental elements are believed to contribute to the pathogenesis of the disease. The extent to which the initiation and progress of this autoimmune blistering disease may be influenced by the expression of human endogenous retroviruses (HERVs) remains to be elucidated. In this study, we evaluated the expression of HERV groups (K, W, and H) in pemphigus vulgaris (PV) patients in comparison to controls. Peripheral blood samples were collected from 24 PV patients and the corresponding age- and sex-matched healthy controls to extract total RNA for evaluation of HERV-K (HML-2), HERV-W, and HERV-H, env gene expression profile by qPCR. The mRNA expression level of HERV-K, HERV-W, and HERV-H were significantly upregulated in PV patients in comparison to healthy controls (P < 0.0001). The difference in expression of studied HERVs groups between men and women was no significant (P > 0.05). Although rituximab taking patients had a decreased expression level of studied HERVs, the results were not significant (P > 0.05). According to our obtained data, HERVs expression could be measured as a possible diagnostic tool for detection of PV and monitoring of the treatment.
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Affiliation(s)
- Abbas Karimi
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Razi Hospital, Tehran, Iran.
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Nafiseh Esmaili
- Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Razi Hospital, Tehran, Iran.
| | - Mohammadreza Ranjkesh
- Department of Dermatology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Ali Zolfaghari
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Highly diverse cembranoids from the South China Sea soft coral Sinularia scabra as a new class of potential immunosuppressive agents. Bioorg Med Chem 2019; 27:3469-3476. [DOI: 10.1016/j.bmc.2019.06.030] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/29/2019] [Accepted: 06/18/2019] [Indexed: 11/19/2022]
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47
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Pan S, Yu H, Surti A, Cheng I, Marks SD, Brogan PA, Eleftheriou D, Standing JF. Pharmacodynamics of rituximab on B lymphocytes in paediatric patients with autoimmune diseases. Br J Clin Pharmacol 2019; 85:1790-1797. [PMID: 31026092 PMCID: PMC6624401 DOI: 10.1111/bcp.13970] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 03/02/2019] [Accepted: 04/08/2019] [Indexed: 12/16/2022] Open
Abstract
Aims Rituximab is a chimeric IgG‐1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell‐related pharmacodynamics of rituximab in children with autoimmune disease. Methods Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose–response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first‐order kinetics. Results In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days−1 and CD19+ turnover was 0.02 (41%) days−1 corresponding to half‐lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35‐fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6‐month suppression of CD19+ lymphocytes to current dosing. Conclusions Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.
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Affiliation(s)
- Shan Pan
- UCL Great Ormond Street Institute of Child Health, London, UK.,Guy's and St Thomas' NHS Trust, London, UK
| | - Huixin Yu
- UCL Great Ormond Street Institute of Child Health, London, UK.,Novartis Pharma AG, Basel, Switzerland
| | | | - Iek Cheng
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Stephen D Marks
- UCL Great Ormond Street Institute of Child Health, London, UK.,Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Paul A Brogan
- UCL Great Ormond Street Institute of Child Health, London, UK.,Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Despina Eleftheriou
- UCL Great Ormond Street Institute of Child Health, London, UK.,Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Joseph F Standing
- UCL Great Ormond Street Institute of Child Health, London, UK.,Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
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48
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Sahin O, Albayrak M, Yıldız A, Pala Ç, Aktas L, Maral S, Afacan Öztürk HB, Cömert P. Refractory Thrombotic Thrombocytopenic Purpura in a patient with Kaposi sarcoma. Transfus Apher Sci 2019; 58:187-189. [PMID: 30910619 DOI: 10.1016/j.transci.2019.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/21/2019] [Accepted: 02/21/2019] [Indexed: 10/27/2022]
Abstract
The case is here presented of a 70-year old male patient with rare coexistence of Kaposi Sarcoma and resistant Thrombotic Thrombocytopenic Purpura (TTP). The Kaposi lesions were determined before the diagnosis of TTP and were exacerbated after receiving TTP-associated immunosuppressive therapy, in particular associated with rituximab. TTP in this case was resistant to conventional therapies such as steroid and plasma exchange and current immunosuppressive (rituximab, cyclophosphamide, vincristin) treatments. Novel treatment agents consisting of bortezomib and eculizumab given to the patient were also ineffective. To the best of our knowledge, this case presents the first case of coexistence of TTP and Kaposi sarcoma from Turkey and the challenge of refractory TTP management.
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Affiliation(s)
- Osman Sahin
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey.
| | - Murat Albayrak
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Abdulkerim Yıldız
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Çiğdem Pala
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Levent Aktas
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Senem Maral
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Hacer Berna Afacan Öztürk
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
| | - Pınar Cömert
- University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Department of Hematology, Ankara, Turkey
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Sánchez-Trujillo L, Jerjes-Sanchez C, Rodriguez D, Panneflek J, Ortiz-Ledesma C, Garcia-Rivas G, Torre-Amione G. Phase II clinical trial testing the safety of a humanised monoclonal antibody anti-CD20 in patients with heart failure with reduced ejection fraction, ICFEr-RITU2: study protocol. BMJ Open 2019; 9:e022826. [PMID: 30918029 PMCID: PMC6475246 DOI: 10.1136/bmjopen-2018-022826] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Chronic heart failure with reduced ejection fraction (HFrEF) treatment targets neurohormonal inhibition; however, our experimental observations and the recent clinical evidence in myocardial infarction and heart transplant patients support the anti-inflammatory pathway as a potential novel therapeutic target. Therefore, we aimed to assess the safety of human monoclonal antibody-CD20 (rituximab) in patients with HFrEF. METHODS AND ANALYSIS We designed this protocol according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines as a phase II, single-centred, single group and prospective clinical trial. We hypothesise that the use of a monoclonal antibody, rituximab, could be a potentially safe new agent in HFrEF management. We will include patients with EF≤40%, New York Heart Association functional class III/IV and unresponsive to standard treatment. We will use a dosing regimen (1000 mg) previously applied to post-transplant patients and patients with rheumatoid arthritis with favourable results, aiming to provide supplementary evidence of safety in patients with HFrEF. We designed strategies tailored to preserving the integrity of patient safety. The date of study initiation will be 29th of May 2019. ETHICS AND DISSEMINATION The following protocol was approved by IRB committees, and as a requirement, all patients need to sign an informed consent form before being subjected to any procedure prior to the initiation of the study. We are aware that the trial will be run in patients who due to their cardiovascular functional class, have reserved prognosis, with no known therapy that leads to improvement. Hence, this trial searches to establish the safety of an alternative strategy in ameliorating prognosis. Regardless of the study outcomes, whether favourable or not, they will be published. If a favourable outcome is evidenced, it will prompt performing a phase III, efficacy-based study. TRIAL REGISTRATION NUMBER The trial was approved by the IRB (CONBIOÉTICA-19-CEI-011-20161017 and COFEPRIS-17-CI-19-039-003), and registered at Clinicaltrials.gov (NCT03332888; Pre-Results).
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Affiliation(s)
- Luis Sánchez-Trujillo
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - Carlos Jerjes-Sanchez
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - David Rodriguez
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - Jathniel Panneflek
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - Claudia Ortiz-Ledesma
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - Gerardo Garcia-Rivas
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
| | - Guillermo Torre-Amione
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., Mexico
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50
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Xin GLL, Khee YP, Ying TY, Chellian J, Gupta G, Kunnath AP, Nammi S, Collet T, Hansbro PM, Dua K, Chellappan DK. Current Status on Immunological Therapies for Type 1 Diabetes Mellitus. Curr Diab Rep 2019; 19:22. [PMID: 30905013 DOI: 10.1007/s11892-019-1144-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) occurs when there is destruction of beta cells within the islets of Langerhans in the pancreas due to autoimmunity. It is considered a complex disease, and different complications can surface and worsen the condition if T1D is not managed well. Since it is an incurable disease, numerous treatments and therapies have been postulated in order to control T1D by balancing hyperglycemia control while minimizing hypoglycemic episodes. The purpose of this review is to primarily look into the current state of the available immunological therapies and their advantages for the treatment of T1D. RECENT FINDINGS Over the years, immunological therapy has become the center of attraction to treat T1D. Immunomodulatory approaches on non-antigens involving agents such as cyclosporine A, mycophenolate mofetil, anti-CD20, cytotoxic T cells, anti-TNF, anti-CD3, and anti-thymocyte globulin as well as immunomodulative approaches on antigens such as insulin, glutamic acid decarboxylase, and heat shock protein 60 have been studied. Aside from these two approaches, studies and trials have also been conducted on regulatory T cells, dendritic cells, interleukin 2, interleukin 4, M2 macrophages, and rapamycin/interleukin 2 combination therapy to test their effects on patients with T1D. Many of these agents have successfully suppressed T1D in non-obese diabetic (NOD) mice and in human trials. However, some have shown negative results. To date, the insights into the management of the immune system have been increasing rapidly to search for potential therapies and treatments for T1D. Nevertheless, some of the challenges are still inevitable. A lot of work and effort need to be put into the investigation on T1D through immunological therapy, particularly to reduce complications to improve and enhance clinical outcomes.
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Affiliation(s)
- Griselda Lim Loo Xin
- School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Yap Pui Khee
- School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Tan Yoke Ying
- School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Jestin Chellian
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Gaurav Gupta
- School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, 302017, India
| | - Anil Philip Kunnath
- Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Srinivas Nammi
- School of Science and Health, Western Sydney University, Sydney, NSW, 2751, Australia
- NICM Health Research Institute, Western Sydney University, Sydney, NSW, 2751, Australia
| | - Trudi Collet
- Innovative Medicines Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland, 4059, Australia
| | - Philip Michael Hansbro
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, NSW, 2007, Australia
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy, The University of Newcastle (UoN), Callaghan, Newcastle, NSW, 2308, Australia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, NSW, 2007, Australia
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy, The University of Newcastle (UoN), Callaghan, Newcastle, NSW, 2308, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
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