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Strand V, McCabe D, Bender S. Immunogenicity of adalimumab reference product and adalimumab-adbm in patients with rheumatoid arthritis, Crohn's disease and chronic plaque psoriasis: a pooled analysis of the VOLTAIRE trials. BMJ Open 2024; 14:e081687. [PMID: 39551590 PMCID: PMC11574400 DOI: 10.1136/bmjopen-2023-081687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 09/28/2024] [Indexed: 11/19/2024] Open
Abstract
OBJECTIVE This post hoc analysis compared the immunogenicity of the biosimilar adalimumab-adbm (Cyltezo) with the adalimumab reference product (RP; Humira) across indications, including rheumatoid arthritis (RA), Crohn's disease (CD) and plaque psoriasis (PsO), and by patient sex in the VOLTAIRE trials programme. METHODS In each active-comparator randomised controlled trial (RCT), immunogenicity was assessed at various time points by the proportion of patients with antidrug antibodies (ADAs) and neutralising antibodies (nAbs), using acid dissociation followed by electrochemiluminescence assay. Assay sensitivity was 50 ng/mL, and drug tolerance was ≥30 µg/mL (free drug) at the low positive control level. RESULTS Minor differences in immunogenicity parameters (ADAs, ADA titres and nAbs) were evident between adalimumab-adbm and adalimumab RP across these three immune-mediated inflammatory diseases (IMIDs). The proportion of ADA-positive and nAb-positive patients increased from baseline over time in all three RCTs, as expected, and was similar in the RA and CD RCTs but with higher numbers of ADA-positive and nAb-positive patients reported in the PsO trial. Subgroup analysis by patient sex showed the same trend. CONCLUSIONS Differences among the RCTs may partially be explained by concomitant background therapy (methotrexate) in the RA trial, stable doses of azathioprine, 6-mercaptopurine or methotrexate in 36% of patients with CD and absence of background therapy in the PsO RCT. The analyses further confirm the biosimilarity of adalimumab-adbm with the adalimumab RP across IMIDs and provide supporting evidence that adalimumab-adbm is an interchangeable biosimilar with consistent clinical results in patients originally treated with the RP. TRIAL REGISTRATION NUMBERS VOLTAIRE-RA (NCT02137226; EudraCT 2012-002945-40); VOLTAIRE-CD (NCT02871635; EudraCT 2016-000612-14); VOLTAIRE-PsO (NCT02850965; EudraCT 2016-000613-79).
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Affiliation(s)
- Vibeke Strand
- Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Dorothy McCabe
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Shaun Bender
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
- Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts, USA
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2
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Luo L, Tang X, Hu X, Li L, Xu J, Zhong X. The causal effects of inflammatory bowel disease on skin carcinoma: A two-sample Mendelian randomization study. Medicine (Baltimore) 2024; 103:e39997. [PMID: 39465853 PMCID: PMC11479435 DOI: 10.1097/md.0000000000039997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 09/19/2024] [Indexed: 10/29/2024] Open
Abstract
Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanoma skin carcinoma (NMSC) than healthy people. However, whether there is a causal relationship between the 2 is unclear. The purpose of this study was to evaluate the causality of IBD on SC using the Mendelian randomization (MR) analysis. We performed a two-sample MR analysis using publicly available genome-wide association study data. Eligible instrumental variables were selected based on the 3 core assumptions of MR analysis. The inverse-variance weighted (IVW) approach served as the primary analytical method. Supplementary analyses were conducted using MR-Egger regression, the weighted median, the weighted mode, and MR pleiotropy residual sum and outlier methods. Genetically predicted IBD (IVW odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.02-1.13, P = .011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = .003) were associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method with the exception of the weighted mode. In addition, Crohn disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = .128) did not have a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = .034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = .045) were associated with an increased risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = .803) was not significantly associated with an increased risk of NMSC. Our study revealed genetically predicted associations between IBD and the risks of MSC and NMSC in European populations. Furthermore, UC was associated with an increased risk of MSC, while CD was associated with a higher risk of NMSC. However, the potential influence of immunosuppressive agents or biologics cannot be excluded.
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Affiliation(s)
- Lian Luo
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xiaowei Tang
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xinyue Hu
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Limin Li
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Jia Xu
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xiaolin Zhong
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
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Pimentel CQ, Medeiros-Ribeiro AC, Shimabuco AY, Sampaio-Barros PD, Moraes JCB, Schainberg CG, Gonçalves CR, Leon EP, Kupa LDVK, Pasoto SG, Aikawa NE, Silva CA, Bonfa E, Saad CGS. Long-Term Follow-Up of Anti-Infliximab Antibodies in Patients With Radiographic Axial Spondyloarthritis: A Marker of Drug Survival and Tapering. Arthritis Rheumatol 2024; 76:1488-1500. [PMID: 38801195 DOI: 10.1002/art.42923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 04/01/2024] [Accepted: 05/22/2024] [Indexed: 05/29/2024]
Abstract
OBJECTIVE The aim of this study was to evaluate the influence of anti-infliximab (IFX) antibodies on three different points of care: response/tolerance to IFX, tapering strategy, and in a subsequent treatment with a second tumor necrosis factor inhibitor (TNFi). METHODS A prospective cohort of 60 patients with radiographic axial spondyloarthritis who received IFX were evaluated retrospectively regarding clinical/laboratorial data, IFX levels, and anti-IFX antibodies at baseline, after 6, 12 to 14, 22 to 24, 48 to 54, 96 to 102 weeks, and before tapering or switching. RESULTS Anti-IFX antibodies were detected in 27 patients (45%), of whom 23 (85.1%) became positive in the first year of IFX treatment. In comparison to the group that was negative for anti-IFX antibodies, patients who were positive for anti-IFX antibodies demonstrated the following: less use of methotrexate as a concomitant treatment to IFX (5 [18.5%] vs 14 [42.4%]; P = 0.048), more infusion reactions at 22 to 24 weeks (P = 0.020) and 48 to 54 weeks (P = 0.034), more treatment failures (P = 0.028) at 48 to 54 weeks, reduced overall IFX survival (P < 0.001), and lower sustained responses (P = 0.044). Of note, patients who were positive for anti-IFX antibodies exhibited a shorter tapering survival (9.9 months [95% confidence interval (CI) 4.0-15.8] vs 63.4 months [95% CI 27.9-98.8]; P = 0.004) in comparison with patients who were negative for anti-IFX antibodies. Conversely, for patients who failed IFX, patients who were positive for anti-IFX antibodies had better clinical response to the second TNFi at three months (15 [83.3%] vs 3 [27.3%]; P = 0.005) and six months (15 [83.3%] vs 4 [36.4%]; P = 0.017) than the patients who were negative for anti-IFX antibodies after switching. CONCLUSION This study provided novel data that anti-IFX antibodies is a parameter for reduced tapering survival, reinforcing its detection to guide clinical decision. Additionally, we confirmed in a long-term cohort the anti-IFX antibody association with worse IFX performance and as predictor of the second TNFi good clinical response.
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Affiliation(s)
- Clarissa Q Pimentel
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Ana Cristina Medeiros-Ribeiro
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Andrea Y Shimabuco
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Percival D Sampaio-Barros
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Júlio César B Moraes
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Claudia G Schainberg
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Celio Roberto Gonçalves
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Elaine P Leon
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Léonard De Vinci K Kupa
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Sandra G Pasoto
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Nádia E Aikawa
- Pediatric Rheumatology Unit, Instituto da Criança e do Adolescente, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Clovis A Silva
- Pediatric Rheumatology Unit, Instituto da Criança e do Adolescente, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Eloisa Bonfa
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Carla G S Saad
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Lee IWZ, Baikunje S, Tan PH, Guo W. Case report: Crescentic IgA nephropathy with anti-neutrophil cytoplasmic antibodies, in a patient on golimumab. Int J Rheum Dis 2024; 27:e15330. [PMID: 39239851 DOI: 10.1111/1756-185x.15330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/17/2024] [Accepted: 08/25/2024] [Indexed: 09/07/2024]
Affiliation(s)
- Ivan Wei Zhen Lee
- Department of Renal Medicine, Sengkang General Hospital, Singapore, Singapore
| | - Shashidhar Baikunje
- Department of Renal Medicine, Sengkang General Hospital, Singapore, Singapore
| | | | - Weiwen Guo
- Department of Renal Medicine, Sengkang General Hospital, Singapore, Singapore
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Yatsuzuka K, Muto J, Shiraishi K, Murakami M, Fujisawa Y. A Successful Switch From Ustekinumab to an Extended Dosing Interval of Guselkumab Without Induction in a Patient With Psoriasis Vulgaris. Cureus 2024; 16:e61567. [PMID: 38962596 PMCID: PMC11221387 DOI: 10.7759/cureus.61567] [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] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Psoriasis vulgaris, also known as plaque-type psoriasis, is the most common form of psoriasis. It is characterized by erythematous plaques covered with scales. Among the available treatments, the fully human monoclonal antibodies ustekinumab (UST) and guselkumab (GUS) have low immunogenicity. Additionally, GUS has not been found to have a significant risk of inducing the development of clinically relevant neutralizing antibodies. Therefore, we sometimes consider switching to GUS when UST is insufficiently effective. However, switching to another biological agent usually requires an induction phase, potentially incurring additional costs. We herein present the first case of a successful transition from UST 90 mg to an extended dosing interval of GUS without an induction phase. This approach may be a viable and cost-saving option, especially for patients with relatively low disease activity.
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Affiliation(s)
- Kazuki Yatsuzuka
- Department of Dermatology, Ehime University Graduate School of Medicine, Toon, JPN
| | - Jun Muto
- Department of Dermatology, Ehime University Graduate School of Medicine, Toon, JPN
| | - Ken Shiraishi
- Department of Dermatology, Ehime University Graduate School of Medicine, Toon, JPN
| | - Masamoto Murakami
- Department of Dermatology, Ehime University Graduate School of Medicine, Toon, JPN
| | - Yasuhiro Fujisawa
- Department of Dermatology, Ehime University Graduate School of Medicine, Toon, JPN
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Kraev K, Hristov B, Uchikov P, Kraeva M, Geneva-Popova M, Popova S, Basheva-Kraeva Y, Stoyanova NS, Mitkova-Hristova V. Prognostic models of drug-induced neutralizing antibody formation in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis treated with TNF-α blockersockers. Folia Med (Plovdiv) 2024; 66:188-195. [PMID: 38690813 DOI: 10.3897/folmed.66.e114887] [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: 10/29/2023] [Accepted: 02/23/2024] [Indexed: 05/03/2024] Open
Abstract
AIM This study aimed to construct prognostic mathematical models utilizing multifactorial regression analysis to assess the risk of developing drug-induced neutralizing antibodies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with tumor necrosis factor alpha blockers.
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Sumida K, Shrestha P, Mallisetty Y, Thomas F, Gyamlani G, Streja E, Kalantar-Zadeh K, Kovesdy CP. Anti-Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease. JAMA Netw Open 2024; 7:e246822. [PMID: 38625700 PMCID: PMC11022116 DOI: 10.1001/jamanetworkopen.2024.6822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/16/2024] [Indexed: 04/17/2024] Open
Abstract
Importance Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD. Objective To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality. Design, Setting, and Participants This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024. Exposures Incident use of TNF inhibitors. Main Outcomes and Measures The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Results Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses. Conclusions and Relevance In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.
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Affiliation(s)
- Keiichi Sumida
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis
| | - Prabin Shrestha
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis
| | - Yamini Mallisetty
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis
| | - Fridtjof Thomas
- Division of Biostatistics, Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis
| | - Geeta Gyamlani
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis
- Nephrology Section, Memphis VA Medical Center, Memphis, Tennessee
| | - Elani Streja
- Division of Nephrology, Hypertension, and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange
- Tibor Rubin Veterans Affairs Medical Center, Long Beach, California
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology, Hypertension, and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange
- Tibor Rubin Veterans Affairs Medical Center, Long Beach, California
| | - Csaba P. Kovesdy
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis
- Nephrology Section, Memphis VA Medical Center, Memphis, Tennessee
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Gu P, Dube S, Gellada N, Choi SY, Win S, Lee YJ, Yang S, Haritunians T, Melmed GY, Vasiliauskas EA, Bonthala N, Syal G, Yarur AJ, Ziring D, Rabizadeh S, Fleshner P, Kallman C, Devkota S, Targan SR, Li D, McGovern DPB. Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn's disease. World J Gastrointest Surg 2024; 16:740-750. [PMID: 38577075 PMCID: PMC10989343 DOI: 10.4240/wjgs.v16.i3.740] [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: 11/30/2023] [Revised: 01/04/2024] [Accepted: 01/30/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence (POR) of Crohn's disease (CD). However, its prognostic value is uncertain, in part, due to difficulties studying it non-invasively. AIM To evaluate the prognostic value of pre-operative radiographic mesenteric parameters for early endoscopic POR (ePOR). METHODS We conducted a retrospective cohort study of CD subjects ≥ 12 years who underwent ileocecal or small bowel resection between 1/1/2007 to 12/31/2021 with computerized tomography abdomen/pelvis ≤ 6 months pre-operatively and underwent ileocolonoscopy ≤ 15 months post-operatively. Visceral adipose tissue (VAT) volume (cm3), ratio of VAT:subcutaneous adipose tissue (SAT) volume, VAT radiodensity, and ratio of VAT:SAT radiodensity were generated semiautomatically. Mesenteric lymphadenopathy (LAD, largest lymph node > 10 mm) and severe vasa recta (VR) engorgement (diameter of the VR supplying diseased bowel ≥ 2 × VR supplying healthy bowel) were derived manually. The primary outcome was early ePOR (Rutgeert's score ≥ i2 on first endoscopy ≤ 15 months post-operatively) and the secondary outcome was ePOR severity (Rutgeert's score i0-4). Regression analyses were performed adjusting for demographic and disease-related characteristics to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS Of the 139 subjects included, 45% of subjects developed early ePOR (n = 63). VAT radiodensity (aOR 0.59, 95%CI: 0.38-0.90) and VAT:SAT radiodensity (aOR 8.54, 95%CI: 1.48-49.28) were associated with early ePOR, whereas, VAT volume (aOR 1.23, 95%CI: 0.78-1.95), VAT:SAT volume (aOR 0.80, 95%CI: 0.53-1.20), severe VR engorgement (aOR 1.53, 95%CI: 0.64-3.66), and mesenteric LAD (aOR 1.59, 95%CI: 0.67-3.79) were not. Similar results were observed for severity of ePOR. CONCLUSION VAT radiodensity is potentially a novel non-invasive prognostic imaging marker to help risk stratify CD patients for POR.
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Affiliation(s)
- Phillip Gu
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Shishir Dube
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Norman Gellada
- Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - So Yung Choi
- Department of Biostatistics Shared Resource, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Susan Win
- Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu 42601, South Korea
| | - Shaohong Yang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Talin Haritunians
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Gil Y Melmed
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Eric A Vasiliauskas
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Niru Bonthala
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
| | - Gaurav Syal
- Department of Medicine, University of California at San Diego, San Diego, CA 92093, United States
| | - Andres J Yarur
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - David Ziring
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Shervin Rabizadeh
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Phillip Fleshner
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Cindy Kallman
- Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Suzanne Devkota
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Stephan R Targan
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Dalin Li
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Dermot PB McGovern
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
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Akçadağ G, Cansaran-Duman D, Aras ES, Ataoğlu H. Study on Cloning and Expression of TNF-α Variants in E. coli: Production, Purification, and Interaction with Anti-TNF-α Inhibitors. Protein Pept Lett 2024; 31:395-408. [PMID: 38847260 DOI: 10.2174/0109298665312592240516111404] [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: 02/24/2024] [Revised: 04/15/2024] [Accepted: 04/18/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND TNF-α is a proinflammatory cytokine and plays a role in cell proliferation, differentiation, survival, and death pathways. When administered at high doses, it may cause damage to the tumor vasculature, thereby increasing the permeability of the blood vessels. Therefore, monitoring the dose and the response of the TNF-α molecule is essential for patients' health. OBJECTIVES This study aimed to clone, express, and purify the active form of the TNF-α protein, which can interact with various anti-TNF-α inhibitors with high efficiency. METHODS Recombinant DNA technology was used to clone three different versions of codon-optimized human TNF-α sequences to E. coli. Colony PCR protocol was used for verification and produced proteins were analyzed through SDS-PAGE and western blot. Size exclusion chromatography was used to purify sTNF-α. ELISA techniques were used to analyze and compare binding efficiency of sTNF-α against three different standards. RESULTS Under native condition (25°C), interaction between sTNF-α and anti-TNF-α antibody was 3,970, compared to positive control. The interaction was 0,587, whereas it was 0,535 for TNF- α and anti-TNF-α antibodies under denaturing conditions (37°C). F7 of sTNF-α (920 μg/mL) had the same/higher binding efficiency to adalimumab, etanercept, and infliximab, compared to commercial TNF-α. CONCLUSION This study was the first to analyze binding efficiency of homemade sTNF-α protein against three major TNF-α inhibitors (adalimumab, etanercept, and infliximab) in a single study. The high binding efficiency of sTNF-α with adalimumab, etanercept, and infliximab, evidenced in this study supports the feasibility of its use in therapeutic applications, contributing to more sustainable, cost-effective, and independent healthcare system.
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Affiliation(s)
- Gülşah Akçadağ
- Department of Biology, Science Faculty, Ankara University, Tandogan, Ankara, Turkey
- Matriks Biotechnology Industry and Trade Ltd. Co., Gazi Teknopark, Ankara, Turkey
| | | | - Emine Sümer Aras
- Department of Biology, Science Faculty, Ankara University, Tandogan, Ankara, Turkey
| | - Haluk Ataoğlu
- Matriks Biotechnology Industry and Trade Ltd. Co., Gazi Teknopark, Ankara, Turkey
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Karstarlı Bakay OS, Bakay U. A case of certolizumab-induced purpura annularis telangiectodes of Majocchi and literature review. Int J Rheum Dis 2024; 27:e14854. [PMID: 37522716 DOI: 10.1111/1756-185x.14854] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 06/16/2023] [Accepted: 07/18/2023] [Indexed: 08/01/2023]
Abstract
Tumor necrosis factor alpha (TNFα) inhibitors are now widely used to treat immune-mediated inflammatory diseases. Although they have a good safety profile, they are also associated with adverse cutaneous events. Pigmented purpuric dermatoses (PPD) include a variety of skin diseases characterized by multiple petechial hemorrhages due to capillaritis. Five major clinical types of PPD have been described and purpura annularis telangiectodes of Majocchi (PATM) is a rare subtype of PPD. The cause of PPD is unknown, but drugs are implicated in a minority of cases. There are very few cases in the literature triggered by TNFα inhibitors. We present a case of PATM induced by certolizumab pegol and perform a review including 4 articles in the literature reporting 5 PPD cases induced by TNFα inhibitors. When purpuric eruptions develop in patients treated with TNFα inhibitors, PPD and vasculitis should be differentiated. Thus, patients are not exposed to unnecessary evaluations and treatments.
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Affiliation(s)
| | - Umut Bakay
- Department of Rheumatology, Denizli State Hospital, Denizli, Turkey
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11
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Dong W, Hu X, Wu C, Wang G, Fang Y, Shi L, Nie X. Efficacy, safety, and cost-effectiveness of therapeutic drug monitoring (TDM) for TNF inhibitor therapy in rheumatic disease: A systematic review and meta-analysis. Semin Arthritis Rheum 2023; 63:152302. [PMID: 37951128 DOI: 10.1016/j.semarthrit.2023.152302] [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: 06/19/2023] [Revised: 10/17/2023] [Accepted: 10/26/2023] [Indexed: 11/13/2023]
Abstract
OBJECTIVE The benefits of TDM-guided TNFi therapy in patients with rheumatic disease was still controversial. This systematic review and meta-analysis was conducted to explore if the TDM-guided TNFi therapy is superior to empirical-guided therapy. METHODS We systematically searched PubMed, Web of Science, Cochrane Library, and EMBASE databases for articles published between database inception and October 05, 2023. Studies reporting endpoints in TDM-guided TNFi therapy and empirical therapy were included. Results would be presented in risk ratio (RR) and mean difference, with 95 % confidence interval (CI) reported. This study is registered with PROSPERO (CRD42022353956). RESULTS A total of 14 studies (eight RCTs and six cohort studies) involving 2427 patients were included in this meta-analysis. In the scenario of response prediction, compared with empirical-guided therapy, TDM-guided TNFi therapy had association with higher treat-to-target rates (RR 1.30, 95 % CI 1.02-1.65, P=0.03, I2=79 %), more specifically, higher low disease activity rates (RR 2.11, 95 % CI 1.22-3.66, P=0.007, I2=61 %), but no difference in clinical remission rates (RR 0.98,95 % CI 0.87-1.11, P=0.75, I2=0 %). In the scenario of dose reduction prediction, lower relapse rates (RR 0.73, 95 % CI 0.65-0.82, P <0.00001, I2=0 %) were observed compared with empirical-guided dose reduction strategy, but no difference (RR 1.24, 95 % CI 0.85-1.80, P=0.27, I2=57 %) between TDM-guided dose reduction and standard-dosing therapy. No significant difference was observed in change of disease activity score, mean disease activity score, radiographic progression, and safety. And TDM-guided therapy was associated with reduced cost per patient per year calculated as the total accumulated sum of therapy cost. CONCLUSION TDM-guided TNFi therapy was associated with increased rates of low disease activity and decreased risks of relapse, and may save cost compared with empirical-guided therapy in patients with rheumatic disease. But this does not mean that the use of TDM-guided TNFi therapy can be advocated, because there is no difference in clinical remission rates and many other outcomes. More researches, especially randomized clinical trials are needed to verify this conclusion in the future.
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Affiliation(s)
- Wenliang Dong
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Clinical Trial Institution, Peking University People's Hospital, Beijing 101109, China
| | - Xiaowen Hu
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Caiying Wu
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Gengchen Wang
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Yi Fang
- Clinical Trial Institution, Peking University People's Hospital, Beijing 101109, China.
| | - Luwen Shi
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; International Research Center for Medicinal Administration, Peking University, Beijing 100191, China.
| | - Xiaoyan Nie
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; International Research Center for Medicinal Administration, Peking University, Beijing 100191, China.
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12
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Axiaris G, Ioannou A, Papoutsaki M, Marinos L, Liontos M, Michopoulos S, Zampeli E. Case Report: Malignant melanoma in a patient with Crohn's disease treated with ustekinumab. F1000Res 2023; 11:424. [PMID: 37867623 PMCID: PMC10589619 DOI: 10.12688/f1000research.110356.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2023] [Indexed: 10/24/2023] Open
Abstract
The cornerstone of inflammatory bowel disease (IBD) treatment is immunomodulators. IBD patients are at increased risk of intestinal and extraintestinal malignancy. Ustekinumab is a fully humanized monoclonal anti-IL12/23 antibody with a good safety profile. Malignancies of breast, colon, head and neck, kidney, prostate, thyroid, and non-melanoma skin cancer have been reported among patients who received ustekinumab. We report the case of a 42-year-old Crohn's patient on long-term treatment with ustekinumab, who developed achromatic malignant melanoma. Crohn's was diagnosed at the age of 15, with upper and lower gastrointestinal involvement and was initially treated with azathioprine (2mg/kg for 4 years) and infliximab (5mg/kg for 6 weeks). Due to ileal obstruction, the patient underwent stricturoplasty and received adalimumab (40mg every other week) for two years. He then discontinued therapy and a year later underwent right hemicolectomy. Adalimumab was reinstituted (40mg every other week) and the patient remained in clinical remission for two years. His overall exposure to adalimumab was four years. Ustekinumab was initiated due to a relapse and after 3 years, an incident of scalp itching led to the diagnosis metastatic achromatic malignant melanoma bearing BRAF V600E mutation. He received targeted therapy with an initial good response. We aim to point out the risk of dermatologic malignancy in IBD patients on long-term immunosuppression and the lifelong and meticulous evaluation that is required.
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Affiliation(s)
- Georgios Axiaris
- Gastroenterology Department, Alexandra General Hospital, Athens, Greece, 11528, Greece
| | - Alexandros Ioannou
- Gastroenterology Department, Alexandra General Hospital, Athens, Greece, 11528, Greece
| | - Marina Papoutsaki
- Dermatology Department, Syggros Hospital, Athens, Greece, 11528, Greece
| | - Leonidas Marinos
- Pathology Department, Evangelismos Hospital, Atherns, Greece, 11528, Greece
| | - Michael Liontos
- Oncology Department, Alexandra General Hospital, Athens, Greece, 11528, Greece
| | - Spyridon Michopoulos
- Gastroenterology Department, Alexandra General Hospital, Athens, Greece, 11528, Greece
| | - Evanthia Zampeli
- Gastroenterology Department, Alexandra General Hospital, Athens, Greece, 11528, Greece
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De Stefano L, Guerini M, Pelizza J, Ferracane G, Piccin V, Montecucco C, Bugatti S. A case of a rheumatoid nodule on the aortic valve in a patient with rheumatoid arthritis in sustained remission with anti-TNFα. Scand J Rheumatol 2023; 52:577-579. [PMID: 37139805 DOI: 10.1080/03009742.2023.2201065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 05/05/2023]
Affiliation(s)
- L De Stefano
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - M Guerini
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - J Pelizza
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - G Ferracane
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - V Piccin
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C Montecucco
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - S Bugatti
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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14
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Song YJ, Nam SW, Suh CH, Choe JY, Yoo DH. Biosimilars in the treatment of rheumatoid arthritis: a pharmacokinetic overview. Expert Opin Drug Metab Toxicol 2023; 19:751-768. [PMID: 37842948 DOI: 10.1080/17425255.2023.2270407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/10/2023] [Indexed: 10/17/2023]
Abstract
INTRODUCTION As of May 2023, 19 and 18 biosimilars have been approved for the treatment of rheumatoid arthritis (RA) by the European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) respectively. AREA COVERED Pharmacokinetic results of phase 1 studies of approved biosimilars were reviewed by systematic literature search. The impact of immunogenicity on the pharmacokinetic data and clinical response was assessed, and the potential benefit of monitoring serum concentrations of biologic drugs is discussed. The advantage of subcutaneous CT-P13 (an infliximab biosimilar) in clinical practice is reviewed. EXPERT OPINION Biosimilars are approved based on the totality of evidence including comparable physiochemical properties, PK / PD profiles, and clinical efficacy and safety to the originator. To utilize biosimilars more effectively, physicians should be aware of the utility of combination DMARD therapy to reduce immunogenicity and maintain efficacy and PK profile. PK monitoring, however, is not currently recommended in clinical practice. CT-P13 subcutaneous (SC) is the first SC infliximab used for treatment of RA patients. Based on data from clinical studies and the real world, SC-infliximab is an attractive therapeutic option compared to IV formulations of infliximab based on its efficacy, pharmacokinetics, patient-reported outcomes, and safety profile.
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Affiliation(s)
- Yeo-Jin Song
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
- Hanyang University Institute of Rheumatologic Research, Seoul, Republic of Korea
| | - Seoung Wan Nam
- Department of Rheumatology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Chang Hee Suh
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jung Yoon Choe
- Department of Rheumatology, Daegu Catholic University Medical Center, Daegu, Republic of Korea
| | - Dae Hyun Yoo
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
- Hanyang University Institute of Rheumatologic Research, Seoul, Republic of Korea
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Pizano-Martinez O, Mendieta-Condado E, Vázquez-Del Mercado M, Martínez-García EA, Chavarria-Avila E, Ortuño-Sahagún D, Márquez-Aguirre AL. Anti-Drug Antibodies in the Biological Therapy of Autoimmune Rheumatic Diseases. J Clin Med 2023; 12:jcm12093271. [PMID: 37176711 PMCID: PMC10179320 DOI: 10.3390/jcm12093271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Autoimmune rheumatic diseases are a cluster of heterogeneous disorders that share some clinical symptoms such as pain, tissue damage, immune deregulation, and the presence of inflammatory mediators. Biologic disease-modifying antirheumatic drugs are some of the most effective treatments for rheumatic diseases. However, their molecular and pharmacological complexity makes them potentially immunogenic and capable of inducing the development of anti-drug antibodies. TNF inhibitors appear to be the main contributors to immunogenicity because they are widely used, especially in rheumatoid arthritis. Immunogenicity response on these treatments is crucial since the appearance of ADAs has consequences in terms of safety and efficacy. Therefore, this review proposes an overview of the immunogenicity of biological agents used in autoimmune rheumatic diseases highlighting the prevalence of anti-drug antibodies.
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Affiliation(s)
- Oscar Pizano-Martinez
- Instituto de Investigación en Reumatología y del Sistema Músculo-Esquelético (IIRSME), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Departamento de Morfología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Cuerpo Académico UDG-CA-703, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
| | - Edgar Mendieta-Condado
- Laboratorio Estatal de Salud Pública (LESP), Secretaría de Salud Jalisco, Zapopan 46170, JAL, Mexico
| | - Mónica Vázquez-Del Mercado
- Instituto de Investigación en Reumatología y del Sistema Músculo-Esquelético (IIRSME), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Cuerpo Académico UDG-CA-703, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
| | - Erika Aurora Martínez-García
- Instituto de Investigación en Reumatología y del Sistema Músculo-Esquelético (IIRSME), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Cuerpo Académico UDG-CA-703, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
| | - Efrain Chavarria-Avila
- Instituto de Investigación en Reumatología y del Sistema Músculo-Esquelético (IIRSME), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Departamento de Disciplinas Filosófico, Metodológicas e Instrumentales, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
| | - Daniel Ortuño-Sahagún
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
| | - Ana Laura Márquez-Aguirre
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, JAL, Mexico
- Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C. (CIATEJ), Guadalajara 44270, JAL, Mexico
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16
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Lopetuso LR, Cuomo C, Mignini I, Gasbarrini A, Papa A. Focus on Anti-Tumour Necrosis Factor (TNF)-α-Related Autoimmune Diseases. Int J Mol Sci 2023; 24:ijms24098187. [PMID: 37175894 PMCID: PMC10179362 DOI: 10.3390/ijms24098187] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Anti-tumour necrosis factor (TNF)-α agents have been increasingly used to treat patients affected by inflammatory bowel disease and dermatological and rheumatologic inflammatory disorders. However, the widening use of biologics is related to a new class of adverse events called paradoxical reactions. Its pathogenesis remains unclear, but it is suggested that cytokine remodulation in predisposed individuals can lead to the inflammatory process. Here, we dissect the clinical aspects and overall outcomes of autoimmune diseases caused by anti-TNF-α therapies.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Claudia Cuomo
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
| | - Irene Mignini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University, 00168 Rome, Italy
| | - Alfredo Papa
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Gemelli, IRCCS, 00168 Rome, Italy
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University, 00168 Rome, Italy
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Leone GM, Mangano K, Petralia MC, Nicoletti F, Fagone P. Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy. J Clin Med 2023; 12:jcm12041630. [PMID: 36836166 PMCID: PMC9963154 DOI: 10.3390/jcm12041630] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
Due to the key role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of immunoinflammatory diseases, TNF-α inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. Currently, five anti-TNF-α drugs have been approved: infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. Anti-TNF-α biosimilars are also available for clinical use. Here, we will review the historical development as well as the present and potential future applications of anti-TNF-α therapies, which have led to major improvements for patients with several autoimmune diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PS) and chronic endogenous uveitis. Other therapeutic areas are under evaluation, including viral infections, e.g., COVID-19, as well as chronic neuropsychiatric disorders and certain forms of cancer. The search for biomarkers able to predict responsiveness to anti-TNF-α drugs is also discussed.
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Affiliation(s)
- Gian Marco Leone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95123 Catania, Italy
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95123 Catania, Italy
| | - Maria Cristina Petralia
- Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95123 Catania, Italy
- Correspondence:
| | - Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95123 Catania, Italy
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18
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Fernandez CA. Pharmacological strategies for mitigating anti-TNF biologic immunogenicity in rheumatoid arthritis patients. Curr Opin Pharmacol 2023; 68:102320. [PMID: 36580770 PMCID: PMC10540078 DOI: 10.1016/j.coph.2022.102320] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/19/2022] [Indexed: 12/28/2022]
Abstract
Tumor necrosis factor alpha (TNFα) inhibitors are a mainstay of treatment for rheumatoid arthritis (RA) patients after failed responses to conventional disease-modifying antirheumatic drugs (DMARDs). Despite the clinical efficacy of TNFα inhibitors (TNFi), many RA patients experience TNFi treatment failure due to the development of anti-drug antibodies (ADAs) that can neutralize drug levels and lead to RA disease relapse. Methotrexate (MTX) therapy with concomitant TNFα inhibitors decreases the risk of TNFi immunogenicity, but additional and/or alternative strategies are needed to reduce MTX-associated toxicities and to further increase its potency for preventing TNFα inhibitor immunogenicity. In this review, we highlight the limitations of MTX for mitigating TNFα inhibitor immunogenicity, and we discuss potential alternative pharmacological targets for decreasing the risk of immunogenicity during TNFα inhibitor therapy based on the key kinases, second messengers, and shared signaling mechanisms of lymphocyte receptor signaling.
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Affiliation(s)
- Christian A Fernandez
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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19
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Gehin JE, Goll GL, Brun MK, Jani M, Bolstad N, Syversen SW. Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs 2022; 36:731-748. [PMID: 36315391 PMCID: PMC9649489 DOI: 10.1007/s40259-022-00559-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2022] [Indexed: 11/30/2022]
Abstract
Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.
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Affiliation(s)
- Johanna Elin Gehin
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway.
| | - Guro Løvik Goll
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Marthe Kirkesæther Brun
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Meghna Jani
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
- Department of Rheumatology, Salford Royal NHS Foundation Trust, Salford, UK
| | - Nils Bolstad
- Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424, Oslo, Norway
| | - Silje Watterdal Syversen
- Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
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20
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Liao T, Li M, Yuan T, Hong Q, Zeng Y, Yu D, Yu Q, Yu L, Pu T. Case Report: Severe thrombocytopenia induced by adalimumab in rheumatoid arthritis: A case report and literature review. Front Pharmacol 2022; 13:1041884. [DOI: 10.3389/fphar.2022.1041884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. In recent decades, biological agents such as anti-tumor necrosis factor-α (TNF-α) drugs have been applied in the treatment of RA and it achieved great improvement. The treatment has its side effects, but severe thrombocytopenia is very rare. In this case report we described the occurrence of severe thrombocytopenia in a patient with RA who was treated with adalimumab. Specially, the symptoms of the RA are not significantly improved by adalimumab treatment and severe thrombocytopenia it induced is resistant to treatment. After receiving four doses of adalimumab, the patient’s platelet count dropped to 4 × 103/μl. We halted adalimumab and administered glucocorticoids, interleukins, and platelet transfusion. On the sixth day, the platelet count rose to 52 × 103/μl. Lab tests and bone marrow pictures were unremarkable. Patient was treated with prednisone for maintenance. On day 17, the platelet count declined to 12 × 103/μl. We started the patient on methylprednisolone and recombinant human thrombopoietin (rh-TPO), but the effect was not significant. On day 25, intravenous immune globulin (IVIG) was applied in place of the rh-TPO. On 29th day, the patient’s platelets returned to normal. We summarized the existing literature on thrombocytopenia induced by anti-TNF-α drugs. This case suggested immunoglobulins could be considered for the treatment of refractory thrombocytopenia.
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Valdes L, Cox JT, Yang J, Susarla G, Han S, Papaliodis GN, Sobrin L. Anti-infliximab antibodies and clinical response in noninfectious uveitis and scleritis patients treated with infliximab: A retrospective review. Am J Ophthalmol Case Rep 2022; 27:101634. [PMID: 35800400 PMCID: PMC9253593 DOI: 10.1016/j.ajoc.2022.101634] [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: 02/05/2022] [Revised: 06/14/2022] [Accepted: 06/21/2022] [Indexed: 12/01/2022] Open
Abstract
Purpose To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA. Observations A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable. Conclusions and Importance In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary.
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Affiliation(s)
| | | | | | - Gayatri Susarla
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Samuel Han
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - George N. Papaliodis
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Lucia Sobrin
- Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
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22
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Mora JR, Wong R, Shaikh M, Askelson M. Analysis of the Immunogenicity from Abatacept-Treated Pediatric Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Findings From Two Phase III Clinical Trials. ACR Open Rheumatol 2021; 4:177-186. [PMID: 34792858 PMCID: PMC8843768 DOI: 10.1002/acr2.11375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 11/20/2022] Open
Abstract
Objective The goal of this article is to present the analysis of anti‐abatacept antibody data from children with polyarticular‐course juvenile idiopathic arthritis (pJIA), treated with abatacept. The data are from 395 participants with pJIA from two abatacept registrational trials. Methods We analyzed immunogenicity data according to age groups, administration route (intravenous [IV] or subcutaneous [SC]), drug treatment interruption, and co‐medications (with or without methotrexate [MTX]) to assess impact on the incidence of anti‐abatacept antibodies. Results The overall immunogenicity incidences observed in both JIA trials ranged between 4.7% and 23.3%. There was a slightly higher immunogenicity incidence in the 2–5‐year‐old participants (15.2%) compared with 6–17‐year‐old participants (4.7%). In the study with SC dosing, the overall incidence on treatment was 2.3% (3% if co‐dosed with MTX), similar to the incidence for Period A of the IV study (similar duration of treatment as the SC study), which was 2.1% (1.4% if co‐dosed with MTX). In the IV study, the period following a 6‐month interruption in treatment had comparable immunogenicity incidences (22.9% with interruption vs. 18.2% without interruption, both co‐dosed with MTX and 0% for both not co‐dosed with MTX). In most cases, participants co‐dosed with MTX had higher immunogenicity incidences than those on abatacept alone. Conclusion Although some trends were noted in terms of incidence according to age and MTX co‐dosing, none where conclusive owing to differences in population size. Drug holiday had no impact on immunogenicity incidence once treatment was resumed, and incidences across SC and IV dosing were comparable. There was no impact of immunogenicity on pharmacokinetics, safety, and efficacy.
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Affiliation(s)
- Johanna R Mora
- Non-clinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey
| | - Robert Wong
- Immunology and Fibrosis, Bristol Myers Squibb, Princeton, New Jersey
| | - Mehmooda Shaikh
- Non-clinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey
| | - Margarita Askelson
- Global Biometrics and Data Science, Bristol Myers Squibb, Princeton, New Jersey
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Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective. Drugs 2021; 81:1881-1896. [PMID: 34596876 PMCID: PMC8578115 DOI: 10.1007/s40265-021-01601-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 12/18/2022]
Abstract
Background Biosimilars have been used for 15 years in the European Union (EU), and have been shown to reduce costs and increase access to important biological medicines. In spite of their considerable exposure and excellent safety record, many prescribers still have doubts on the safety and interchangeability of biosimilars, especially monoclonal antibodies (mAbs) and fusion proteins. Objectives The aim of this study was to analyse the short- and long-term safety and interchangeability data of biosimilar mAbs and fusion proteins to provide unbiased information to prescribers and policy makers. Methods Data on the safety, immunogenicity and interchangeability of EU-licensed mAbs and fusion proteins were examined using European Public Assessment Reports (EPARs) and postmarketing safety surveillance reports from the European Medicines Agency (EMA). As recent biosimilar approvals allow self-administration by patients by the subcutaneous route, the administration devices were also analyzed. Results Prelicensing data of EPARs (six different biosimilar adalimumabs, three infliximabs, three etanercepts, three rituximabs, two bevacizumabs, and six trastuzumabs) revealed that the frequency of fatal treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, serious adverse events (SAEs), and main immune-mediated adverse events (AEs) were comparable between the biosimilars and their reference products. The availability of new biosimilar presentations and administration devices may add to patient choice and be an emerging factor in the decision to switch patients. Analysis of postmarketing surveillance data covering up to 7 years of follow-up did not reveal any biosimilar-specific adverse effects. No product was withdrawn for safety reasons. This is in spite of considerable exposure to biosimilars in treatment-naïve patients and in patients switched from the reference medicinal product to the biosimilar. Analysis of data from switching studies provided in regulatory submissions showed that single or multiple switches between the originator and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity. Conclusions In line with previous reports of prelicensing studies of biosimilar mAbs and etanercepts, this study demonstrated comparable efficacy, safety, and immunogenicity compared with the reference products. This is the first study to comprehensively analyze postmarketing surveillance data of the biosimilar mAbs and etanercept. An analysis of more than 1 million patient-treatment years of safety data raised no safety concerns. Based on these data, we argue that biosimilars approved in the EU are highly similar to and interchangeable with their reference products. Thus, additional systematic switch studies are not required to support the switching of patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01601-2.
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24
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Weitman M, Bejar C, Melamed M, Weill T, Yanovsky I, Zeeli S, Nudelman A, Weinstock M. Comparison of the tissue distribution and metabolism of AN1284, a potent anti-inflammatory agent, after subcutaneous and oral administration in mice. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2077-2089. [PMID: 34309687 DOI: 10.1007/s00210-021-02125-y] [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: 04/21/2021] [Accepted: 07/08/2021] [Indexed: 11/29/2022]
Abstract
This study is to compare the tissue distribution and metabolism of AN1284 after subcutaneous and oral administration at doses causing maximal reductions in IL-6 in plasma and tissues of mice. Anti-inflammatory activity of AN1284 and its metabolites was detected in lipopolysaccharide (LPS) activated RAW 264.7 macrophages. Mice were given AN1284 by injection or gavage, 15 min before LPS. IL-6 protein levels were measured after 4 h. Using a liquid chromatography/mass spectrometry method we developed, we showed that AN1284 is rapidly metabolized to the indole (AN1422), a 7-OH derivative (AN1280) and its glucuronide. AN1422 has weaker anti-inflammatory activity than AN1284 in LPS-activated macrophages and in mice. AN1284 (0.5 mg/kg) caused maximal reductions in IL-6 in the plasma, brain, and liver when injected subcutaneously and after gavage only in the liver. Similar reductions in the plasma and brain required a dose of 2.5 mg/kg, which resulted in 5.5-fold higher hepatic levels than after injection of 0.5 mg/kg, but 7, 11, and 19-fold lower ones in the plasma, brain, and kidneys, respectively. Hepatic concentrations produced by AN1284 were 2.5 mg/kg/day given by subcutaneously implanted mini-pumps that were only 12% of the peak levels seen after acute injection of 0.5 mg/kg. Similar hepatic concentrations were obtained by (1 mg/kg/day), administered in the drinking fluid. These were sufficient to decrease hepatocellular damage and liver triglycerides in previous experiments in diabetic mice. AN1284 can be given orally by a method of continuous release to treat chronic liver disease, and its preferential concentration in the liver should limit any adverse effects.
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Affiliation(s)
- Michal Weitman
- Department of Chemistry, Bar-Ilan University, 5290002, Ramat Gan, Israel
| | - Corina Bejar
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Ein Kerem, 9112002, Jerusalem, Israel
| | - Michal Melamed
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Ein Kerem, 9112002, Jerusalem, Israel
| | - Tehilla Weill
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Ein Kerem, 9112002, Jerusalem, Israel
| | - Inessa Yanovsky
- Department of Chemistry, Bar-Ilan University, 5290002, Ramat Gan, Israel
| | - Shani Zeeli
- Department of Chemistry, Bar-Ilan University, 5290002, Ramat Gan, Israel
| | - Abraham Nudelman
- Department of Chemistry, Bar-Ilan University, 5290002, Ramat Gan, Israel
| | - Marta Weinstock
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Ein Kerem, 9112002, Jerusalem, Israel.
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Paknikar SS, Crowson CS, Davis JM, Thanarajasingam U. Exploring the Role of Antinuclear Antibody Positivity in the Diagnosis, Treatment, and Health Outcomes of Patients With Rheumatoid Arthritis. ACR Open Rheumatol 2021; 3:422-426. [PMID: 34060254 PMCID: PMC8207683 DOI: 10.1002/acr2.11271] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/16/2021] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The objective of this study was to describe differences in the clinical course of patients with rheumatoid arthritis (RA) who are antinuclear antibody (ANA)-positive compared with those who are ANA-negative. METHODS This was a retrospective population-based cohort study of residents in Olmsted County, Minnesota, who first fulfilled 1987 American College of Rheumatology criteria for RA in 2009-2014. Data were collected on first documentation of joint swelling. Data on rheumatoid factor or anti-cyclic citrullinated peptide antibody testing and the ANA level were also collected. Comparisons between groups were performed by using χ2 and rank sum tests. RESULTS In this cohort, 64% of patients were tested for ANA within ±90 days of RA criteria fulfillment. In the161 patients with ANA testing, 25% were ANA-positive. Patients who were ANA-positive were younger, female, and less likely to be current smokers. ANA positivity did not differ between patients with RA who were seropositive and seronegative. In seropositive patients who were ANA-positive, there was an increased time to fulfillment of RA criteria, increased time to treatment with disease-modifying antirheumatic drugs (DMARDs), and increased likelihood of being treated with hydroxychloroquine as opposed to methotrexate. Other outcomes, including disease activity and mortality, did not differ significantly between groups. CONCLUSION In patients with RA, important differences exist between those who are ANA-positive and ANA-negative in terms of time to fulfillment of RA criteria and time to DMARD initiation as well as choice of initial pharmacotherapy. These findings could indicate a difference in clinical presentation or perception of patients with RA who are ANA-positive. Further research is needed to study the long-term outcomes of patients with RA who are ANA-positive.
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Coxon CH, Yu X, Beavis J, Diaz-Saez L, Riches-Duit A, Ball C, Diamond SL, Raut S. Characterisation and application of recombinant FVIII-neutralising antibodies from haemophilia A inhibitor patients. Br J Haematol 2021; 193:976-987. [PMID: 33973229 DOI: 10.1111/bjh.17227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
The development of anti-drug antibodies (ADAs) is a serious outcome of treatment strategies involving biological medicines. Coagulation factor VIII (FVIII) is used to treat haemophilia A patients, but its immunogenicity precludes a third of severe haemophiliac patients from receiving this treatment. The availability of patient-derived anti-drug antibodies can help us better understand drug immunogenicity and identify ways to overcome it. Thus, there were two aims to this work: (i) to develop and characterise a panel of recombinant, patient-derived, monoclonal antibodies covering a range of FVIII epitopes with varying potencies, kinetics and mechanism of action, and (ii) to demonstrate their applicability to assay development, evaluation of FVIII molecules and basic research. For the first objective we used recombinant antibodies to develop a rapid, sensitive, flexible and reproducible ex vivo assay that recapitulates inhibitor patient blood using blood from healthy volunteers. We also demonstrate how the panel can provide important information about the efficacy of FVIII products and reagents without the need for patient or animal material. These materials can be used as experimental exemplars or controls, as well as tools for rational, hypothesis-driven research and assay development in relation to FVIII immunogenicity and FVIII-related products.
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Affiliation(s)
- Carmen H Coxon
- National Institute for Biological Standards and Control, Hertfordshire, UK
| | - Xinren Yu
- University of Pennsylvania, Philadelphia, PA, USA
| | - James Beavis
- Oxford Haemophilia Centre, Churchill Hospital, Oxford, UK
| | | | - Andrew Riches-Duit
- National Institute for Biological Standards and Control, Hertfordshire, UK
| | - Chris Ball
- National Institute for Biological Standards and Control, Hertfordshire, UK
| | | | - Sanj Raut
- National Institute for Biological Standards and Control, Hertfordshire, UK
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27
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Choi SJ, Ahn SM, Oh JS, Hong S, Lee CK, Yoo B, Ye BD, Yang SK, Park SH, Kim YG. Anti-tumor necrosis factor-induced lupus in patients with inflammatory bowel disease: a hospital-based cohort study from Korea. Therap Adv Gastroenterol 2021; 14:1756284821997794. [PMID: 33747126 PMCID: PMC7940731 DOI: 10.1177/1756284821997794] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/05/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Anti-tumor necrosis factor (TNF) agents are increasingly used for rheumatic diseases and inflammatory bowel disease (IBD), but are associated with the development of anti-TNF-induced lupus (ATIL). Nonetheless, few ATIL studies on non-Caucasian IBD patients exist. Here, we investigated the incidence, clinical features, and risk factors of ATIL in Korea. METHODS We retrospectively reviewed the medical records of IBD patients undergoing anti-TNF therapy at our tertiary IBD center between 2008 and 2020. ATIL was diagnosed as a temporal association between symptoms and anti-TNF agents, and the presence of at least one serologic and non-serologic American College of Rheumatology criterion. The risk factors for ATIL occurrence were assessed using multivariate Cox regression analysis. RESULTS Of 1362 IBD patients treated with anti-TNF agents, 50 (3.7%) ATIL cases were suspected, of which 14 (1.0%) received a definitive diagnosis. Arthritis and mucocutaneous symptoms were observed in 13 and 4 patients, respectively. All ATIL cases were positive for anti-nuclear and anti-dsDNA antibodies. Four patients (30.8%) improved while continuing anti-TNF therapy. At the final follow up, the ATIL group (n = 14) had a lower IBD remission rate (30.8% versus 68.8%, p = 0.019) than the non-ATIL group (n = 36). Ulcerative colitis and longer disease duration were associated with ATIL occurrence, with hazard ratios of 7.017 (p = 0.005) and 1.118 (p = 0.002), respectively. CONCLUSION Although rare, ATIL is associated with poor treatment response to IBD in Korean patients. ATIL should be considered if arthritis and mucocutaneous symptoms develop during anti-TNF therapy for IBD.
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Affiliation(s)
- Su Jin Choi
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Soo Min Ahn
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ji Seon Oh
- Department of Information Medicine, Asan Medical Center, Seoul, South Korea
| | - Seokchan Hong
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Chang-Keun Lee
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Bin Yoo
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | | | - Yong-Gil Kim
- Department of Rheumatology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
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Biologics and Targeted Synthetic Drugs Can Induce Immune-Mediated Glomerular Disorders in Patients with Rheumatic Diseases: An Updated Systematic Literature Review. BioDrugs 2021; 35:175-186. [PMID: 33595833 PMCID: PMC7952370 DOI: 10.1007/s40259-021-00467-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2021] [Indexed: 12/12/2022]
Abstract
Objective Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the “certain” and “probable” categories were deemed clinically relevant relationships. Results The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started.
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Kim H, Alten R, Cummings F, Danese S, D'Haens G, Emery P, Ghosh S, Gilletta de Saint Joseph C, Lee J, Lindsay JO, Nikiphorou E, Parker B, Schreiber S, Simoens S, Westhovens R, Jeong JH, Peyrin-Biroulet L. Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters. MAbs 2021; 13:1868078. [PMID: 33557682 PMCID: PMC7889098 DOI: 10.1080/19420862.2020.1868078] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as “biobetters” or “value-added medicines,” are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.
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Affiliation(s)
- HoUng Kim
- Celltrion Healthcare , Incheon, Republic of Korea.,Department of Pharmacology, College of Medicine, Chung-Ang University , Seoul, Republic of Korea
| | - Rieke Alten
- Rheumatology Research Center, Schlosspark-Klinik Charité, University Medicine Berlin , Berlin, Germany
| | - Fraser Cummings
- Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust , Southampton, UK
| | - Silvio Danese
- Humanitas Clinical and Research Center - IRCCS and Department of Biomedical Sciences, Humanitas University , Milan, Italy
| | - Geert D'Haens
- Department of Inflammatory Bowel Disease, Amsterdam University Medical Centers , Amsterdam, The Netherlands
| | - Paul Emery
- Leeds NIHR Biomedical Research Centre, The Leeds Teaching Hospital Trust, and Leeds Institute of Rheumatic & Musculoskeletal Medicine, University of Leeds , UK
| | - Subrata Ghosh
- The Institute of Translational Medicine, Immunology and Immunotherapy, NIHR BRC, University of Birmingham , Birmingham, UK
| | | | - JongHyuk Lee
- Department of Pharmaceutical Engineering, College of Life and Health Science, Hoseo University , Asan, Republic of Korea
| | - James O Lindsay
- Department of Gastroenterology, The Royal London Hospital, Barts Health NHS Trust , London, UK
| | - Elena Nikiphorou
- Centre for Rheumatic Diseases, King's College, London, and Rheumatology Department, King's College Hospital , London, UK
| | - Ben Parker
- Kellgren Centre for Rheumatology, Manchester Royal Infirmary, NIHR Manchester Biomedical Research Centre , Manchester, UK
| | - Stefan Schreiber
- Department of Medicine I, Christian-Albrechts-University, University Hospital Schleswig-Holstein , Kiel, Germany
| | - Steven Simoens
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , Leuven, Belgium
| | - Rene Westhovens
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center , Leuven, Belgium
| | - Ji Hoon Jeong
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University and Department of Pharmacology, College of Medicine, Chung-Ang University , Seoul, Republic of Korea
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital , Vandoeuvre-Les-Nancy, France.,Inserm U1256 NGERE, Lorraine University , Vandoeuvre-Les-Nancy, France
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Lorenzo-Vizcaya A, Isenberg DA. The use of anti-TNF-alpha therapies for patients with systemic lupus erythematosus. Where are we now? Expert Opin Biol Ther 2021; 21:639-647. [PMID: 33216641 DOI: 10.1080/14712598.2021.1853096] [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] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by multiple pathologies in which sustained inflammatory activity leads to progressive tissue destruction and organ damage. One of the main proinflammatory cytokines playing a key role in autoimmune diseases such as rheumatoid arthritis (RA) or SLE, is tumor necrosis factor (TNF) alpha. AREAS COVERED The introduction of TNF-alpha inhibitors revolutionized the treatment of RA and other conditions including psoriatic arthritis and ankylosing spodylitis. We review here the efficacy and safety of TNF-alpha blockers in SLE focussing on why it has not been more widely used since TNF-alpha was reported to be increased in SLE patients and to correlate with disease activity. EXPERT OPINION We summarize the reported SLE cases that have received TNF-alpha blockers and the main results to date. We reflect on whether there is a case to reconsider the use of TNF-alpha blockade in SLE.
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Affiliation(s)
- Ana Lorenzo-Vizcaya
- Department of Internal Medicine, Hospital Universitario De Ourense. Ourense, Spain
| | - David A Isenberg
- Department of Rheumatology, Division of Medicine, University College London. London, UK
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Esatoglu SN, Akkoc-Mustafayev FN, Ozguler Y, Ozbakır F, Nohut OK, Cevirgen D, Hamuryudan V, Hatemi I, Celik AF, Yazici H, Hatemi G. Immunogenicity of Infliximab Among Patients With Behçet Syndrome: A Controlled Study. Front Immunol 2020; 11:618973. [PMID: 33414791 PMCID: PMC7782473 DOI: 10.3389/fimmu.2020.618973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 11/23/2020] [Indexed: 01/14/2023] Open
Abstract
Background Immunogenicity of tumor necrosis factor alpha inhibitors (TNFis) has been recognized as an important problem that may cause loss of efficacy and adverse events such as infusion reactions. TNFis are being increasingly used among patients with Behçet syndrome (BS) and scarce data exist on this topic. Objective We aimed to investigate the prevalence of anti-infliximab (IFX) antibodies in patients with Behçet syndrome together with suitable controls. Methods We collected serum samples from 66 consecutive Behçet syndrome patients (51 M, 15 F, mean age 37 ± 9 years) who were treated with IFX. Additionally, similarly treated 27 rheumatoid arthritis, 53 ankylosing spondylitis, 25 Crohn's disease patients, and 31 healthy subjects were included as controls. Samples were collected just before an infusion, stored at -80°C until analysis, and serum IFX trough levels and anti-IFX antibodies were measured by ELISA. We used a cut-off value of 1 μg/ml for serum IFX trough level, extrapolating from rheumatoid arthritis studies. Results Anti-IFX antibodies were detected in four (6%) Behçet syndrome, five (18.5%) rheumatoid arthritis, three (12%) Crohn's disease, and one (2%) ankylosing spondylitis patient. The median serum IFX trough level was significantly lower in patients with anti-IFX antibodies compared to those without antibodies [2.32 (IQR: 0.6-3.6) vs. 3.35 (IQR: 1.63-5.6); p = 0.019]. The serum IFX trough level was lower than the cut-off value in 6/13 (46%) patients with anti-IFX antibodies and in 25/158 (16%) patients without anti-IFX antibodies (p = 0.015). Among the four Behçet syndrome patients with anti-IFX antibodies, two experienced relapses and two had infusion reactions. Conclusions Immunogenicity does not seem to be a frequent problem in Behçet syndrome patients treated with IFX, but may be associated with relapses and infusion reactions, when present.
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Affiliation(s)
- Sinem Nihal Esatoglu
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | | | - Yesim Ozguler
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Fatma Ozbakır
- Central Research Laboratory, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Okan K. Nohut
- Central Research Laboratory, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Dilsen Cevirgen
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Vedat Hamuryudan
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ibrahim Hatemi
- Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Aykut Ferhat Celik
- Division of Gastroenterology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hasan Yazici
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Gulen Hatemi
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
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Mori A, Saito T, Takahashi M, Shibata M, Tsuji G, Hatachi S, Takahashi S, Kumagai S. Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis. PLoS One 2020; 15:e0243729. [PMID: 33315881 PMCID: PMC7735569 DOI: 10.1371/journal.pone.0243729] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 11/27/2020] [Indexed: 11/18/2022] Open
Abstract
This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.
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Affiliation(s)
- Ayano Mori
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
| | - Toshiharu Saito
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
| | - Miho Takahashi
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
| | - Miho Shibata
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
| | - Goh Tsuji
- The Center for Rheumatic Disease, Shinko Hospital, Kobe, Japan
| | - Saori Hatachi
- The Center for Rheumatic Disease, Shinko Hospital, Kobe, Japan
| | - Soshi Takahashi
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
- The Center for Rheumatic Disease, Shinko Hospital, Kobe, Japan
| | - Shunichi Kumagai
- The Shinko Institute for Medical Research, Shinko Hospital, Kobe, Japan
- The Center for Rheumatic Disease, Shinko Hospital, Kobe, Japan
- * E-mail:
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Murphy MJ, Cohen JM, Vesely MD, Damsky W. Paradoxical eruptions to targeted therapies in dermatology: A systematic review and analysis. J Am Acad Dermatol 2020; 86:1080-1091. [PMID: 33307146 DOI: 10.1016/j.jaad.2020.12.010] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Antibody-based therapies that inhibit proinflammatory cytokine signaling are commonly used in dermatology. Paradoxically, these medications may induce or exacerbate inflammatory disorders. OBJECTIVE To summarize the spectrum of manifestations, incidence, timing, potential mechanisms of, and general management approaches to paradoxical cutaneous reactions induced by cytokine-targeted antibodies in dermatology. METHODS We performed a systematic review and analysis of published cases of cutaneous paradoxical reactions (PRs) reported in association with tumor necrosis factor α, interleukin (IL) 12/23 (p40), IL-17A/17R, IL-23 (p19), and IL-4Rα inhibitors. RESULTS We identified 313 articles reporting 2049 cases of PRs. Tumor necrosis factor α inhibitors resulted in 91.2% (1869/2049) of all cases, followed by IL-17/17R (3.5%), IL-4Rα (2.7%), IL-12/23 (2.4%), and IL-23 (0.01%) inhibitors. Psoriasiform and eczematous eruptions were the most commonly reported, but a wide spectrum of patterns were described. Phenotypically overlapping reaction patterns were common. Time to onset typically ranged from weeks to months but could occur more than a year later. Improvement or resolution upon discontinuation of the inciting drug was common. LIMITATIONS This was a retrospective analysis. CONCLUSIONS Familiarity with the clinical features of PRs from cytokine-blocking antibodies may facilitate efficient recognition and management.
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Affiliation(s)
| | - Jeffrey M Cohen
- Department of Dermatology, Yale School of Medicine, New Haven
| | | | - William Damsky
- Department of Dermatology, Yale School of Medicine, New Haven.
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Kim JW, Jung JY, Suh CH. Real-world observational study of biosimilars in inflammatory arthritis treatment: a systematic literature review. Expert Opin Biol Ther 2020; 21:57-73. [PMID: 32808557 DOI: 10.1080/14712598.2020.1812575] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The use of biological agents in patients with rheumatic diseases has achieved the therapeutic target, i.e., remission or low disease activity. The share of biological agents has been growing with the approval of biosimilars, which have been recognized for their equivalent efficacy, safety, pharmacokinetics, and immunogenicity to the original as well as their reduced economic burden. AREA COVERED Biosimilars are being examined for their bioequivalence to reference products in randomized-controlled trials; however, the use of biosimilars in actual clinical practice is complicated owing to issues with switching and comorbidities. Therefore, this review describes real-world data in the rapidly evolving field of biosimilars in the treatment of rheumatoid arthritis and spondyloarthropathy, including ankylosing spondylitis and psoriatic arthritis. EXPERT OPINION According to published data, the use of biosimilars for inflammatory arthritis led to no significant inferiority in treatment outcomes and resulted in considerable cost savings in the real-world. Currently, beyond the use of biosimilars, issues with the interchangeability of biosimilars, including immunogenicity, should be addressed. Strategies to overcome these concerns will improve treatment efficacy and safety in patients with inflammatory arthritis.
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Affiliation(s)
- Ji-Won Kim
- Department of Rheumatology, Ajou University School of Medicine , Suwon, Korea
| | - Ju-Yang Jung
- Department of Rheumatology, Ajou University School of Medicine , Suwon, Korea
| | - Chang-Hee Suh
- Department of Rheumatology, Ajou University School of Medicine , Suwon, Korea
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Yoshikawa N, Matsubara E, Yamamoto M, Yamazaki H, Uehara M, Kamata M, Tanaka H. Drug-induced Bullous Pemphigoid and Lupus Erythematosus Occurring under Anti-TNF-α and IL-6 Therapy in a Patient with Rheumatoid Arthritis. Intern Med 2020; 59:2611-2618. [PMID: 32641647 PMCID: PMC7662041 DOI: 10.2169/internalmedicine.4646-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A 65-year-old Japanese woman, who was diagnosed with rheumatoid arthritis and Sjögren's syndrome with various autoantibodies including anti-DNA antibody, developed bullous pemphigoid (BP) and hematological abnormalities like lupus erythematosus after adalimumab therapy. The discontinuation of adalimumab resolved those disorders but polyarthritis thereafter relapsed. The introduction of abatacept was not effective, but tocilizumab was found to be effective for polyarthritis, however, thereafter both bullous disease and severe pancytopenia developed. Discontinuation of tocilizumab was effective, but polyarthritis again developed, and baricitinib resolved it. There is an increasing number of reports of drug-induced BP and lupus erythematosus, and biologics might trigger an alteration in the pathophysiological/clinical course of rheumatic disorder.
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Affiliation(s)
- Noritada Yoshikawa
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
- Division of Rheumatology, Center for Antibody and Vaccine Therap, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Erika Matsubara
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Motohisa Yamamoto
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
- Division of Rheumatology, Center for Antibody and Vaccine Therap, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Hiroki Yamazaki
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Masaaki Uehara
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Masahiro Kamata
- Department of Dermatology, Teikyo University School of Medicine, Japan
| | - Hirotoshi Tanaka
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
- Division of Rheumatology, Center for Antibody and Vaccine Therap, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
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Kharlamova N, Hermanrud C, Dunn N, Ryner M, Hambardzumyan K, Vivar Pomiano N, Marits P, Gjertsson I, Saevarsdottir S, Pullerits R, Fogdell-Hahn A. Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier. Front Immunol 2020; 11:1365. [PMID: 32793189 PMCID: PMC7385065 DOI: 10.3389/fimmu.2020.01365] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/28/2020] [Indexed: 01/14/2023] Open
Abstract
A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
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Affiliation(s)
- Nastya Kharlamova
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Stockholm, Sweden
| | - Christina Hermanrud
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Stockholm, Sweden
| | - Nicky Dunn
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Stockholm, Sweden
| | - Malin Ryner
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Stockholm, Sweden
| | - Karen Hambardzumyan
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Nancy Vivar Pomiano
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Per Marits
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Inger Gjertsson
- Department of Rheumatology and Inflammation Research, Institution of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Saedis Saevarsdottir
- Rheumatology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Rille Pullerits
- Department of Rheumatology and Inflammation Research, Institution of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anna Fogdell-Hahn
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Stockholm, Sweden
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Dermatomyositis-lupuslike syndrome overlap under treatment with etanercept for rheumatoid arthritis. JAAD Case Rep 2020; 6:758-760. [PMID: 32715073 PMCID: PMC7369515 DOI: 10.1016/j.jdcr.2020.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Bodio C, Grossi C, Pregnolato F, Favalli EG, Biggioggero M, Marchesoni A, Murgo A, Filippini M, Migliorini P, Caporali R, Pellerito R, Ciccia F, Sarzi-Puttini P, Perosa F, Paolazzi G, Hollan I, Bendtzen K, Meroni PL, Borghi MO. Personalized medicine in rheumatoid arthritis: How immunogenicity impacts use of TNF inhibitors. Autoimmun Rev 2020; 19:102509. [DOI: 10.1016/j.autrev.2020.102509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 11/22/2019] [Indexed: 01/30/2023]
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Mehta P, Manson JJ. What Is the Clinical Relevance of TNF Inhibitor Immunogenicity in the Management of Patients With Rheumatoid Arthritis? Front Immunol 2020; 11:589. [PMID: 32318070 PMCID: PMC7154129 DOI: 10.3389/fimmu.2020.00589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/13/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor necrosis factor-α inhibitors (TNFis) have revolutionized the management of rheumatoid arthritis (RA), however despite considerable progress, only a small proportion of patients maintain long-term clinical response. Selection of, and switching between, biologics is mainly empirical, experiential, and not evidence-based. Most biopharmaceutical proteins (BP) can induce an immune response against the foreign protein component. Immunogenicity and the development of anti-drug antibodies (ADAs) is considered one of the main reasons for loss of therapeutic efficacy (secondary failure). ADAs may neutralize and/or promote clearance of circulating BP with resultant low serum drug levels, loss of clinical response, poor drug survival and adverse events, such as infusion reactions. ADA identification is technically difficult and not standardized, making interpretation of immunogenicity data from published clinical studies challenging. Trough TNFi drug levels correlate with clinical outcomes, exhibiting a "concentration-response" relationship. Measurement of ADA and drug levels may improve patient care and improve cost-effectiveness of BP use. However, in the absence of clinically-validated, reliable assays and consensus guidelines, therapeutic drug monitoring (TDM) and immunogenicity testing have not been widely adopted in routine clinical practice in Rheumatology. Here we discuss the utility and relevance of TDM and immunogenicity testing of TNFis in RA (focusing on the most widely used TNFis globally, with the most available data, i.e., infliximab, adalimumab, and etanercept), the limitations of currently available assays and potential future immunopharmacological strategies to personalize disease management.
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Affiliation(s)
- Puja Mehta
- Department of Rheumatology, University College London Hospital (UCLH), London, United Kingdom
| | - Jessica J Manson
- Department of Rheumatology, University College London Hospital (UCLH), London, United Kingdom
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Perry M, Abdullah A, Frleta M, MacDonald J, McGucken A. The potential value of blood monitoring of biologic drugs used in the treatment of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2020; 12:1759720X20904850. [PMID: 32095163 PMCID: PMC7011331 DOI: 10.1177/1759720x20904850] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022] Open
Abstract
The advent of biological therapies has been a major therapeutic advance in rheumatology. Many patients now enjoy improved quality of life through better disease control. The number of therapies continues to grow both within drug class (including biosimilar drugs) and via new mechanisms. For the first time, nonbiological drugs such as small-molecule inhibitors (Janus kinase inhibitors) have shown clinical equivalence. However, clinical unmet need remains with up to a third of patients commenced on a biologic therapy having minimal or no response: (a) Generally, the first biologic used secures the best response, with likelihood of remission falling thereafter with successive therapies; (b) the success of strategy trials using biological therapies can be difficult to replicate in clinical practice due to a combination of patient factors and service limitations. Accordingly, ensuring optimization of initial treatment is an important consideration before switching to alternatives. Therapeutic drug monitoring (TDM) is the measurement of serum levels of a biologic drug with the aim of improving patient care. It is usually combined with detection of any antidrug antibodies that could neutralize the effect of the therapy. This technology has the potential to be a form of 'personalized medicine' by individualizing therapy, in particular, dosing and likelihood of sustained treatment response. It requires a clear relationship between drug dose, blood concentration and therapeutic effect. This paper will outline the technology behind TDM and unpack what we can learn from our colleagues in gastroenterology, where the adoption of TDM is at a more advanced stage than in rheumatology. It will explore and set out a number of clinical scenarios where rheumatologists might find TDM helpful in day-to-day practice. Finally, an outline is given of international developments, including regulatory body appraisals and guideline development.
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Affiliation(s)
- Martin Perry
- Department Rheumatology, Royal Alexandra
Hospital, 9 Corsebar Road, Paisley Renfrewshire PA2 9PN, UK
| | - Azhar Abdullah
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
| | - Marina Frleta
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
| | - Jonathan MacDonald
- Department Gastroenterology, Queen Elizabeth
University Hospital, Glasgow, UK
| | - Andrew McGucken
- Department Rheumatology, Royal Alexandra
Hospital, Paisley, UK
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Kim H, Alten R, Avedano L, Dignass A, Gomollón F, Greveson K, Halfvarson J, Irving PM, Jahnsen J, Lakatos PL, Lee J, Makri S, Parker B, Peyrin-Biroulet L, Schreiber S, Simoens S, Westhovens R, Danese S, Jeong JH. The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases. Drugs 2020; 80:99-113. [PMID: 32002851 PMCID: PMC7007415 DOI: 10.1007/s40265-020-01256-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biologics have transformed the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Biosimilars-biologic medicines with no clinically meaningful differences in safety or efficacy from licensed originators-can stimulate market competition and have the potential to expand patient access to biologics within the parameters of treatment recommendations. However, maximizing the benefits of biosimilars requires cooperation between multiple stakeholders. Regulators and developers should collaborate to ensure biosimilars reach patients rapidly without compromising stringent quality, safety, or efficacy standards. Pharmacoeconomic evaluations and payer policies should be updated following biosimilar market entry, minimizing the risk of imposing nonmedical barriers to biologic treatment. In RA, disparities between treatment guidelines and national reimbursement criteria could be addressed to ensure more uniform patient access to biologics and enable rheumatologists to effectively implement treat-to-target strategies. In IBD, the cost-effectiveness of biologic treatment earlier in the disease course is likely to improve when biosimilars are incorporated into pharmacoeconomic analyses. Patient understanding of biosimilars is crucial for treatment success and avoiding nocebo effects. Full understanding of biosimilars by physicians and carefully considered communication strategies can help support patients initiating or switching to biosimilars. Developers must operate efficiently to be sustainable, without undermining product quality, the reliability of the supply chain, or pharmacovigilance. Developers should also facilitate information sharing to meet the needs of other stakeholders. Such collaboration will help to ensure a sustainable future for both the biosimilar market and healthcare systems, supporting the availability of effective treatments for patients.
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Affiliation(s)
- HoUng Kim
- Celltrion Healthcare, Incheon, Republic of Korea
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Rieke Alten
- Department of Internal Medicine and Rheumatology, Schlosspark-Klinik, University Medicine Berlin, Berlin, Germany
| | - Luisa Avedano
- European Federation of Crohn's and Ulcerative Colitis Associations, Brussels, Belgium
| | - Axel Dignass
- Department of Medicine 1, Agaplesion Markus Hospital, Frankfurt am Main, Germany
| | - Fernando Gomollón
- Gastroenterology Unit, Clinical University Hospital Lozano Bless IIS Aragón, Zaragoza, Spain
| | - Kay Greveson
- Centre for Gastroenterology, Royal Free Hospital, London, UK
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Peter M Irving
- IBD Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Jørgen Jahnsen
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Péter L Lakatos
- Division of Gastroenterology, McGill University, Montreal, QC, Canada
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - JongHyuk Lee
- Department of Pharmaceutical Engineering, College of Life and Health Science, Hoseo University, Asan, Republic of Korea
| | - Souzi Makri
- Cyprus League Against Rheumatism, Nicosia, Cyprus
| | - Ben Parker
- Kellgren Centre for Rheumatology, NIHR Manchester Musculoskeletal Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
- Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Stefan Schreiber
- Department Medicine I, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
| | - Steven Simoens
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Rene Westhovens
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center KU Leuven, Rheumatology University Hospital Leuven, Leuven, Belgium
| | - Silvio Danese
- Department of Gastroenterology, Istituto Clinico Humanitas, Milan, Italy.
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Ewart D, Peterson EJ, Steer CJ. A new era of genetic engineering for autoimmune and inflammatory diseases. Semin Arthritis Rheum 2019; 49:e1-e7. [DOI: 10.1016/j.semarthrit.2019.05.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 05/09/2019] [Indexed: 02/06/2023]
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Jani M, Chinoy H, Barton A. Association of Pharmacological Biomarkers with Treatment Response and Longterm Disability in Patients with Psoriatic Arthritis: Results from OUTPASS. J Rheumatol 2019; 47:1204-1208. [DOI: 10.3899/jrheum.190253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2019] [Indexed: 11/22/2022]
Abstract
Objective.To identify (1) whether tumor necrosis factor inhibitor (TNFi) drug levels/anti-drug antibodies (ADAb) are associated with treatment response and disability in patients with psoriatic arthritis (PsA); and (2) the factors associated with TNFi drug levels.Methods.Patients were recruited from a national multicenter prospective cohort with longitudinal serum samples and 28-joint count Disease Activity Scores (DAS28)/Health Assessment Questionnaire (HAQ) measurement over 12 months.Results.Adalimumab (ADA) drug levels were significantly associated with ΔDAS28 (β 0.055, 95% CI 0.011–0.099; p = 0.014) and inversely with HAQ over 12 months (β −0.022, 95% CI −0.043 to −0.00063). Factors significantly associated with ADA drug levels were ADAb levels and body mass index.Conclusion.Drug level testing in ADA-initiated PsA patients may be useful in determining treatment response/disability over 12 months.
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Impact of Adverse Events Associated With Medications in the Treatment and Prevention of Rheumatoid Arthritis. Clin Ther 2019; 41:1376-1396. [DOI: 10.1016/j.clinthera.2019.04.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/28/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
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Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn's Disease. BioDrugs 2019; 32:627-634. [PMID: 30298387 DOI: 10.1007/s40259-018-0311-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Darvadstrocel (Alofisel®) consists of a suspension of expanded human allogeneic adipose-derived mesenchymal stem cells (eASCs). It is the first mesenchymal stem cell (MSC) advanced therapy approved in the EU for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease, when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy. In the pivotal phase 3 ADMIRE-CD trial in this difficult-to-treat patient population, after standard-of-care fistula conditioning, add-on therapy with a single dose of darvadstrocel (120 million eASC) administered into the tissue surrounding complex perianal fistulas was significantly more effective than placebo (saline), with the darvadstrocel group having a higher combined remission rate (i.e. clinically-assessed fistula closure plus MRI-assessed absence of abscesses) at 24 weeks in intent-to-treat (ITT primary analysis), modified ITT and per-protocol analyses. Clinical remission was maintained in > 50% of patients at 52 weeks' follow-up. Given the very limited treatment options available for this difficult-to-treat rare condition, darvadstrocel is a promising, novel, minimally invasive therapy that represents an important advance in the therapeutic options for complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn's disease when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy.
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Ewart DT, Peterson EJ, Steer CJ. Gene editing for inflammatory disorders. Ann Rheum Dis 2019; 78:6-15. [PMID: 30077989 DOI: 10.1136/annrheumdis-2018-213454] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 12/24/2022]
Abstract
Technology for precise and efficient genetic editing is constantly evolving and is now capable of human clinical applications. Autoimmune and inflammatory diseases are chronic, disabling, sometimes life-threatening, conditions that feature heritable components. Both primary genetic lesions and the inflammatory pathobiology underlying these diseases represent fertile soil for new therapies based on the capabilities of gene editing. The ability to orchestrate precise targeted modifications to the genome will likely enable cell-based therapies for inflammatory diseases such as monogenic autoinflammatory disease, acquired autoimmune disease and for regenerative medicine in the setting of an inflammatory environment. Here, we discuss recent advances in genome editing and their evolving applications in immunoinflammatory diseases. Strengths and limitations of older genetic modification tools are compared with CRISPR/Cas9, base editing, RNA editing, targeted activators and repressors of transcription and targeted epigenetic modifiers. Commonly employed delivery vehicles to target cells or tissues of interest with genetic modification machinery, including viral, non-viral and cellular vectors, are described. Finally, applications in animal and human models of inflammatory diseases are discussed. Use of chimeric autoantigen receptor T cells, correction of monogenic diseases with genetically edited haematopoietic stem and progenitor cells, engineering of induced pluripotent stem cells and ex vivo expansion and modification of regulatory T cells for a range of chronic inflammatory diseases are reviewed.
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Affiliation(s)
- David T Ewart
- Division of Rheumatic and Autoimmune Diseases, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Erik J Peterson
- Division of Rheumatic and Autoimmune Diseases, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Clifford J Steer
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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