|
1
|
Chauhan K, Tyagi M. Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1412930. [PMID: 39157460 PMCID: PMC11327136 DOI: 10.3389/fopht.2024.1412930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/16/2024] [Indexed: 08/20/2024]
Abstract
Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.
Collapse
Affiliation(s)
- Khushboo Chauhan
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
| | - Mudit Tyagi
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
| |
Collapse
|
|
2
|
Wang Y, Cao C, Liu S, Hu L, Du Y, Lv Y, Liu Q. Identification of potential biomarkers and therapeutic targets for antineutrophil cytoplasmic antibody-associated glomerulonephritis. iScience 2023; 26:108157. [PMID: 37915598 PMCID: PMC10616314 DOI: 10.1016/j.isci.2023.108157] [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: 04/15/2023] [Revised: 08/21/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023] Open
Abstract
Exploring key genes for antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is of great significance. Through bioinformatics analysis, 79 immune protein-differentially expressed genes (IP-DEGs) were obtained. Six hub genes (PTPRC, CD86, TLR2, IL1B, CSF-1R, and CCL2) were identified and verified to be increased in ANCA-GN patients. Random forest algorithm and ROC analysis showed that CSF-1R was a potential biomarker. Plasma CSF-1R levels increased significantly in ANCA-GN-active patients compared with remission stage and control. Correlation analysis revealed that CSF-1R levels had positive relationship with serum creatinine and Birmingham scoring, while inversely correlated with eGFR. Multivariate analysis revealed that plasma CSF-1R were an independent poor prognostic variable for end-stage renal disease or death, after adjusting for age and gender (HR = 3.05, 95% CI = 1.45-6.43, p = 0.003). Overall, we revealed that the CSF-1R is related to disease activity and might be a vital gene associated with the pathogenesis of ANCA-GN.
Collapse
Affiliation(s)
- Yiru Wang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenlin Cao
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of the Second Clinical College, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Siyang Liu
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Hu
- Health Management Center, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yueliang Du
- Department of Nephrology, Luohe Central Hospital, Luohe, China
| | - Yongman Lv
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingquan Liu
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
3
|
Krol RM, Remmelts HHF, Klaasen R, Frima A, Hagen EC, Kamalski DMA, Heijstek MW, Spierings J. Systemic and Local Medical or Surgical Therapies for Ear, Nose and/or Throat Manifestations in ANCA-Associated Vasculitis: A Systematic Literature Review. J Clin Med 2023; 12:jcm12093173. [PMID: 37176613 PMCID: PMC10179364 DOI: 10.3390/jcm12093173] [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: 04/07/2023] [Revised: 04/21/2023] [Accepted: 04/23/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Ear, nose and throat (ENT) manifestations are common in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), yet how to treat these manifestations remains controversial. Therefore, we systematically reviewed the literature on the efficacy of therapies on ENT manifestations in AAV. METHODS A systematic review was conducted in accordance with the PRISMA guidelines, searching Medline, Embase and Cochrane libraries, including clinical studies between January 2005 and January 2022, in adults with AAV and ENT involvement, reporting on the effects of local and systemic therapy. The critical appraisal was performed using tools provided by the Cochrane Library and the level of evidence (LoE) was scored according to the Oxford Centre for Evidence-based Medicine. RESULTS After screening 5609 identified studies, 136 full-text articles were assessed. Finally, 31 articles were included for critical appraisal and data-extraction. Nearly all studies (n = 29) were retrospective and scored low on LoE. The included studies evaluated local interventions (n = 11), glucocorticoids combined with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) (n = 8), rituximab (n = 6), or mepolizumab (n = 6). Due to heterogeneity across studies meta-analysis was not performed. Four studies on mepolizumab for sinonasal symptoms (n = 92) showed response in 33-100% and relapse in 35%. Local therapy for subglottic stenosis was effective in 80-100% of patients in 11 studies (n = 157), but relapses were common (up to 83%). In five studies, hearing improvement was observed in 56-100%, with better outcomes when glucocorticoids were combined with csDMARDs compared to glucocorticoids only. CONCLUSION Response rates of ENT manifestations varied widely in studies and relapses were observed frequently. Heterogeneity among studies impaired comparison.
Collapse
Affiliation(s)
- Roline M Krol
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Hilde H F Remmelts
- Department of Nephrology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands
| | - Ruth Klaasen
- Department of Rheumatology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands
| | - Annelies Frima
- Department of Otorhinolaryngology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands
| | - E Christiaan Hagen
- Department of Nephrology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands
| | - Digna M A Kamalski
- Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Marloes W Heijstek
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Julia Spierings
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| |
Collapse
|
|
4
|
Habibi MA, Alesaeidi S, Zahedi M, Hakimi Rahmani S, Piri SM, Tavakolpour S. The Efficacy and Safety of Rituximab in ANCA-Associated Vasculitis: A Systematic Review. BIOLOGY 2022; 11:biology11121767. [PMID: 36552276 PMCID: PMC9774915 DOI: 10.3390/biology11121767] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Background and aim: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease developed by autoantibody production against human neutrophilic granulocytes, including proteinase-3 (PR3) and myeloperoxidase (MPO). The management of AAV patients is difficult due to the multiorgan involvement, high rate of relapse, and complications of immunosuppressive agents that make it challenging. This study aims to investigate the efficacy and safety of rituximab (RTX) therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) subtypes. Method: The PubMed/Medline database was searched for any studies related to RTX therapy in ANCA-associated vasculitis (GPA and MPA subtypes), from inception to 1 August 2022, and proceeded in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Our search resulted in 1082 initial records. After the elimination of review papers, irrelevant studies, and non-English records, 223 articles were included, and the data related to the efficacy and safety of RTX therapy were extracted. Several randomized and non-randomized studies showed that RTX is an effective treatment option for patients with AAV. Most of the studies showed the very effective effect of RTX in controlling disease in AAV patients, including pediatrics, adults, and elderlies, although RTX cannot completely prevent relapse. However, maintenance therapy helps delay the disease's relapse and causes sustained remission. Not only the licensed dose (375 mg/m2 intravenous per week for 4 weeks) could induce disease remission, but studies also showed that a single infusion of RTX could be effective. Although RTX could resolve many rare manifestations in AAV patients, there are few reports showing treatment failure. Additionally, few sudies have reported the unexpeted worsening of the disease after RTX administration. Generally, RTX is relatively safe compared to conventional therapies, but some serious adverse effects, mainly infections, cytopenia, hypogammaglobinemia, malignancy, and hypersensitivity have been reported. Conclusions: RTX is an effective and relatively safe therapeutic option for AAV. Studies on the evaluation of the safety profiles of RTX and the prevention of severe RTX-related side effects in AAV patients are required.
Collapse
Affiliation(s)
- Mohammad Amin Habibi
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982166757001, Iran
| | - Samira Alesaeidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982188220065, Iran
| | - Mohadeseh Zahedi
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
| | - Samin Hakimi Rahmani
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
| | - Seyed Mohammad Piri
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982166757001, Iran
| | - Soheil Tavakolpour
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Correspondence: ; Tel.: +1-(617)-906-2978
| |
Collapse
|
|
5
|
Schnell A, Ruppel R, Tremel C, Galiano M, Meßbacher ME, Krickau T. Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report. J Med Case Rep 2022; 16:129. [PMID: 35361259 PMCID: PMC8970636 DOI: 10.1186/s13256-022-03370-2] [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: 07/09/2021] [Accepted: 03/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. Case presentation We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. Conclusions The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.
Collapse
Affiliation(s)
- Alexander Schnell
- Pediatric Pneumology and Allergology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
| | - Renate Ruppel
- Pediatric Pneumology and Allergology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
| | - Christina Tremel
- Pediatric Pneumology and Allergology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
| | - Matthias Galiano
- Pediatric Nephrology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
| | - Maria-Elena Meßbacher
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
| | - Tobias Krickau
- Pediatric Rheumatology, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
| |
Collapse
|
|
6
|
Suzuki H, Asano T, Tanaka T, Kaneko MK, Kato Y. Epitope Mapping of the Anti-CD20 Monoclonal Antibodies (C20Mab-11 and 2H7) Using HisMAP Method. Monoclon Antib Immunodiagn Immunother 2022; 41:20-26. [PMID: 35225660 DOI: 10.1089/mab.2021.0051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
CD20, which is expressed on B lymphocytes, has been studied as a therapeutic target for B cell lymphomas and autoimmune disorders. Identifying the binding epitopes of monoclonal antibodies (mAbs) can contribute to our understanding of their functions. We have previously developed an anti-CD20 mAb (clone C20Mab-11) using a Cell-Based Immunization and Screening (CBIS) method. In this study, we aimed to determine the binding epitopes of anti-CD20 mAbs, such as C20Mab-11 and 2H7, using the His-tag insertion for epitope mapping (HisMAP). The results showed that 171-NPSE-174 and 168-EPANPSE-174 in the second loop of CD20 were essential for C20Mab-11 binding and 2H7 binding, respectively. Although we developed many mAbs that recognize conformational epitopes using the CBIS method, there are many difficulties in epitope mapping for these mAbs. HisMAP could be useful for determining the conformational epitopes of other mAbs against membrane proteins.
Collapse
Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| |
Collapse
|
|
7
|
Burster T, Mustafa Z, Myrzakhmetova D, Zhanapiya A, Zimecki M. Hindrance of the Proteolytic Activity of Neutrophil-Derived Serine Proteases by Serine Protease Inhibitors as a Management of Cardiovascular Diseases and Chronic Inflammation. Front Chem 2021; 9:784003. [PMID: 34869231 PMCID: PMC8634265 DOI: 10.3389/fchem.2021.784003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/20/2021] [Indexed: 12/23/2022] Open
Abstract
During inflammation neutrophils become activated and segregate neutrophil serine proteases (NSPs) to the surrounding environment in order to support a natural immune defense. However, an excess of proteolytic activity of NSPs can cause many complications, such as cardiovascular diseases and chronic inflammatory disorders, which will be elucidated on a biochemical and immunological level. The application of selective serine protease inhibitors is the logical consequence in the management of the indicated comorbidities and will be summarized in this briefing.
Collapse
Affiliation(s)
- Timo Burster
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Zhadyra Mustafa
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Dinara Myrzakhmetova
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Anuar Zhanapiya
- Department of Biology, School of Sciences and Humanities, Nazarbayev University, Nur-Sultan, Kazakhstan
| | - Michal Zimecki
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| |
Collapse
|
|
8
|
Valenzuela RA, Flores I, Urrutia B, Fuentes F, Sabat PE, Llanos C, Cuitino L, Urzua CA. New Pharmacological Strategies for the Treatment of Non-Infectious Uveitis. A Minireview. Front Pharmacol 2020; 11:655. [PMID: 32508634 PMCID: PMC7250389 DOI: 10.3389/fphar.2020.00655] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 04/22/2020] [Indexed: 12/14/2022] Open
Abstract
Non-infectious uveitis (NIU) is a group of disorders characterized by intraocular inflammation at different levels of the eye. NIU is a leading cause of irreversible blindness in working-age population in the developed world. The goal of uveitis treatment is to control inflammation, prevent recurrences, and preserve vision, as well as minimize the adverse effects of medications. Currently, the standard of care for NIU includes the administration of corticosteroids (CS) as first-line agents, but in some cases a more aggressive therapy is required. This includes synthetic immunosuppressants, such as antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine), calcineurinic inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil). In those patients who become intolerant or refractory to CS and conventional immunosuppressive treatment, biologic agents have arisen as an effective therapy. Among the most evaluated treatments, TNF-α inhibitors, IL blockers, and anti-CD20 therapy have emerged. In this regard, anti-TNF agents (infliximab and adalimumab) have shown the strongest results in terms of favorable outcomes. In this review, we discuss latest evidence concerning to the effectiveness of biologic therapy, and present new therapeutic approaches directed against immune components as potential novel therapies for NIU.
Collapse
Affiliation(s)
- Rodrigo A Valenzuela
- Laboratory of Ocular and Systemic Autoimmune Diseases, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Chemical and Biological Sciences, Faculty of Health, Universidad Bernardo O Higgins, Santiago, Chile
| | - Iván Flores
- Laboratory of Ocular and Systemic Autoimmune Diseases, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Beatriz Urrutia
- Rheumatology Service, Department of Medicine, Hospital Clinico Universidad de Chile, Santiago, Chile
| | - Francisca Fuentes
- Laboratory of Ocular and Systemic Autoimmune Diseases, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Pablo E Sabat
- Department of Ophthalmology, University of Chile, Santiago, Chile.,Department of Ophthalmology, Clínica las Condes, Santiago, Chile
| | - Carolina Llanos
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Loreto Cuitino
- Laboratory of Ocular and Systemic Autoimmune Diseases, Faculty of Medicine, University of Chile, Santiago, Chile.,Servicio de Oftalmología, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Cristhian A Urzua
- Laboratory of Ocular and Systemic Autoimmune Diseases, Faculty of Medicine, University of Chile, Santiago, Chile.,Department of Ophthalmology, University of Chile, Santiago, Chile.,Faculty of Medicine, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile
| |
Collapse
|
|
9
|
Thery-Casari C, Euvrard R, Mainbourg S, Durupt S, Reynaud Q, Durieu I, Belot A, Lobbes H, Cabrera N, Lega JC. Severe infections in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides receiving rituximab: A meta-analysis. Autoimmun Rev 2020; 19:102505. [PMID: 32173512 DOI: 10.1016/j.autrev.2020.102505] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 12/31/2019] [Indexed: 12/23/2022]
Abstract
INTRODUCTION The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known. OBJECTIVE The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX. METHODS PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I2 > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression. RESULTS The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I2 = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I2 = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I2 = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I2 = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03). CONCLUSION Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.
Collapse
Affiliation(s)
- Clémence Thery-Casari
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France
| | - Romain Euvrard
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France
| | - Sabine Mainbourg
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France
| | - Stéphane Durupt
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France
| | - Quitterie Reynaud
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Univ Lyon, Health Services and Performance Research EA7425, Claude Bernard University Lyon, F-69003, France
| | - Isabelle Durieu
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Univ Lyon, Health Services and Performance Research EA7425, Claude Bernard University Lyon, F-69003, France
| | - Alexandre Belot
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; INSERM U1111, National Referral Centre for rare Juvenile Rheumatological and Autoimmune Diseases (RAISE) and Department of Paediatric Rheumatology, Lyon University Hospital, University of Lyon, France
| | - Hervé Lobbes
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Internal Medicine Department, University Hospital Clermont-Ferrand, 1 place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
| | - Natalia Cabrera
- Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France
| | - Jean-Christophe Lega
- Department of Internal and Vascular Medicine, National Referral Centre for Rare Juvenile Rheumatological and Autoimmune Diseases (RAISE), Hôpital Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; Faculty of Medicine, Université de Lyon, Université Lyon 1, France; Lyon Immunopathology Federation (LIFE), University of Lyon, Hospices Civils de Lyon, France; Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5558, F-69622 Villeurbanne, France.
| |
Collapse
|
|
10
|
Ashtari F, Hakamifard A, Hariri A, Gholipour-Shahraki T. Rituximab associated necrosis: A case report. Mult Scler Relat Disord 2019; 37:101429. [PMID: 31675638 DOI: 10.1016/j.msard.2019.101429] [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: 07/11/2019] [Revised: 09/18/2019] [Accepted: 10/01/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Rituximab is a B-cell-depleting unconjugated monoclonal IgG1 antibody that targets the transmembrane protein CD20. This article reports on a case with the rare complication known as Rituximab-associated mucosal necrosis. CASE PRESENTATION The present case report addresses, for the first time, a patient affected by Devic's syndrome presenting with oral manifestations of palatal necrosis after rituximab treatment. CONCLUSION The present case raises the possibility of anti-CD20 antibody contributing to the development of palatal mucosal necrosis in some patients. Given the increasing administration of rituximab as a result of its efficacy against several diseases, a report on the potential iatrogenic effects of this drug is essential.
Collapse
Affiliation(s)
- Fereshteh Ashtari
- Isfahan Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Atousa Hakamifard
- Department of Infectious Diseases, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amirali Hariri
- School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tahereh Gholipour-Shahraki
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
11
|
Salvadori M, Tsalouchos A. Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: Open challenges in the remission induction therapy. World J Nephrol 2018; 7:71-83. [PMID: 29736379 PMCID: PMC5937030 DOI: 10.5527/wjn.v7.i3.71] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/12/2018] [Accepted: 04/18/2018] [Indexed: 02/06/2023] Open
Abstract
Renal involvement with rapidly progressive glomerulonephritis is a common manifestation of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, which is characterized by end-stage renal disease and high mortality rates in untreated and/or late referral patients. The long-term renal survival has improved dramatically since the addition of cyclophosphamide (CYC) and recently of rituximab (RTX) in association with corticosteroids in the remission induction therapeutic regimens. However, renal prognosis remains unfavorable for many patients and the mortality rate is still significantly high. In this review, we analyze the open challenges to be addressed to optimize the induction remission therapy, principally in patients with advanced kidney failure. This concern the first-line therapy (CYC or RTX) based on different parameters (estimated glomerular filtration rate at baseline, new or relapsed disease, ANCA specificity, tissue injury, safety), the role of plasma exchange and the role of new therapies. Indeed, we discuss future perspectives in induction remission therapy by reporting recent advances in new targeted therapies with particular reference to avacopan, an orally administered selective C5a receptor inhibitor.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Nephrology and Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Department of Nephrology and Dialysis, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
| |
Collapse
|
|
12
|
Rituximab for anti-neutrophil cytoplasmic antibodies-associated vasculitis: experience of a single center and systematic review of non-randomized studies. Rheumatol Int 2018; 38:607-622. [PMID: 29322343 DOI: 10.1007/s00296-018-3928-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/02/2018] [Indexed: 10/27/2022]
Abstract
Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.
Collapse
|
|
13
|
Shi L. Anti-neutrophil cytoplasmic antibody-associated vasculitis: prevalence, treatment, and outcomes. Rheumatol Int 2017; 37:1779-1788. [DOI: 10.1007/s00296-017-3818-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 09/12/2017] [Indexed: 10/18/2022]
|
|
14
|
|
|
15
|
Successful Treatment Strategies in Granulomatosis With Polyangiitis-Associated Peripheral Ulcerative Keratitis. Cornea 2016; 35:1459-1465. [DOI: 10.1097/ico.0000000000000919] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
16
|
Sen M, Dogra S, Rathi M, Sharma A. Successful treatment of large refractory pyoderma gangrenosum-like presentation of granulomatosis with polyangiitis by rituximab. Int J Rheum Dis 2016; 20:2200-2202. [PMID: 27126548 DOI: 10.1111/1756-185x.12882] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Mitali Sen
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunil Dogra
- Department of Dermatology and Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Manish Rathi
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aman Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
17
|
Pascoe VL, Fenves AZ, Wofford J, Jackson JM, Menter A, Kimball AB. The spectrum of nephrocutaneous diseases and associations. J Am Acad Dermatol 2016; 74:247-70; quiz 271-2. [DOI: 10.1016/j.jaad.2015.05.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/26/2015] [Accepted: 05/26/2015] [Indexed: 12/31/2022]
|
|
18
|
Besada E. Low immunoglobulin levels increase the risk of severe hypogammaglobulinemia in granulomatosis with polyangiitis patients receiving rituximab. BMC Musculoskelet Disord 2016; 17:6. [PMID: 26738559 PMCID: PMC4702309 DOI: 10.1186/s12891-015-0860-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 12/23/2015] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Randomized controlled trials and retrospective studies in ANCA-associated vasculitis (AAV) concurred that rituximab (RTX) is effective to induce and maintain remission. Infections and hypogammaglobulinemia during RTX were usually infrequent and uncomplicated. But in the Tromsø study cohort, 45% of patients with granulomatosis with polyangiitis (GPA) developed hypogammaglobulinemia during RTX maintenance leading to its discontinuation in 62%. METHODS To explain these differences in outcome when using RTX in AAV to maintain remission, we used statistical structural methods to compare the Tromsø study cohort with other published cohorts. RESULTS GPA patients' characteristics of the Tromsø study cohort were not so different compared with other cohorts. Rates of hypogammaglobulinemia and discontinuation of RTX seemed closely related to the cut-off used and to the levels of immunoglobulin (Ig) at baseline. Combination of low IgG serum levels at baseline (7.7 g/L) and low cut-off to define hypogammaglobulinemia in the Tromsø study cohort explained the high rate of hypogammaglobulinemia and discontinuation of RTX. CONCLUSIONS Patients' characteristics in the Tromsø study cohort were not skewed, apart from IgG levels. Low IgG level at baseline seemed to contribute the most to hypogammaglobulinemia and its complications.
Collapse
Affiliation(s)
- Emilio Besada
- Bone and Joint Research Group, Institute of Clinical Medicine, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
| |
Collapse
|
|
19
|
Implication of B lymphocytes in the pathogenesis of ANCA-associated vasculitides. Autoimmun Rev 2015; 14:996-1004. [DOI: 10.1016/j.autrev.2015.06.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 06/29/2015] [Indexed: 12/23/2022]
|
|
20
|
Biologic therapy for refractory scleritis: a new treatment perspective. Int Ophthalmol 2015; 35:903-12. [DOI: 10.1007/s10792-015-0124-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 08/23/2015] [Indexed: 12/12/2022]
|
|
21
|
McGregor JG, Hogan SL, Kotzen ES, Poulton CJ, Hu Y, Negrete-Lopez R, Kidd JM, Katsanos SL, Bunch DO, Nachman PH, Falk RJ. Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant 2015; 30 Suppl 1:i123-31. [PMID: 25805743 DOI: 10.1093/ndt/gfv076] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort. METHODS Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (≤2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests. RESULTS Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9-29). Time to remission and relapse were similar between rituximab infusion courses (≤2 versus >2; remission P = 0.86 and relapse P = 0.78, respectively). Incidence of relapse was 0.22 PPY (0.14, 0.31) and of severe infection was 0.12 PPY (0.08, 0.24). Time to relapse was shorter in those never exposed to cyclophosphamide (n = 20): 50% by 8 months versus 50% by 24 and 30 months for those with prior or concurrent exposure to cyclophosphamide (n = 100). Compared with those who never received rituximab, rituximab-treated patients were younger (P < 0.001), more likely to have granulomatosis with polyangiitis (P = 0.001) and had more upper airway (P = 0.01) and less kidney involvement (P = 0.007). CONCLUSIONS Rituximab is beneficial when prescribed outside of a trial setting. Response to treatment and relapse is similar regardless of infusion number. Rituximab without cyclophosphamide may result in a shorter time to relapse supporting combination of these therapies.
Collapse
Affiliation(s)
| | - Susan L Hogan
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Elizabeth S Kotzen
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Duke University Medical Center, Durham, NC, USA
| | | | - Yichun Hu
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Roberto Negrete-Lopez
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Hospital Universitario-UANL Monterrey, Nuevo Leon, Mexico
| | - Jason M Kidd
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Medical College of Virginia, Richmond, VA, USA
| | | | - Donna O Bunch
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Ronald J Falk
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| |
Collapse
|
|
22
|
Biologics in vasculitides: Where do we stand, where do we go from now? Presse Med 2015; 44:e231-9. [DOI: 10.1016/j.lpm.2015.04.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 04/15/2015] [Indexed: 12/14/2022] Open
|
|
23
|
Lutalo PMK, D'Cruz DP. Biological drugs in ANCA-associated vasculitis. Int Immunopharmacol 2015; 27:209-12. [PMID: 25907243 DOI: 10.1016/j.intimp.2015.04.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/13/2015] [Accepted: 04/13/2015] [Indexed: 12/20/2022]
Abstract
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) constitute a wide spectrum of clinical manifestations of systemic vasculitis which may range from limited disease to organ or life-threatening disease. The introduction of biologics for the management of severe ANCA-associated vasculitis and severe, relapsing disease refractory to conventional immunosuppressants, has significantly improved the clinical prognosis of these autoimmune disorders. Rituximab, an anti-CD20 monoclonal antibody is licenced for remission induction in severe GPA and MPA and the management of severe relapsing, refractory GPA and MPA. Belimumab, an anti-B lymphocyte stimulatory monoclonal antibody is in clinical trials for the management of the ANCA-associated vasculitis GPA. Mepolizumab and Omalizumab are biologics which have been reported to be efficacious in refractory asthma associated with EGPA. The role of anti-TNF therapy and T cell targeting drugs in ANCA-associated vasculitis is less clear due to limited study data. This review will summarise the clinical trials and clinical practice use of biologic treatment strategies for the management of ANCA-associated vasculitis.
Collapse
Affiliation(s)
- Pamela M K Lutalo
- Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| | - David P D'Cruz
- Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| |
Collapse
|
|
24
|
Fanouriakis A, Kougkas N, Vassilopoulos D, Fragouli E, Repa A, Sidiropoulos P. Rituximab for eosinophilic granulomatosis with polyangiitis with severe vasculitic neuropathy: Case report and review of current clinical evidence. Semin Arthritis Rheum 2015; 45:60-6. [PMID: 25908179 DOI: 10.1016/j.semarthrit.2015.03.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 03/09/2015] [Accepted: 03/17/2015] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Rituximab is approved for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Our objective was to review published clinical evidence on the efficacy of rituximab in the treatment of eosinophilic granulomatosis and polyangiitis (EGPA). METHODS We describe a case of refractory EGPA with severe vasculitic neuropathy, which responded impressively to B-cell-depleting therapy. A systematic search of the English literature was also performed to capture all available clinical evidence on the use of rituximab in EGPA. RESULTS We identified a total of 73 EGPA patients who have been treated with rituximab, all data coming from case series or isolated case reports. The majority of patients (85.1%) were treated for refractory or relapsing disease; a mean (SD) of 2.1 (0.9) different immunosuppressive agents were used prior to rituximab administration. Efficacy of RTX therapy was significant in the majority of cases and in a wide variety of disease manifestations; however, a lack of standardized assessment of disease activity before and after treatment was observed in many reports. Overall, 54.0% of patients were treated with a single cycle of rituximab and only 10.8% experienced relapses of the disease. Few significant side effects were observed during a highly variable period of follow-up (3 months to 5 years), mainly severe infections and allergic reactions. CONCLUSIONS RTX seems to be effective in cases of severe EGPA refractory to standard of care immunosuppressive treatment, although support comes from case reports and non-controlled studies.
Collapse
Affiliation(s)
- Antonis Fanouriakis
- Department of Rheumatology, Clinical Immunology, and Allergy, University Hospital of Heraklion, Stavrakia Voutes, 71110, Heraklion, Crete, Greece.
| | - Nikolaos Kougkas
- Department of Rheumatology, Clinical Immunology, and Allergy, University Hospital of Heraklion, Stavrakia Voutes, 71110, Heraklion, Crete, Greece
| | - Dimitrios Vassilopoulos
- 2nd Department of Medicine, Hippokration General Hospital, Athens University School of Medicine, Athens, Greece
| | - Eleni Fragouli
- Department of Rheumatology, Clinical Immunology, and Allergy, University Hospital of Heraklion, Stavrakia Voutes, 71110, Heraklion, Crete, Greece
| | - Argyro Repa
- Department of Rheumatology, Clinical Immunology, and Allergy, University Hospital of Heraklion, Stavrakia Voutes, 71110, Heraklion, Crete, Greece
| | - Prodromos Sidiropoulos
- Department of Rheumatology, Clinical Immunology, and Allergy, University Hospital of Heraklion, Stavrakia Voutes, 71110, Heraklion, Crete, Greece
| |
Collapse
|
|
25
|
Knight A, Hallenberg H, Baecklund E. Efficacy and safety of rituximab as maintenance therapy for relapsing granulomatosis with polyangiitis—a case series. Clin Rheumatol 2015; 33:841-8. [PMID: 23959445 PMCID: PMC4058072 DOI: 10.1007/s10067-013-2351-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 07/03/2013] [Accepted: 07/25/2013] [Indexed: 12/02/2022]
Abstract
The objective of this work was to study the efficacy and safety of pre-emptive rituximab (RTX) in a series of patients with severe relapsing granulomatosis with polyangiitis (GPA). GPA is a systemic vasculitis with a high relapse rate despite successful remission induction. Drug toxicity with repeated induction treatments and long-standing immunosuppression poses a problem. Based on the findings in reports on RTX for rheumatoid arthritis, we treated patients with severe relapsing GPA with pre-emptive RTX, 1,000 mg 2 weeks apart every 6 months, aiming at achieving sustainable remission. All patients at one centre with relapsing GPA in spite of traditional maintenance treatment, who had received more than or equal to three cycles of RTX as regularly repeated pre-emptive maintenance therapy every 6 months, were included in this retrospective study. Information on disease manifestations and activity, treatments, lab parameters and adverse events was extracted from the medical files. Of the 12 included patients, all with a positive proteinase 3–anti-neutrophil cytoplasmic antibodies, generalised disease and a median disease duration of 35 months (21–270), 92 % (11/12) achieved sustainable remission during a median follow-up time of 32 months (range 21–111) from first RTX treatment. Concomitant immunosuppressants were reduced. Infections were the most common adverse events, but infections were an issue also before the start of RTX. RTX administered every 6 months seems to be an effective maintenance treatment in a population with severe, relapsing long-standing GPA. Granulomatous as well as vasculitic manifestations responded equally well. Infections are a problem in this patient group but no new safety problems were identified.
Collapse
Affiliation(s)
- A. Knight
- Department of Medical Sciences, Unit of Rheumatology, Uppsala University, S-751 85 Uppsala, Sweden
| | - H. Hallenberg
- Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden
| | - E. Baecklund
- Department of Medical Sciences, Unit of Rheumatology, Uppsala University, S-751 85 Uppsala, Sweden
| |
Collapse
|
|
26
|
Mohammad AJ, Weiner M, Sjöwall C, Johansson ME, Bengtsson AA, Ståhl-Hallengren C, Nived O, Eriksson P, Sturfelt G, Segelmark M. Incidence and disease severity of anti-neutrophil cytoplasmic antibody-associated nephritis are higher than in lupus nephritis in Sweden. Nephrol Dial Transplant 2014; 30 Suppl 1:i23-30. [PMID: 25540097 DOI: 10.1093/ndt/gfu396] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden. METHODS In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period. RESULTS Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020. CONCLUSIONS In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage.
Collapse
Affiliation(s)
- Aladdin J Mohammad
- Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden Department of Renal Medicine, Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Cambridge, UK
| | - Maria Weiner
- Department of Nephrology, Linköping University, Linköping, Sweden Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Christopher Sjöwall
- Department of Rheumatology/AIR, Linköping University, Linköping, Sweden Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Martin E Johansson
- Department of Laboratory Medicine Malmö, Clinical Pathology, Lund University, Malmö, Sweden
| | - Anders A Bengtsson
- Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
| | | | - Ola Nived
- Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
| | - Per Eriksson
- Department of Rheumatology/AIR, Linköping University, Linköping, Sweden Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Gunnar Sturfelt
- Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden
| | - Mårten Segelmark
- Department of Nephrology, Linköping University, Linköping, Sweden Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| |
Collapse
|
|
27
|
Jones RB. Rituximab in the Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis. ACTA ACUST UNITED AC 2014; 128:243-9. [DOI: 10.1159/000368580] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
28
|
Current therapy of granulomatosis with polyangiitis and microscopic polyangiitis: the role of rituximab. J Nephrol 2014; 28:17-27. [PMID: 25185728 PMCID: PMC4322237 DOI: 10.1007/s40620-014-0135-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 08/26/2014] [Indexed: 02/03/2023]
Abstract
Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Despite improvements in outcomes, recurrence of disease and drug-related toxicity continue to produce significant morbidity and mortality. Better understanding of the pathogenesis of AAV and the mechanism of action of cyclophosphamide has led to investigation of therapies that target B cells. Two randomized controlled trials have shown that rituximab is not inferior to cyclophosphamide for induction of remission in severe AAV, with no significant difference in the incidence of overall adverse events in rituximab- versus cyclophosphamide-treated patients. Data from ongoing clinical trials will determine the role of rituximab in the maintenance of remission.
Collapse
|
|
29
|
Venhoff N, Niessen L, Kreuzaler M, Rolink AG, Hässler F, Rizzi M, Voll RE, Thiel J. Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA-associated vasculitides treated with rituximab for relapsing or refractory disease. Autoimmunity 2014; 47:401-8. [DOI: 10.3109/08916934.2014.914174] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
30
|
Clain JM, Cartin-Ceba R, Fervenza FC, Specks U. Experience with rituximab in the treatment of antineutrophil cytoplasmic antibody associated vasculitis. Ther Adv Musculoskelet Dis 2014; 6:58-74. [PMID: 24688606 PMCID: PMC3956138 DOI: 10.1177/1759720x13516239] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Prior to the 1970s, severe cases of antineutrophil cytoplasmic antibody associated vasculitis (AAV) were thought to be invariably fatal. However, the use of cyclophosphamide-based treatment regimens fundamentally altered disease outcomes, transforming AAV into a manageable, chronic illness. Despite the tremendous success of cyclophosphamide in the treatment of AAV, there remained a need for alternative therapies, due to high rates of treatment failures and significant toxicities. In recent years, with the introduction of targeted biologic response modifiers into clinical practice, many have hoped that the treatment options for AAV could be expanded. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, has been the most successful biologic response modifier to be used in AAV. Following the first report of its use in AAV in 2001, experience with rituximab for treatment of AAV has rapidly expanded. Rituximab, in combination with glucocorticosteroids, is now well established as a safe and effective alternative to cyclophosphamide for remission induction for severe manifestations of granulomatosis with polyangiitis and microscopic polyangiitis. In addition, initial experiences with rituximab for remission maintenance in these diseases have been favorable, as have experiences for remission induction in eosinophilic granulomatosis with polyangiitis.
Collapse
Affiliation(s)
- Jeremy M Clain
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Rodrigo Cartin-Ceba
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Ulrich Specks
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| |
Collapse
|
|
31
|
Turner-Stokes T, Sandhu E, Pepper RJ, Stolagiewicz NE, Ashley C, Dinneen D, Howie AJ, Salama AD, Burns A, Little MA. Induction treatment of ANCA-associated vasculitis with a single dose of rituximab. Rheumatology (Oxford) 2014; 53:1395-403. [DOI: 10.1093/rheumatology/ket489] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
32
|
Zand L, Specks U, Sethi S, Fervenza FC. Treatment of ANCA-associated vasculitis: new therapies and a look at old entities. Adv Chronic Kidney Dis 2014; 21:182-93. [PMID: 24602467 DOI: 10.1053/j.ackd.2014.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/14/2014] [Accepted: 01/15/2014] [Indexed: 01/30/2023]
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. There is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. In this article, we will review the evidence supporting the various treatment choices for patients with AAV.
Collapse
|
|
33
|
Ooka S, Maeda A, Ito H, Omata M, Yamada H, Ozaki S. Treatment of refractory retrobulbar granuloma with rituximab in a patient with ANCA-negative Wegener’s granulomatosis: a case report. Mod Rheumatol 2014. [DOI: 10.3109/s10165-008-0119-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
34
|
Pelegrin L, Jakob E, Schmidt-Bacher A, Schwenger V, Becker M, Max R, Lorenz HM, Mackensen F. Experiences with rituximab for the treatment of autoimmune diseases with ocular involvement. J Rheumatol 2013; 41:84-90. [PMID: 24241484 DOI: 10.3899/jrheum.130206] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To report the efficacy of rituximab (RTX) in the treatment of ocular or orbital inflammation accompanying autoimmune diseases refractory to previous standard immunosuppressive therapy. METHODS We reviewed medical records of 9 consecutive patients with noninfectious ocular or orbital inflammation treated with RTX. RESULTS Over a mean followup of 42 months, 7 patients were in clinical remission, 1 had partial response to treatment, and 1 did not respond. Best corrected visual acuity improved ≥ 1 line in 4 patients, was stable in another 4 patients, and worsened in 1. Concomitant immunosuppressive therapy was tapered in 6 cases. Systemic corticosteroids were tapered or kept below 7.5 mg a day in 5 patients 1 year after the first RTX cycle. CONCLUSION RTX therapy, in patients who are refractory to standard immunosuppressive therapy, was effective and showed a beneficial response to treatment including induction of clinical remission of inflammation in most patients.
Collapse
Affiliation(s)
- Laura Pelegrin
- From the Hospital Clinic de Barcelona, Universidad de Barcelona, Spain; Department of Ophthalmology, Department of Nephrology, Interdisciplinary Uveitis Center, Rheumatology Department for Internal Medicine V, University of Heidelberg, Heidelberg, Germany; and the Department of Ophthalmology, Triemli Spital, Zürich, Switzerland
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Tanna A, Tam FWK, Pusey CD. B-cell-targeted therapy in adult glomerulonephritis. Expert Opin Biol Ther 2013; 13:1691-706. [PMID: 24188581 DOI: 10.1517/14712598.2013.851191] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION There are many mechanisms through which B lymphocytes have been implicated in the pathogenesis of glomerulonephritis. There are a number of trials and clinical studies in glomerulonephritis involving depletion of CD20(+) B lymphocytes using rituximab. Newer anti-CD20 agents are currently under evaluation, as are drugs targeting alternative B-cell targets such as B lymphocyte stimulator. Such selective, targeted B-cell therapies, if shown to be effective, may be of value in minimising toxicity from more conventional agents. AREAS COVERED This article reviews the role of B cells as a target for therapy in adult renal disease resulting from primary glomerulonephritis and that occurring secondary to systemic disease. It will not address intracellular signalling or co-stimulatory pathways as therapeutic targets. EXPERT OPINION There are indications for B-cell targeted therapies in a number of adult glomerulonephritides, with varying degrees of evidence. Further understanding of the mechanisms of B-cell depletion and repletion, and interplay with B-cell survival factors, is necessary in order to identify patients who will respond favourably.
Collapse
Affiliation(s)
- Anisha Tanna
- Wellcome Trust Clinical Research Training Fellow, Imperial College London, Department of Medicine, Renal and Vascular Inflammation Section , Hammersmith Campus, Du Cane Road, London W12 0NN , UK
| | | | | |
Collapse
|
|
36
|
Silva-Fernández L, Loza E, Martínez-Taboada VM, Blanco R, Rúa-Figueroa I, Pego-Reigosa JM, Muñoz-Fernández S. Biological therapy for systemic vasculitis: a systematic review. Semin Arthritis Rheum 2013; 43:542-57. [PMID: 23978781 DOI: 10.1016/j.semarthrit.2013.07.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Relapses and failure are frequent in systemic vasculitis (SV) patients. Biological agents have been prescribed as rescue therapies. The aim of this systematic review is to analyze the current evidence on the therapeutic use of biological agents for SV. METHODS MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to the end of April 2013. Systematic reviews and meta-analysis, clinical trials, cohort studies, and case series with >3 patients were included. Independent article review and study quality assessment was done by 2 investigators with consensus resolution of discrepancies. RESULTS Of 3447 citations, abstracts, and hand-searched studies screened, 90 were included. Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients. Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV. A number of studies used different anti-TNFα agents with contrasting results. A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found. CONCLUSION Current evidence on the use of biological therapies for SV is mainly based on uncontrolled, observational data. Rituximab is not inferior to cyclophosphamide for remission induction in AAV and might be superior in relapsing disease. Infliximab and adalimumab are effective as steroid-sparing agents. Etanercept is not effective to maintain remission in patients with granulomatosis with polyangiitis, and serious adverse events have been reported. For LVV, both infliximab and etanercept had a role as steroid-sparing agents, and tocilizumab might be effective also for remission induction in LVV.
Collapse
Affiliation(s)
| | | | - Víctor M Martínez-Taboada
- Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
| | - Ricardo Blanco
- Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
| | - Iñigo Rúa-Figueroa
- Rheumatology Department, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | - José María Pego-Reigosa
- Rheumatology Department, Complejo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica de Vigo, Vigo, Spain
| | - Santiago Muñoz-Fernández
- Rheumatology Department, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Spain
| | | |
Collapse
|
|
37
|
Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Autoimmun Rev 2013; 12:854-9. [DOI: 10.1016/j.autrev.2012.09.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2012] [Indexed: 11/23/2022]
|
|
38
|
Abstract
PURPOSE OF REVIEW Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies. RECENT FINDINGS A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV. SUMMARY Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.
Collapse
|
|
39
|
Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sánchez-Menéndez M, Ytterberg SR, Fervenza FC, Specks U. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. ACTA ACUST UNITED AC 2013; 64:3770-8. [PMID: 22730028 DOI: 10.1002/art.34584] [Citation(s) in RCA: 209] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegener's) (GPA). METHODS We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. RESULTS Fifty-three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. CONCLUSION RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long-term remission merits further formal investigation.
Collapse
|
|
40
|
Abstract
Vasculitis syndromes are relative rare conditions but can cause significant mortality and morbidity if not treated adequately. Recent advances in immunosuppressant therapy have radically changed the course of these diseases. However, the standard therapy is not always well tolerated by patients, and some cases are refractory to treatment. New therapeutic possibilities have emerged with the use of so-called "biologics," a new class of genetically engineered drugs used for inflammatory rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. In the present review, summarized are the most recent data on the efficacy and safety of biologics in the treatment of vasculitis syndromes that cannot be treated with standard therapy.
Collapse
Affiliation(s)
- Marino Paroli
- Division of Clinical Immunology and Rheumatology, Department of Biotechnology and Medical-Surgical Sciences, Sapienza University of Rome, Italy
| |
Collapse
|
|
41
|
Iglesias-Gamarra A, Peñaranda-Parada E, Cajas-Santana LJ, Quintana-López G, Restrepo-Suárez JF, Arbeláez-Cortés Á, Rondón-Herrera F. Historia del tratamiento de las vasculitis primarias. REVISTA COLOMBIANA DE REUMATOLOGÍA 2012; 19:131-157. [DOI: 10.1016/s0121-8123(12)70022-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
42
|
Dharmapalaiah C, Watts RA. The role of biologics in treatment of ANCA-associated vasculitis. Mod Rheumatol 2012. [DOI: 10.3109/s10165-011-0548-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
43
|
|
|
44
|
Chapter 13: Pauci-immune focal and segmental necrotizing glomerulonephritis. Kidney Int Suppl (2011) 2012; 2:233-239. [PMID: 25018938 PMCID: PMC4089768 DOI: 10.1038/kisup.2012.26] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
|
|
45
|
Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dörner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Sieper J, Singer NG, Smolen JS, Van Riel PLCM, Weisman MH, Winthrop K. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2011. Ann Rheum Dis 2012; 71 Suppl 2:i2-45. [PMID: 22460137 DOI: 10.1136/annrheumdis-2011-201036] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- D E Furst
- Rheumatology Department, David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, California 90025, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr Opin Rheumatol 2012; 24:15-23. [PMID: 22089095 DOI: 10.1097/bor.0b013e32834d5730] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW To review the present knowledge about the use of rituximab (RTX) in patients with granulomatosis with polyangiitis (Wegener's; GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss; EGPA), also collectively referred to as antineutrophil cytoplasmic antibody-associated vasculitis. RECENT FINDINGS More than 20 case series and cohort studies involving more than 200 patients focusing on RTX use for patients with refractory GPA and MPA have been reported. Two randomized controlled trials have shown that RTX is not inferior to cyclophosphamide (CYC) for induction of remission in severe GPA and MPA. The RAVE trial has further shown that RTX is superior to CYC for patients with severe disease relapses. In addition, reports are emerging on the use of RTX for remission maintenance in chronically relapsing patients. There are also preliminary reports on the beneficial use of RTX in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). SUMMARY RTX is the first proven alternative to CYC for remission induction in severe GPA and MPA. RTX is the preferred agent for patients presenting with severe disease flares, and its use had become the de facto standard of care for patients with chronically relapsing refractory GPA. Its use in EGPA requires further investigation.
Collapse
|
|
47
|
Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, Reinhold-Keller E, Gross WL. Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis 2012; 71:327-33. [PMID: 22021864 DOI: 10.1136/ard.2011.153601] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE First, to investigate the overall efficacy and safety of rituximab (RTX) in refractory granulomatosis with polyangiitis (GPA) in a tertiary referral centre. Second, to compare the efficacy of RTX in granulomatous and vasculitic manifestations in GPA. PATIENTS AND METHODS This study comprised a retrospective, standardised data collection from all patients who received RTX for refractory Wegener's granulomatosis from 2002 to 2010. Patients were assessed by a standardised interdisciplinary diagnostic procedure (including ear, nose and throat and ophthalmology assessment, MRI, immunodiagnostics, B-cell levels and Birmingham Vasculitis Activity Score) and were treated by standardised therapeutic regimens according to available evidence. RESULTS 59 patients received 75 cycles of RTX. 9.3% achieved complete remission. A response was documented in 61.3% (improvement in 52%, unchanged disease activity in 9.3%), 26.7% had refractory disease. Birmingham Vasculitis Activity Score, disease extent index, erythrocyte sedimentation rate, C-reactive protein and prednisolone demand decreased significantly. All patients achieved B-cell depletion. Granulomatous manifestations such as orbital granuloma and pachymeningitis were more frequently refractory to RTX than vasculitis or other granulomatous manifestations. Thus, for example, complete remission/improvement was found in 89.2% of patients with renal disease and in only 44.4% of those with orbital masses (p=0.003). The relapse rate was 44.4% after a median period of 13.5 months. Adverse events occurred in 29%, pneumonia in 15% and death in 3%. CONCLUSION The overall response rate of refractory GPA to RTX was high (61.3% complete remission or improvement). Response rates of vasculitic manifestations were excellent; failure of response/progress was mostly due to granulomatous manifestations, especially orbital masses. Relapse rates were high (40%) despite maintenance treatment.
Collapse
Affiliation(s)
- Julia U Holle
- Department of Rheumatology and Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein, Campus Lübeck and Klinikum Bad Bramstedt, Bad Bramstedt, Germany.
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Alba MA, Flores-Suárez LF. [Rituximab for the treatment of ANCA associated vasculitis: the future today?]. ACTA ACUST UNITED AC 2011; 7 Suppl 3:S41-6. [PMID: 22115869 DOI: 10.1016/j.reuma.2011.10.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 10/05/2011] [Indexed: 11/26/2022]
Abstract
Since cyclophosphamide was introduced for the treatment of ANCA-associated vasculitis, the mortality of these diseases has decreased considerably. However, such treatment is related to acute and chronic serious adverse effects, which contribute to the morbidity and mortality of such diseases. Therefore, one of the main challenges in the treatment of such conditions is to find newer and effective therapies with a safer profile. Rituximab (RTX), an anti-CD20 monoclonal antibody stands at the top of new options for the treatment of ANCA-associated vasculitis, and is the strongest candidate to establish itself as a first choice therapeutic agent. Here, we review the rationale of RTX treatment in ANCA-associated small vessel vasculitis, and the current evidence of both its efficacy and toxicity.
Collapse
Affiliation(s)
- Marco A Alba
- Unidad de investigación en Vasculitis, Servicio de Enfermedades Autoinmunes Sistémicas, Hospital Clínic, Barcelona, España
| | | |
Collapse
|
|
49
|
Berden AE, Jones RB, Erasmus DD, Walsh M, Noël LH, Ferrario F, Waldherr R, Bruijn JA, Jayne DR, Bajema IM. Tubular lesions predict renal outcome in antineutrophil cytoplasmic antibody-associated glomerulonephritis after rituximab therapy. J Am Soc Nephrol 2011; 23:313-21. [PMID: 22095945 DOI: 10.1681/asn.2011040330] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Histopathological features in renal biopsies of patients with antineutrophil cytoplasmic antibody-associated vasculitis have predictive value for renal outcome in patients who receive standard treatment with cyclophosphamide and corticosteroids; however, whether the same holds true for rituximab-treated patients is unknown. We describe associations between renal histopathology and outcomes among patients treated with a rituximab-based regimen in the Randomized Trial of Rituximab versus Cyclophosphamide in ANCA-Associated Vasculitis trial. Two pathologists, blinded to clinical data, reviewed biopsies from 30 patients according to a standardized protocol that included assessment of T cell, B cell, and plasma cell infiltration, as well as scoring for tubulitis, interstitial inflammation, and glomerulitis. We did not observe associations between immunohistology scores and age, sex, estimated GFR at entry, or requirement for dialysis. However, tubulointerstitial inflammation was more severe among patients who had a positive test for the myeloperoxidase antineutrophil cytoplasmic antibody. In a multiple linear regression model, both CD3(+) T cell tubulitis and tubular atrophy independently associated with estimated GFR at 12 months. Tubular atrophy remained an independent predictor at 24 months (P<0.01). These results suggest that in addition to anti-B cell therapy, therapy directed at T cells may improve renal outcomes in antineutrophil cytoplasmic antibody-associated vasculitis.
Collapse
Affiliation(s)
- Annelies E Berden
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Dharmapalaiah C, Watts RA. The role of biologics in treatment of ANCA-associated vasculitis. Mod Rheumatol 2011; 22:319-26. [PMID: 22038317 DOI: 10.1007/s10165-011-0548-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 10/04/2011] [Indexed: 10/15/2022]
Abstract
The vast majority of patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) who receive conventional treatment with glucocorticoids and cyclophosphamide experience frequent relapses and treatment-related side-effects. Increasing knowledge of the pathogenesis of AAV has permitted the development of targeted therapies against tumour necrosis factor (TNF)-α and T and B lymphocytes. Therapy with TNF-α blocking drugs has so far proved disappointing, and this approach is not recommended. B cell depletion using rituximab is effective for remission induction, especially in refractory patients. The long-term side-effects and the best method of using rituximab to maintain remission are still to be determined.
Collapse
Affiliation(s)
- Chethana Dharmapalaiah
- Department of Rheumatology, Ipswich Hospital NHS Trust, Heath Road, Ipswich, IP4 5PD, UK
| | | |
Collapse
|