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Yan L, Shen J, Liu L, Yang M, Wang S. IgA vasculitis induced by tumor necrosis factor-α antagonists: clinical features, diagnosis and management. Arch Dermatol Res 2025; 317:445. [PMID: 39976811 DOI: 10.1007/s00403-025-03965-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/22/2025] [Accepted: 02/03/2025] [Indexed: 05/10/2025]
Abstract
INTRODUCTION Anti-TNF therapies are commonly employed in the treatment of autoimmune disorders, yet they are associated with a rare side effect known as IgA vasculitis (IgAV), whose clinical presentation remains poorly understood. This study aims to clarify the features of IgAV linked to anti-TNF treatments to aid in prompt recognition and management. METHODS Case reports on TNF-α-antagonist-associated IgAV dated up to February 29, 2024, were retrieved for retrospective analysis. RESULTS A total of 35 cases from 30 publications were identified. The average age of patients was 36 years (range 11 to 69), with 31.4% being pediatric cases. The primary conditions treated were Crohn's disease (45.7%) and ulcerative colitis (22.9%). Infliximab (42.9%) and adalimumab (37.1%) were the most frequently used agents. The onset of IgAV after initiating anti-TNF therapy occurred at a median of 10 months (range 1 day to 11 years). Clinical symptoms predominantly involved the skin (97.1%), kidneys (68.6%), joints (57.1%), and gastrointestinal tract (40.0%). Renal failure developed in 11.4% of patients. Histopathology revealed leukocytoclastic vasculitis in the skin and mainly proliferative nephritis in renal biopsies, with significant IgA deposition observed. Most patients (80.0%) ceased anti-TNF treatment, and the majority received corticosteroids (96.2%) and dapsone (15.4%) as part of their treatment. Remission was achieved in 34 patients, while one patient worsened. Among the 14 patients who restarted anti-TNF therapy, 9 experienced a recurrence of IgAV. CONCLUSION IgAV associated with anti-TNF therapy may emerge months into treatment and can lead to severe renal complications necessitating ongoing surveillance. Halting anti-TNF therapy is imperative, but the decision to resume treatment must be weighed carefully against the risk of primary disease exacerbation and IgAV recurrence.
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Affiliation(s)
- Lu Yan
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
- Hunan Clinical Research Center of Pediatric Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Jie Shen
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
- Hunan Clinical Research Center of Pediatric Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Lin Liu
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
- Hunan Clinical Research Center of Pediatric Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Minghua Yang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
- Hunan Clinical Research Center of Pediatric Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
| | - Shengfeng Wang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
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Venetsanopoulou AI, Mavridou K, Voulgari PV, Drosos AA. Cutaneous immune-related phenomena in patients with inflammatory arthritides treated with biological therapies: Clinical and pathophysiological considerations. Semin Arthritis Rheum 2023; 63:152272. [PMID: 37788595 DOI: 10.1016/j.semarthrit.2023.152272] [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: 04/17/2023] [Revised: 07/14/2023] [Accepted: 09/04/2023] [Indexed: 10/05/2023]
Abstract
In recent years, identifying the pathophysiologic mechanisms underlying autoimmune arthritides and systematic diseases has led to the use of biological drugs. The primary targets of those biological therapies are cytokines, B cells, and co-stimulation molecules. So far, these targeted therapies have shown good clinical improvement and an acceptable toxicity profile. However, by blocking components of an intact immune system, autoimmune phenomena and paradoxical inflammation have emerged, and among them many cutaneous immune-related adverse events (irAEs). In this article, we review the current state of knowledge on the clinical features and mechanisms of specific cutaneous irAEs observed during treatment with biological therapies. Among those, psoriatic skin lesions are the most commonly observed. Herein, we also report new cases of cutaneous irAEs recently seen in our clinic to help physicians treating inflammatory arthritides recognize cutaneous irAEs early and better manage patients receiving biologic therapies.
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Affiliation(s)
- Aliki I Venetsanopoulou
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | | | - Paraskevi V Voulgari
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece.
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3
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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: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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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Cutaneous vasculitis associated with molecular tergeted therapies: systematic review of the literature. Clin Rheumatol 2023; 42:339-357. [PMID: 36369405 DOI: 10.1007/s10067-022-06406-6] [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: 06/19/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022]
Abstract
Cutaneo us vasculitis (CV) has a broad spectrum of etiologies, and drugs are one of the main culprits. With the increasing use of targeted therapies in medicine, especially in rheumatology and oncology, the number of CV cases reported due to these drugs has increased. Therefore, the recognition and treatment of CV associated with targeted agents have become more and more important. In the literature, anti-TNFs (n = 73, 59.5%), secukinumab (n = 7, 6%), rituximab (n = 5, 4%), tocilizumab (n = 1, 0.8%), ustekinumab (n = 8, 6.5%), abatacept (n = 3, 2.4%), Janus kinase inhibitors (n = 3, 2.4%), alemtuzumab (n = 3, 2.4%), and immune checkpoint inhibitors (n = 20, 16%) have been reported as responsible agents. However, our knowledge of the pathogenetic mechanisms is fairly limited, and the standardized management is yet to be established. Furthermore, though it is uncommon, this complication may pose a safety issue. In this manuscript, we reviewed the literature on CV with or without systemic involvement related to targeted agents. We also proposed the pathogenetic mechanisms of these adverse events. Thus, we aimed to make it easier for clinicians to manage similar cases by reviewing the diagnosis and treatment processes.
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5
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da Silva Cendon Duran C, da Paz AS, Barreto Santiago M. Vasculitis induced by biological agents used in rheumatology practice: A systematic review. Arch Rheumatol 2021; 37:300-310. [PMID: 36017201 PMCID: PMC9377167 DOI: 10.46497/archrheumatol.2022.9049] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/23/2021] [Indexed: 11/03/2022] Open
Abstract
Objectives: Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as psoriasiform lesions, alopecia, lupus and, vasculitis, which more often affects the skin (small-sized vessels) and eventually other organs. In this review, we describe the clinical profile of patients with vasculitis induced by the main biological agents used in rheumatology.
Patients and methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The PubMed database was used for searching eligible articles. We included case reports, case series, and letter to the editor of patients on anti-tumor necrosis factor-alpha (anti-TNF-a) molecules, as well as tocilizumab, ustekinumab, secukinumab, rituximab, and abatacept, who had vasculitis induced by these agents.
Results: Eighty-one articles were included for final analysis (n=89). Twenty-seven patients were using infliximab, 20 adalimumab, 18 etanercept, seven secukinumab, four certolizumab, four rituximab, three golimumab, three ustekinumab, two abatacept, and one tocilizumab. Unspecific leukocytoclastic vasculitis (LCV) was the most common type of vasculitis (n=37), followed by anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (n=16). The medication was replaced with another biological molecule in 23 cases, with only four relapses. In six cases, the biological was maintained, but vasculitis worsened/persisted in one case, being necessary drug removal.
Conclusion: Infections, infusion reaction, cancer, and autoimmune events are well-known side effects of biological therapy. This review demonstrates that vasculitis is another adverse effect of this type of therapy, particularly the anti-TNF-a molecules, and LCV the most reported type of vasculitis.
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Affiliation(s)
| | - Adriane Souza da Paz
- Department of Rheumatology, Serviços Especializados Em Reumatologia Da Bahia, Salvador, Brazil
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6
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Al-Chalabi S, Wu HHL, Chinnadurai R, Ponnusamy A. Etanercept-Induced Anti-Glomerular Basement Membrane Disease. Case Rep Nephrol Dial 2021; 11:292-300. [PMID: 34722648 PMCID: PMC8543357 DOI: 10.1159/000518984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/09/2021] [Indexed: 11/25/2022] Open
Abstract
Anti-glomerular basement membrane (anti-GBM) disease is a rare form of small-vessel vasculitis that typically causes rapidly progressive glomerulonephritis with or without alveolar haemorrhage. Previously, there has only been one reported case of tumour necrosis factor-α (TNF-α) antagonist-induced anti-GBM disease. Here, we describe the first reported case of etanercept-induced anti-GBM disease. A 55-year-old Caucasian man was referred to our tertiary specialist renal centre with a history of painless macroscopic haematuria. The patient has been receiving weekly etanercept injections over the past 12 months for psoriatic arthropathy. The serum immunology panel results highlighted a significantly raised anti-GBM titre (370.1 U). Etanercept was stopped, and the patient was empirically commenced on pulsed methylprednisolone, cyclophosphamide, and plasma exchange. A renal biopsy showed crescentic glomerulonephritis. Few days after admission, he tested positive for coronavirus disease 2019 (COVID-19), and a decision was made to withhold cyclophosphamide. There was further decline in renal function with hyperkalaemia for which he received 2 sessions of haemodialysis. He was restarted on cyclophosphamide upon discharge. The patient was switched to rituximab treatment afterwards as he developed leucopenia 2 weeks following the commencement of cyclophosphamide. The serum creatinine level continued to improve and remained dialysis-independent. In conclusion, with the increased use of etanercept and other TNF-α antagonists, the prescribing clinician must be aware of the rare but life-threatening drug-induced vasculitis. We recommend careful monitoring of renal indices with the use of this class of medications.
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Affiliation(s)
- Saif Al-Chalabi
- Department of Renal Medicine, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Fulwood, United Kingdom
| | - Henry H L Wu
- Department of Renal Medicine, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Fulwood, United Kingdom.,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Rajkumar Chinnadurai
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Departement of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, United Kingdom
| | - Arvind Ponnusamy
- Department of Renal Medicine, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Fulwood, United Kingdom.,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
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Bounia CA, Theodoropoulou EN, Liossis SNC. Glomerulonephritis in Two Patients with SpA Treated with TNF-α Blockers and a Review of the Literature. Biologics 2021; 15:61-66. [PMID: 33762816 PMCID: PMC7982436 DOI: 10.2147/btt.s297712] [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] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/16/2021] [Indexed: 11/23/2022]
Abstract
Renal failure or acute/chronic kidney damage may present as a clinical manifestation of rheumatic diseases. In addition treatment with DMARDs or biologic drugs may induce nephrotoxicity. In this case-based review, we present two patients with SpA under anti-TNF-α treatment admitted to our hospital because of renal failure and proteinuria. We review previously published yet isolated cases of TNF-α blocker-induced glomerular disease in patients with SpA. Renal manifestations are occasionally seen in patients with ankylosing spondylitis and psoriatic arthritis with IgA nephropathy being the most common of them. Anti-TNF-α agents although reportedly used for the treatment of glomerular nephropathy as a disease manifestation, they have been considered responsible for provoking renal damage in some cases. A diagnostic approach for patients with SpA treated with anti-TNF-α agents presenting with renal manifestations is proposed herein.
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Affiliation(s)
| | | | - Stamatic-Nick C Liossis
- Division of Rheumatology, Patras University Hospital, Patras, Greece.,Department of Internal Medicine, University of Patras Medical School, Patras, Greece
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8
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Condamina M, Diaz E, Jamart C, Loget J, Durlach A, Salmon JH, Cadiot G, Viguier M. Severe Attack of Henoch-Schönlein Purpura With Neurological Involvement During Adalimumab Treatment for Crohn's Disease. J Crohns Colitis 2020; 14:538-542. [PMID: 31589303 DOI: 10.1093/ecco-jcc/jjz164] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tumour necrosis factor-α [TNF-α] inhibitors have revolutionised the management of chronic inflammatory conditions. A number of cutaneous adverse events have been reported with TNF inhibition, including vasculitis. Most reactions are mild and rarely warrant treatment withdrawal. Here we describe a patient with Crohn's disease treated with adalimumab in whom severe multivisceral Henoch-Schönlein purpura developed, including neurological involvement, requiring definitive TNF blocker withdrawal.
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Affiliation(s)
- Morgane Condamina
- Department of Dermatology-Venereology, Hôpital Robert-Debré, Reims, France
| | - Emmanuelle Diaz
- Department of Dermatology-Venereology, Hôpital Robert-Debré, Reims, France
| | - Céline Jamart
- Department of Internal Medicine, Hôpital Cochin, Paris, France
| | - Jeffrey Loget
- Department of Dermatology-Venereology, Hôpital Robert-Debré, Reims, France
| | - Anne Durlach
- Department of Pathology, Hôpital Maison-Blanche, Reims, France
| | | | - Guillaume Cadiot
- Department of Gastroenterology, Hôpital Robert-Debré, Reims, France
| | - Manuelle Viguier
- Department of Dermatology-Venereology, Hôpital Robert-Debré, Reims, France
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9
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Havmose M, Thomsen SF. Development of paradoxical inflammatory disorders during treatment of psoriasis with TNF inhibitors: a review of published cases. Int J Dermatol 2017; 56:1087-1102. [DOI: 10.1111/ijd.13691] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/18/2017] [Accepted: 05/22/2017] [Indexed: 12/29/2022]
Affiliation(s)
- Martin Havmose
- Department of Dermatology; Bispebjerg Hospital; Copenhagen Denmark
| | - Simon Francis Thomsen
- Department of Dermatology; Bispebjerg Hospital; Copenhagen Denmark
- Department of Biomedical Sciences; University of Copenhagen; Copenhagen Denmark
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10
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Xue Y, Cohen JM, Wright NA, Merola JF. Skin Signs of Rheumatoid Arthritis and its Therapy-Induced Cutaneous Side Effects. Am J Clin Dermatol 2016; 17:147-62. [PMID: 26649439 DOI: 10.1007/s40257-015-0167-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that primarily affects the joints, but may exhibit extra-articular, including cutaneous, manifestations such as rheumatoid nodules, rheumatoid vasculitis, granulomatous skin disorders, and neutrophilic dermatoses. A large burden of cutaneous disease may be an indication of RA disease activity and the need for more aggressive treatment. Many of the therapeutic agents used to treat RA can also result in cutaneous adverse effects, which pose their own diagnostic and therapeutic challenges. Anti-TNFα agents, in particular, have a wide variety of adverse effects including psoraisiform eruptions, granulomatous conditions, and cutaneous connective tissue disorders. Herein we provide an update on the clinical presentations and management of RA-associated cutaneous findings as well as drug-induced cutaneous effects, with particular attention to the adverse effects of biologic disease-modifying agents.
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11
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Alkhunaizi AM, Dawamneh MF. ANCA-positive crescentic glomerulonephritis in a patient with rheumatoid arthritis treated with anti-tumor necrosis factor alpha. Int J Rheum Dis 2015; 20:1843-1847. [PMID: 26012729 DOI: 10.1111/1756-185x.12612] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Ahmed M Alkhunaizi
- Nephrology Section, Internal Medicine Services Division, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Mohamad F Dawamneh
- Division of Pathology, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
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12
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Song Y, Shi YH, He C, Liu CQ, Wang JS, Zhao YJ, Guo YM, Wu RJ, Feng XY, Liu ZJ. Severe Henoch-Schönlein purpura with infliximab for ulcerative colitis. World J Gastroenterol 2015; 21:6082-6087. [PMID: 26019477 PMCID: PMC4438047 DOI: 10.3748/wjg.v21.i19.6082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 01/16/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn’s disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schönlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX.
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14
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Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: systematic literature review and analysis of a monocentric cohort. Autoimmun Rev 2014; 13:873-9. [PMID: 24840285 DOI: 10.1016/j.autrev.2014.05.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 05/02/2014] [Indexed: 12/25/2022]
Abstract
The use of biologic drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. The aim of this study was to describe the features of biologics-induced autoimmune renal disorders (AIRD) through a systematic review and a cohort study of 707 adult patients affected with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (SA) and Psoriatic Arthritis (PsA). The literature search identified 2687 articles of which 21 were considered relevant for the present study, accounting for 26 case reports. The cohort analysis retrieved 3 cases. According to clinical manifestations and kidney histology the identified AIRD cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Twenty-two out of 29 cases with AIRD were reported in patients affected by RA, 5 in AS and 2 in PsA. The biologic drug most frequently associated with development of AIRD was Etanercept (15 cases, 51.7%), followed by Adalimumab (9 cases, 31.0%) and Infliximab (3 cases, 10.3%) while Tocilizumab and Abatacept were reported in 1 case (3.4%) for each. Thirteen out of 29 (44.8%) cases were classified as affected by IARD, 12 (41.3%) as GNSV and 4 (13.9%) as GNLS. Worse prognosis was associated with GNSV and lack of biologic withdrawal. Although rare, AIRD may be life-threatening and may lead to renal failure and death. If AIRD occurs, biologic drugs must be stopped and patient should be treated according to clinical manifestations and kidney biopsy findings.
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15
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Xiao X, Chang C. Diagnosis and classification of drug-induced autoimmunity (DIA). J Autoimmun 2014; 48-49:66-72. [PMID: 24456934 DOI: 10.1016/j.jaut.2014.01.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 11/13/2013] [Indexed: 12/17/2022]
Abstract
Since sulfadiazine associated lupus-like symptoms were first described in 1945, certain drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases (named drug-induced autoimmunity, DIA), exemplified by systemic lupus erythematosus (SLE). Among the drugs, procainamide and hydralazine are considered to be associated with the highest risk for developing lupus, while quinidine has a moderate risk, and all other drugs have low or very low risk. More recently, drug-induced lupus has been associated with the use of newer biological modulators, such as tumor necrosis factor (TNF)-alpha inhibitors and cytokines. In addition to lupus, other major autoimmune diseases, including vasculitis and arthritis, have also been associated with drugs. Because resolution of symptoms generally occurs after cessation of the offending drugs, early diagnosis is crucial for treatment strategy and improvement of prognosis. Unfortunately, it is difficult to establish standardized criteria for DIA diagnosis. Diagnosis of DIA requires identification of a temporal relationship between drug administration and the onset of symptoms, but the relative risk with respect to dose and duration for each drug has rarely been determined. DIA is affected by multiple genetic and environmental factors, leading to difficulties in establishing a list of global clinical features that are characteristic of most or all DIA patients. Moreover, the distinction between authentic DIA and unmasking of a latent autoimmune disease also poses challenges. In this review, we summarize the highly variable clinical features and laboratory findings of DIA, with an emphasis on the diagnostic criteria.
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Affiliation(s)
- Xiao Xiao
- Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, 145 Shandong Middle Road, Shanghai 200001, China
| | - Christopher Chang
- Division of Allergy, Asthma and Immunology, Thomas Jefferson University, Wilmington, DE 19803, USA.
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Abstract
Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the axial skeleton. Extra-articular manifestations are less common relative to other rheumatic diseases, and vasculitic complications typically involve the ascending aorta and aortic valve. The use of tumor necrosis factor inhibitors is efficacious in the treatment of patients with AS. Since their routine use, however, tumor necrosis factor inhibitors have been associated with the development of drug-induced complications including the induction of lupus and both cutaneous and systemic vasculitis. In this report, we describe a patient with severe longstanding AS, who developed Henoch-Schönlein purpura after commencing therapy with etanercept. Tumor necrosis factor inhibitor-induced Henoch-Schönlein purpura has been very rarely reported and has been mostly recognized in patients with rheumatoid arthritis.
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Abstract
PURPOSE OF REVIEW Biological agents are therapies designed to target a specific molecular component of the immune system, and are currently licensed for use in autoimmune rheumatic, digestive, dermatological and systemic diseases. However, their use has been linked with the paradoxical development of autoimmune processes. RECENT FINDINGS More than 1500 cases of autoimmune diseases induced by biologics have been reported, including a wide variety of both systemic (lupus, vasculitis, sarcoidosis, antiphospholipid syndrome and inflammatory myopathies) and organ-specific (interstitial lung disease, uveitis, optic neuritis, peripheral neuropathies, multiple sclerosis, psoriasis, inflammatory bowel disease and autoimmune hepatitis) autoimmune processes. Although these processes are overwhelmingly associated with anti-TNF agents, recent cases have been associated with therapies directed against other cytokines, B or T-cells, illustrating that even though targeting a particular immune molecule may be associated with an excellent clinical response in most patients, an unexpected autoimmune response may arise in some cases. SUMMARY As the use of biological therapies expands, the number and diversity of induced autoimmune disorders should be expected to increase. Paradoxically, for many of these drug-related processes, current treatment indications include the very biological agent producing the adverse event.
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Marques I, Lagos A, Reis J, Pinto A, Neves B. Reversible Henoch-Schönlein purpura complicating adalimumab therapy. J Crohns Colitis 2012; 6:796-9. [PMID: 22445079 DOI: 10.1016/j.crohns.2012.02.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Revised: 02/25/2012] [Accepted: 02/26/2012] [Indexed: 01/09/2023]
Abstract
The tumour necrosis factor antagonists have demonstrated efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. These agents are generally well tolerated but with the increasing number of patients receiving anti-tumour necrosis factor-α (anti-TNFα) therapy, more adverse reactions are expected to occur. Cutaneous eruptions complicating treatment with anti-TNFα agents are common, occurring in around 20% of patients. Most reactions are mild-to-moderate and rarely warrant treatment withdrawal. We herein present a case of Henoch-Shönlein purpura (HSP) vasculitis following treatment with the monoclonal anti-TNFα antibody adalimumab for ileo-colic Crohn's disease. The reaction occurred after 18 months of adalimumab therapy and discontinuation of the anti-TNFα resulted in rapid improvement of the condition. The causal relationship has become even more likely when the purpura reappeared after restarting adalimumab. The patient started infliximab, with disease control and no cutaneous side effects. To the best of our knowledge, this is the second case report of HSP complicating adalimumab therapy. Although adalimumab is theoretically less related to immune-mediated reactions, clinicians must be aware that adverse side effects may still occur. This is the first case that shows that infliximab can be safely used in patients with adalimumab related HSP. We discuss the literature and potential causal mechanisms and propose possible approaches to its management.
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Affiliation(s)
- Inês Marques
- Gastroenterology Department, Hospital Pulido Valente, Lisbon, Portugal.
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Dessinioti C, Stratigos AJ, Katsambas A, Antoniou C. Anti-tumor necrosis factor-α therapies for immune-mediated and inflammatory skin diseases. Drug Dev Res 2011. [DOI: 10.1002/ddr.20471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Patel R, Cafardi JM, Patel N, Sami N, Cafardi JA. Tumor necrosis factor biologics beyond psoriasis in dermatology. Expert Opin Biol Ther 2011; 11:1341-59. [PMID: 21651458 DOI: 10.1517/14712598.2011.590798] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION TNF-α is a cytokine essential for immune response and its receptors has been shown to be dysregulated in a variety of diseases including psoriasis vulgaris. There are a number of TNF-α inhibitors approved for psoriasis, however there is a growing body of literature supporting their use in a wide variety of dermatological conditions. AREAS COVERED The use of biologic TNF-α antagonists in conditions for which they have not yet been approved by the FDA ('off-label' uses) and the literature that supports the most appropriate agents and conditions for use. A PubMed/MEDLINE search was performed with the keywords 'TNFα antagonist', 'biologic therapy', 'off-label' and 'unapproved'. The list of references and citing articles of the articles retrieved were also used as sources. This complete list was evaluated for inclusion, based on relevance to the proposed goal of this review. EXPERT OPINION There are a large number of conditions for which biologic antagonists of TNFα are effective, beyond those already approved by the FDA. The various agents vary in their efficacy in treatment, with infliximab consistently the most effective, particularly in granulomatous diseases. Although effectiveness varies among these conditions, biologic antagonists of TNF-α are promising for the treatment of these diseases.
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Affiliation(s)
- Raj Patel
- University of Alabama at Birmingham, Dermatology, 1530 Third Avenue South, EFH suite 414 Birmingham, AL 35294, USA
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Rahman FZ, Takhar GK, Roy O, Shepherd A, Bloom SL, McCartney SA. Henoch-Schönlein purpura complicating adalimumab therapy for Crohn’s disease. World J Gastrointest Pharmacol Ther 2010; 1:119-22. [PMID: 21577306 PMCID: PMC3091153 DOI: 10.4292/wjgpt.v1.i5.119] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2010] [Revised: 09/09/2010] [Accepted: 09/16/2010] [Indexed: 02/06/2023] Open
Abstract
Anti-tumour necrosis factor-α (TNF) therapy has revolutionised the management of chronic inflammatory conditions. With ever increasing numbers of patients being treated with these agents, uncommon adverse reactions will inevitably occur more frequently. Cutaneous manifestations are associated with many of these chronic conditions and can complicate anti-TNF therapy in about 20% of cases. Vasculitic complications are rarely associated with anti-TNF therapy. Henoch-Schönlein purpura (HSP), a small vessel vasculitis, has been described following infliximab and etanercept therapy but never with adalimumab, a fully humanized TNF antibody. The risk of such immune-mediated reactions is theoretically less with adalimumab compared to infliximab but can still occur. Here we report the first case in the literature of HSP that can be attributed to the use of adalimumab in a 19-year-old male with recalcitrant Crohn’s disease.
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Affiliation(s)
- Farooq Z Rahman
- Farooq Z Rahman, Gagandeep K Takhar, Ovishek Roy, Stuart L Bloom, Sara A McCartney, Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, NW1 2BU, United Kingdom
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Miehsler W, Novacek G, Wenzl H, Vogelsang H, Knoflach P, Kaser A, Dejaco C, Petritsch W, Kapitan M, Maier H, Graninger W, Tilg H, Reinisch W. A decade of infliximab: The Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease. J Crohns Colitis 2010; 4:221-56. [PMID: 21122513 DOI: 10.1016/j.crohns.2009.12.001] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2009] [Accepted: 12/01/2009] [Indexed: 12/15/2022]
Abstract
Infliximab (IFX) has tremendously enriched the therapy of inflammatory bowel diseases (IBD) and other immune mediated diseases. Although the efficacy of IFX was undoubtedly proven during the last decade numerous publications have also caused various safety concerns. To summarize the immense information concerning adverse events and safety issues the Austrian Society of Gastroenterology and Hepatology launched this evidence based consensus on the safe use of IFX which covers the following topics: infusion reactions and immunogenicity, skin reactions, opportunistic infections (including tuberculosis), non-opportunistic infections (bacterial and viral), vaccination, neurological complications, hepatotoxicity, congestive heart failure, haematological side effects, intestinal strictures, stenosis and bowel obstruction (SSO), concomitant medication, malignancy and lymphoma, IFX in the elderly and the young, mortality, fertility, pregnancy and breast feeding. To make the vast amount of information practicable for routine application the consensus was finally condensed into a checklist for a safe use of IFX which consists of two parts: issues to be addressed prior to anti-TNF therapy and issues to be addressed during maintenance. Both parts are further divided into obligatory and facultative items.
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Affiliation(s)
- W Miehsler
- Department of Internal Medicine 3, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.
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Moustou AE, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP, Stratigos AJ. Cutaneous side effects of anti-tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol 2009; 61:486-504. [PMID: 19628303 DOI: 10.1016/j.jaad.2008.10.060] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Revised: 10/17/2008] [Accepted: 10/27/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anti-tumor necrosis factor (anti-TNF) biologic agents have been associated with a number of adverse events. OBJECTIVE To review the cutaneous reactions that have been reported in patients receiving anti-TNF therapy. METHODS We performed a systematic MEDLINE search of relevant publications, including case reports and case series. RESULTS Reported cutaneous events included infusion and injection site reactions, psoriasiform eruptions, lupus-like disorders, vasculitis, granulomatous reactions, cutaneous infections, and cutaneous neoplasms. Infusion reactions and injection site reactions were definitely associated with anti-TNF administration, whereas all other events had a varying strength of association and severity, not necessarily requiring drug discontinuation. LIMITATIONS Most information was derived from spontaneous case reports, where ascertainment biases and frequency of reporting may impair detection methodology and causal relationships. CONCLUSIONS As anti-TNF biologic agents are progressively being used in clinical practice, cutaneous adverse events will be encountered more frequently. Until more data are accumulated with respect to their pathogenesis and potential association with anti-TNF therapy, dermatologists should become more familiar with the clinical presentation and management of such events.
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Nobile S, Catassi C, Felici L. Herpes zoster infection followed by Henoch-Schönlein purpura in a girl receiving infliximab for ulcerative colitis. J Clin Rheumatol 2009; 15:101. [PMID: 19265360 DOI: 10.1097/rhu.0b013e31819bca9e] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Manel Casanova J, Sanmartín V, Martí RM, Ferran M, Pujol RM, Ribera M. Tratamiento de la psoriasis en placas moderada y grave con etanercept. ACTA ACUST UNITED AC 2009. [DOI: 10.1016/s0213-9251(09)70337-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Abstract
Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to these new therapeutic agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of vasculitis developed after TNF-targeted therapy. A total of 132 cases, identified up to July 2008, are included and analyzed in this review.
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Current World Literature. Curr Opin Rheumatol 2008; 20:111-20. [DOI: 10.1097/bor.0b013e3282f408ae] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Immunomodulators: interleukins, interferons, and IV immunoglobulin. CLINICAL NEPHROTOXINS 2008. [PMCID: PMC7120840 DOI: 10.1007/978-0-387-84843-3_29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The outstanding progress in immunology and the development of new technologies have resulted in the introduction of new immunotherapies, the so-called “immunomodulators”, for autoimmune diseases, inflammatory disorders, allograft rejection, and cancer. These immunomodulators comprise recombinant cytokines and specific blocking or depleting antibodies. Many of these therapies achieve their effect by stimulating the release of cytokines. The term cytokines includes interleukins (IL-), chemokines, growth factors, interferons (IFN), colony stimulating factors (CSF), and tumor necrosis factors (TNF). These molecules are involved in inflammation, cell proliferation and apoptosis, tissue injury and repair. These new therapeutic tools can be associated with side effects among which nephrotoxicity. The most common immunomodulators associated with nephrotoxicity are described in Table 1. The nephrotoxic side effects of immunomodulators can be roughly divided into (ischemic) tubular necrosis, thrombotic microangiopathy, serum sickness, and autoimmune disorders.
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Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana D, Bertolaccini L, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86:242-251. [PMID: 17632266 DOI: 10.1097/md.0b013e3181441a68] [Citation(s) in RCA: 514] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific characteristics should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of concomitant methotrexate. In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and interstitial lung disease.
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Affiliation(s)
- Manuel Ramos-Casals
- From Department of Autoimmune Diseases (MR-C, PB-Z, SM, NS, DG), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Hospital Clínic, Barcelona, Spain; and Lupus Research Unit (LB, M-JC, MAK), The Rayne Institute, King's College London School of Medicine at Guy's, King's and St Thomas' Hospitals, St Thomas' Hospital, London, United Kingdom
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John Wiley & Sons, Ltd.. Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2007. [DOI: 10.1002/pds.1374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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