scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Dupilumab as a novel steroid-sparing treatment for IgG4-related disease.

01 Apr 2020-Annals of the Rheumatic Diseases (Ann Rheum Dis)-Vol. 79, Iss: 4, pp 549-550
TL;DR: It was postulated by the authors to investigate dupilumab as a novel steroid-sparing treatment for IgG4-RD.
Abstract: IgG4-related disease (IgG4-RD) is a rare fibroinflammatory, multisystemic condition with a relapsing-remitting progression.1 The level of serum IgG4 correlates with inflammatory activity and organ involvement.1 Glucocorticoids are first line for IgG4-RD, but there are numerous adverse effects with chronic use.2 Dupilumab is a monoclonal antibody that acts on the interleukin 4 (IL-4) receptor alpha, shared by the IL-4 and IL-13 receptors.1 IL-4 causes isotype switching from IgM to IgG4 and IL-13 is implicated in fibrosis.3 Thus, it was postulated by the authors to investigate dupilumab as a novel steroid-sparing treatment for IgG4-RD. A 67-year-old man with no known allergies and a history of sensory neural hearing loss, recurrent bronchitis, spinal stenosis, moderate positional obstructive sleep apnoea, asthma, atopic dermatitis (which caused swelling around his eyes) and allergic rhinoconjunctivitis underwent extensive investigations over the past 2 years due to suspected IgG4-RD. The patient’s initial complaint was pruritic erythematous lesions on the legs, arms, chest and palms. …
Citations
More filters
Journal ArticleDOI
16 Jun 2020-BMJ
TL;DR: IgG4 related disease was recognized as a unified disease entity only 15 years ago as mentioned in this paper, and specialists are now familiar with most of its clinical manifestations, including the involvement of the pancreato-biliary tract, retroperitoneum/aorta, head and neck, and salivary glands.
Abstract: IgG4 related disease was recognized as a unified disease entity only 15 years ago. Awareness of IgG4 related disease has increased worldwide since then, and specialists are now familiar with most of its clinical manifestations. Involvement of the pancreato-biliary tract, retroperitoneum/aorta, head and neck, and salivary glands are the most frequently observed disease phenotypes, differing in epidemiological features, serological findings, and prognostic outcomes. In view of this multifaceted presentation, IgG4 related disease represents a great mimicker of many neoplastic, inflammatory, and infectious conditions. Histopathology remains key to diagnosis because reliable biomarkers are lacking. Recently released classification criteria will be invaluable in improving early recognition of the disease. IgG4 related disease is highly treatable and responds promptly to glucocorticoids, but it can lead to end stage organ failure and even death if unrecognized. Prolonged courses of corticosteroids are often needed to maintain remission because the disease relapses in most patients. Rapid advancement in our understanding of the pathophysiology of IgG4 related disease is leading to the identification of novel therapeutic targets and possible personalized approaches to treatment.

119 citations

Journal ArticleDOI
TL;DR: A 51-year-old man with IgG4-related dacryoadenitis and sialadenitis was treated with dupilumab and left submandibular salivary gland and two cervical lymph nodes biopsies concluded, respectively, to lymphoplasmacytic polyclonal infiltration and reactive hyperplasia.
Abstract: We read with interest the letter by Simpson et al reporting the use of dupilumab in a patient with IgG4-related disease (IgG4-RD).1 Indeed blocking the IL-4/IL-13 pathway is tempting, considering the roles of these cytokines and the physiopathological changes observed during IgG4-RD.2 3 We have also treated with dupilumab a 51-year-old man with IgG4-related dacryoadenitis and sialadenitis (bilateral lacrimal, parotid, sublingual and submandibular involvement, pattern of Mikulicz syndrome). Left submandibular salivary gland and two cervical lymph nodes biopsies concluded, respectively, to lymphoplasmacytic polyclonal infiltration and reactive hyperplasia. Immunohistochemistry was only available on lymph nodes, showing an IgG4+/CD138+ plasma cells ratio over 40% with 40 IgG4+ plasma cells/high power field. Serum IgG4 and IgE levels were found to be 17.7 g/L (normal range <0.8 g/L) and 3499 kIU/L (normal range <100 kIU/L), respectively, with normal complete blood count, liver and renal function tests. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, entry criteria were met, …

14 citations

Journal ArticleDOI
TL;DR: In this paper, the authors describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations and describe two cases of severe recalcitrant dermatitis treated with dupilumab.
Abstract: Background Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome. Objective To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations. Methods A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed. Results Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus. Conclusions Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.

13 citations

Journal ArticleDOI
18 Jan 2021-Heart
TL;DR: In this paper, the authors provide a review of the published literature on cardiovascular manifestations of immunoglobulin G4-related disease and provide a basis for diagnosis and management of the condition by the practising cardiologist.
Abstract: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterised by multiorgan lymphoplasmacytic infiltration, obliterative phlebitis and storiform fibrosis. It can be associated with cardiovascular pathology. The objective of this narrative review is to summarise the published literature on cardiovascular manifestations of IgG4-RD and to provide a basis for diagnosis and management of the condition by the practising cardiologist.We propose the following categorisations of cardiovascular IgG4-RD: aortitis, medium-vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis, myocardial disease and antineutrophilic cytoplasmic antibody-associated vasculitis. We also review herein developments in radiological diagnosis and reported medical and surgical therapies. Cardiovascular lesions frequently require procedural and/or surgical interventions, such as aortic aneurysm repair and valve replacement. IgG4-RD of the cardiovascular system results in serious complications that can be missed if not evaluated aggressively. These are likely underdiagnosed, as clinical presentations frequently mimic cardiovascular disease due to more common aetiologies (myocardial infarction, abdominal aortic aneurysm and so on). While systemic corticosteroids are the mainstay of IgG4-RD treatment, biological and disease-modifying agents are becoming more widely used. Cardiologists should be aware of cardiovascular IgG4-RD as a differential diagnosis, and understand the roles of corticosteroids, disease-modifying agents and biologicals, as well as their integration with surgical approaches. There are several knowledge gaps, including diagnosis, risk factors, pathogenesis and appropriate management in Ig4-RD of the cardiovascular system. Areas lacking well-conducted randomized trials include safety of steroids in the setting of vascular aneurysms and the role of disease-modifying drugs and biological agents in patients with established cardiovascular complications of this multifaceted enigmatic disease.

8 citations

Journal ArticleDOI
TL;DR: Current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, the cellular mechanisms involved in IgG 4 production are described, and the differential response to immunotherapies of the IgG3 producing B cells/plasmablasts are described are described.
Abstract: Organ-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant autoantibodies of the IgG4 subclass (IgG4-autoimmune diseases; IgG4-AID). This group includes pemphigus vulgaris, thrombotic thrombocytopenic purpura, subtypes of autoimmune encephalitis, inflammatory neuropathies, myasthenia gravis and membranous nephropathy. Although the associated autoantibodies target specific antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in genetic predisposition, disease mechanisms, clinical course and response to therapies. IgG4-AID appear to be distinct from another group of rare immune diseases associated with IgG4, which are the IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by antigen-specific IgG4. Importantly, IgG4-AID differ significantly from diseases associated with IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the antibodies cause disease, and the differential response to immunotherapies of the IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding IgG4 immunobiology is a key step towards the development of novel, IgG4 specific treatments. In this review we therefore summarize current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in IgG4 production and provide an overview of treatment responses in IgG4-AID.

8 citations

References
More filters
Journal ArticleDOI
TL;DR: The comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists and have increased the sensitivity of diagnosis to 100% for Igg4-related MD, KD, and AIP.
Abstract: IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz’s disease (MD) and kidney disease (KD) In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists

1,417 citations

Journal ArticleDOI
TL;DR: This 1-year, randomised, double-blinded, placebo-controlled, phase 3 study aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical cortiosteroids in adults with moderate-to-severe atopic dermatitis.

781 citations

Journal ArticleDOI
TL;DR: Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.

717 citations

Journal ArticleDOI
TL;DR: Dupilumab, a human monoclonal antibody that simultaneously inhibits signaling of IL-4 and IL-13, has demonstrated significant clinical efficacy in AD, asthma, and CSwNP, suggesting that there is a common underlying pathogenic pathway, and that IL- 4 and IL -13 cytokines are central to regulating the pathogenesis of these atopic diseases.
Abstract: Introduction: Allergy results from an aberrant Type 2 inflammatory response, triggered by a wide range of environmental antigens (allergens) that lead to various immune responses, culminating in the production of immunoglobulin E (IgE). Two key cytokines, interleukin (IL)-4 and IL-13, are critical to the induction and perpetuation of the Type 2 response, and have been implicated in multiple atopic diseases.Area covered: This review summarizes recent milestone developments that have elucidated components of the pathogenesis of atopic diseases such as atopic dermatitis (AD), asthma, and chronic sinusitis with nasal polyposis (CSwNP).Expert commentary: Several therapeutic agents that selectively target potentiators of the Type 2 pathway have shown efficacy in one or more of these atopic diseases, but few agents have proven to be broadly applicable across all three atopic diseases. Dupilumab, a human monoclonal antibody that simultaneously inhibits signaling of IL-4 and IL-13, has demonstrated signifi...

277 citations

Journal ArticleDOI
TL;DR: There are patients with persistent B-cell dysfunction long after rituximab treatment was discontinued, and these patients should be distinguished from patients with primary immunodeficiency diseases.

93 citations

Related Papers (5)