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.

Advances in the diagnosis and management of IgG4 related disease

This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.

/pdf/urticaria-collegium-internationale-allergologicum-cia-update-4nbrewij0z.pdf

Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020.

Objective Chronic urticaria (CU) is a common, heterogeneous, and debilitating disease. Antihistamines and omalizumab are the mainstay therapies of CU. Additional treatment options are needed. Here, we review the off and beyond label use of licensed drugs, novel treatments that are currently under development, and promising new targets. Data Sources MEDLINE was searched for recent reports of the successful use of treatments in CU and promising targets for the development of novel treatment options. We also searched ClinicalTrials.gov for recent and ongoing randomized clinical trials in CU. Study Selections Relevant articles were selected and reviewed. Results Omalizumab, the treatment of choice in patients with antihistamine-resistant chronic spontaneous urticaria (CSU), should be explored for use in chronic inducible urticaria in children younger than 12 years with CSU and at higher doses. The off-label use of dupilumab, reslizumab, mepolizumab, and benralizumab can be effective in CU. Ligelizumab and UB-221, 2 novel anti-IgE monoclonal antibodies, are in clinical trials for CU. Other promising drugs that are currently under development for CU are a chemoattractant receptor–homologous molecule expressed on TH2 cell antagonist, a monoclonal antibody to Siglec-8 (AK002), Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), a spleen tyrosine kinase inhibitor, and dupilumab. Promising targets of future therapies include the Mas-related G-protein–coupled receptor X2; the histamine4 receptor; C5a and its receptor; inhibitory mast cell receptors other than Siglec-8; interleukin 33, interleukin 25, and thymic stromal lymphopoietin, and stem cell factor. Conclusion Novel and better treatments for CU are very much needed. Some agents are in clinical trials already (eg, ligelizumab), and additional ones should be developed, making use of the many promising targets recently identified and characterized.

New treatments for chronic urticaria

Allergies are typically endemic, complex and heterogeneous diseases with a high impact at quality of life. Mechanistically, type 2 immune responses involving eosinophil and basophil granulocytes, mast cells and humoral factors such as IgE are key drivers of allergic diseases. Fighting allergic diseases knows three strategies: prevention, symptomatic and causative therapy. While remarkable progress was made in understanding molecular events in allergies as a prerequisite for effective prevention and desensitization, this review article focuses on the most efficient symptomatic treatments-that is using more and more specific antibodies neutralizing particular immune pathways. We highlight and classify recent and upcoming developments in the three prototype chronic allergic diseases allergic asthma, chronic spontaneous urticaria and atopic eczema. In all three examples, biologics such as dupilumab or omalizumab become reliable and efficient therapeutic options. Finally, we give an outlook how a diagnostic and therapeutic workflow might look like in the near future for these three major burdens of society.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.14027

New biological treatments for asthma and skin allergies.

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell–driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti–IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging.

The role of eosinophils in chronic spontaneous urticaria

Dupilumab as a novel therapy for difficult to treat chronic spontaneous urticaria.

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. …

https://ard.bmj.com/content/annrheumdis/79/4/549.full.pdf

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

Omalizumab as single-dose therapy for vernal keratoconjunctivitis.

We thank Della-Torre et al for their interest in our paper and for providing their thoughts through correspondence.1 2 As they have summarised, our case described a patient whom was prescribed a 40 mg daily dose of prednisone to treat his IgG4-related disease (IgG4-RD); however, the patient declined to pursue additional adjunct immunosuppressants due to the concern of adverse effects.1 To hopefully mitigate such concerns and control his disease, we proposed that dupilumab, a monoclonal anti-interleukin 4 (IL-4) and IL-13 antibody, would be able to treat the patient’s condition mechanistically through two pathways. First, because IL-4 is the signal which plays a pivotal role in class switching from IgM to IgG, we theorised that dupilumab would be able to reduce the amount of serum IgG and IgG4, which is a hallmark of IgG4-RD pathology. Second, because dupilumab inhibits IL-13, which is implicated in the activation of fibroblasts causing fibrosis,3 we believed dupilumab would also be able to address this component of the IgG4-RD mechanism of disease. Upon initiation of dupilumab treatment, we observed remission of the patient’s condition with improvements starting as soon as 3 months post-dupilumab treatment.1 As such, our theory is that IgG4-RD is an example of type 2 inflammation, similar to other conditions such as chronic spontaneous urticaria (CSU) that have been misclassified as non-type 2 inflammation in the past.4 This is what we believe allows dupilumab to be an …

https://ard.bmj.com/content/annrheumdis/early/2020/02/07/annrheumdis-2020-216955.full.pdf

Rachel S Simpson

Papers

Dupilumab as a novel therapy for difficult to treat chronic spontaneous urticaria.

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

Omalizumab as single-dose therapy for vernal keratoconjunctivitis.

Response to: ‘Dupilumab as a potential steroid-sparing treatment for IgG4-related disease’ by Della-Torre et al

M248 dupilumab as a novel steroid-sparing treatment for igg4-related disease