1 INTRODUCTION

Chronic spontaneous urticaria (CSU) is a serious, debilitating skin condition of long duration with a relapsing–remitting course and an overall lifetime prevalence of about 1.4% in the global population.^{1, 2} The clinical signature of CSU is the recurrent sudden appearance of intensively itchy wheals and/or angioedema.¹ Besides these highly disfiguring visible skin changes, which alone make CSU tremendously burdensome, in many cases, periods of years or even decades elapse before a patient's CSU is fully controlled by responding to treatment or achieving spontaneous remission, meaning they endure a long ordeal (Figure 1). Moreover, the cutaneous signs and symptoms markedly impact patients' quality of life (QoL)³ and have an enormous socioeconomic impact.⁴

Recent interest in CSU pathogenesis has led to major insights into the complexity of the underlying disease mechanisms. Today, it is clear that CSU is a mast cell (MC)-dependent disease and that the activation and degranulation of skin MCs are responsible for the signs and symptoms. It is also clear that CSU is a chronic inflammatory disease. Structural changes of affected tissue or organs occur in many other chronic inflammatory diseases. In asthma, for example, lung changes often lead to alterations in the airway tissue composition and structure, such as increased thickness in airway smooth muscle, known as airway remodeling.⁵ CSU does not involve skin remodeling; nevertheless, the skin of some patients with CSU shows features of chronic inflammation, including increased numbers of MCs, eosinophils, basophils, and other infiltrating cells, upregulated cytokines, neovascularization, and increased expression of vascular adhesion molecules (Figure 2).^{6, 7} Together, these changes are linked to clinical consequences and may explain why the skin of CSU patients is more susceptible to MC-degranulating signals and wheal formation.⁶ For example, raised MC numbers in the skin correlate with disease activity; those with active CSU have more skin MCs than those in remission or healthy controls.⁸ Patients with CSU also have an increased cellular infiltrate of CD4⁺ T cells primarily of the Th2 subtype; however, Th1 cells, Th17 cell-derived cytokines, neutrophils, and monocytes are also present.⁹

Importantly, major downstream drivers of skin MC activation and degranulation have been identified, and two CSU endotypes have been described, which differ in their pathogenic mechanisms: type I autoimmune or autoallergic CSU (aaCSU) and type IIb autoimmune CSU (aiCSU, Figure 3).¹⁰ In aaCSU, autoantigens crosslink IgE autoantibodies bound to their high-affinity receptor, FcεRI, on skin MCs, causing their degranulation.¹¹ In aiCSU, skin MCs are activated and degranulated by IgG autoantibodies that target FcεRI or FcεRI-bound IgE. Most patients with CSU have aaCSU, with MC-activating IgE autoantibodies, or aiCSU, with MC-activating IgG autoantibodies. Some patients have both, and others have neither, pointing to the need to identify and characterize additional relevant mechanisms of MC activation in CSU.^{1, 10-13} More than half of CSU patients have aaCSU, aiCSU is less common, and about 7% have both.¹⁴

Further research is needed to understand what causes the production of MC-activating autoantibodies that leads to CSU and how autoantibody profiles change during the disease.

Immune cells such as basophils, eosinophils and T cells are known to migrate from the blood into the skin of patients with CSU, further contributing to urticaria symptoms. About 14% and 10% of patients show decreased basophil and eosinophil counts, which are associated with aiCSU, high CSU activity, and poor response to treatment.¹⁵

Acute spontaneous urticaria (ASU) is frequent, often associated with upper airway infections, and, in most cases, is self-limited.¹⁶ According to most studies, ASU progresses to CSU in less than 10% of cases, although some studies report higher rates.¹ Based on cumulative average estimates, only 17% of patients experience CSU remission in the first year; in most patients, it persists much longer.¹⁷ Currently, it is unclear what factors drive this. CSU, on average, lasts for several years and can then show spontaneous remission. In most cases, CSU is self-limiting, with patients experiencing spontaneous remission after 2–5 years.¹⁸ However, up to 50% of patients have CSU for over 5 years. Cumulative weighted averages estimate that the proportion of patients remitting at 5 and 20 years is 45% and 73%, respectively.¹⁷ Markers linked to longer disease duration and severity include anti-thyroid antibodies, concomitant chronic inducible urticaria, hypertension, and poor control with antihistamine updosing or second-line treatments.¹ However, what causes spontaneous remission has not been fully defined. CSU relapses in about one-fifth of patients, and those with increased serum levels of IgE and anti-thyroid peroxidase antibodies are at higher risk of CSU recurrence.¹⁹ Many patients with CSU express IgE antibodies against thyroid peroxidase (TPO), which can cause autoallergic MC activation. IgE-anti-TPO may activate MCs in addition to TPO, which is not in the skin, cross-reacting autoantigens such as eosinophil peroxidase, which is present in CSU skin, can crosslink IgE-anti-TPO.²⁰ Wheals can present in IgE-mediated diseases such as allergies and anaphylaxis (usually acute), which is a rare differential diagnosis of CSU.

Patients with CSU develop certain comorbidities more often than the general population, and this can increase in frequency and intensity over time, indicating progression of the disease and increasing patient burden. In around 80% of patients with CSU who have autoimmune diseases, these diseases appeared within 10 years of the CSU diagnosis.²¹ In addition to autoimmune diseases, CSU comorbidities include sleep disorders,^{3, 22} sexual dysfunction,²³ and mental health issues.²⁴ One, 2, and 3 years after disease onset, 7.5%, 9.6%, and 10.9% of patients with CSU have depression and/or anxiety, respectively (Figure 4).²⁵

Currently, available CSU treatments are limited to improving the signs and symptoms.²⁶ Licensed treatments recommended by the international guideline for urticaria, that is, antihistamines and omalizumab, inhibit MC mediator effects and activation, respectively.²⁶ There is a high medical need to develop and introduce novel therapies into clinical practice that modulate CSU pathology with the potential for disease modification. Such treatments must target disease-driving pathways upstream of MC activation so that inhibition of these pathways prevents or delays the progression of CSU, including the development of comorbidities. Upstream drivers of skin MC activation include autoantibodies, cytokines, and possibly gut microbiome changes with subsequent barrier dysfunction (Figure 5).^{12, 27, 28} The concept of disease modification in CSU has not yet been defined. To address this, we developed a definition of disease modification due to a treatment intervention and criteria that must be met by disease-modifying treatments (DMTs) for CSU. We also provide guidance on how to differentiate DMTs from symptom-preventing therapies. Additionally, we outline current limitations and potential DMTs under development for CSU.

2 THE CONCEPT OF DISEASE MODIFICATION

The concept of disease modification was first introduced in the field of rheumatology with the term disease-modifying antirheumatic drugs (DMARDs) in 1976.²⁹ The idea of DMARDs then gained momentum in the 1980s, with several publications describing their use.³⁰ Traditionally, disease-modifying potential was used to describe drugs that slow the progression of rheumatoid arthritis (RA),³¹ “reducing, suppressing, or eliminating disease activity, and thereby preventing the extended and perhaps permanent effects of disease activity.”³² In disease modification, drug treatments target the underlying pathophysiology, with the ultimate long-term aim of achieving an enduring clinical benefit after discontinuation. DMTs are now available for many diseases; Table 1 provides an overview of some selected chronic diseases.

Interestingly, the Food and Drug Administration (FDA) abandoned the “disease-modifying effect” terminology in the recently updated 2018 draft guidance, which now refers to a “persistent effect on disease course”. Whereas the guidelines from the FDA and European Medicines Agency previously provided recommendations on obtaining a specific label claim for disease modification, the guidelines from 2018 provide recommendations relating to treatment goals only, i.e., without guidance on getting specific label claims.³³

3 DIFFERENTIATING DISEASE-MODIFYING TREATMENTS FROM SYMPTOM-PREVENTING TREATMENTS

There are distinct differences between symptom-preventing and disease-modifying drug treatments (Figure 6). The former relieve or prevent the signs and symptoms of a disease without changing its course. For example, first-line CSU treatment with a second-generation H₁-antihistamine stabilizes the histamine H₁ receptor and inhibits its activation by histamine.¹⁶ Histamine plays an important role in CSU downstream of the activation and degranulation of skin MCs. However, histamine does not drive MC activation and degranulation, and antihistamines do not modify CSU. Furthermore, histamine is not the only mediator released when MCs degranulate. Effects of other inflammatory mediators released by MCs may activate tissue-resident immune cells and/or drive the recruitment of other immune cells into the skin.

In contrast, DMTs mediate their effect by targeting a disease's underlying pathophysiology, resulting in a long-term, enduring, therapy-free and clinically beneficial change in the disease course. This could be slowing or preventing the recurrence of further signs and symptoms or the development of comorbidities. Thus, in CSU, a DMT must target pathogenic drivers upstream of skin MC activation and degranulation, for example, by reducing the production of IgE antibodies against autoantigens in aaCSU or MC-activating IgG autoantibodies in aiCSU. DMTs can be curative therapies, such as using antibiotics to treat an infection, which achieves complete disease eradication and restores health.³⁴ “Cure” results from a treatment that heals a health problem, meaning it is unlikely to return. A curative treatment is the ultimate DMT, and for this to apply to CSU, the treatment would need to do two things: achieve clinical remission and reduce the risk of relapse to the level of people who have never experienced CSU.

4 THE DEFINITION OF DISEASE MODIFICATION IN CSU

To evaluate the potential disease-modifying properties of a CSU treatment, it is important to understand the criteria that define disease modification developed for other chronic inflammatory diseases; this can help determine what disease modification for CSU must include, as described below.³⁵

5 DEFINING DISEASE MODIFICATION IN CSU

The concepts of disease modification developed in other chronic inflammatory diseases include one or more of three features: (1) slowing of disease progression, (2) inducing long-lasting remission beyond drug discontinuation, and (3) targeting disease-driving mechanisms. All three of these features are relevant for disease modification in CSU. We, therefore, propose that disease modification in CSU be defined as shown in Box 1.

6 THE CRITERIA FOR TARGETED DISEASE-MODIFYING TREATMENTS IN CSU

DMTs in CSU aim to positively change the pathophysiological processes that drive CSU to prevent disease progression and achieve clinical remission (Figures 7 and 8). Thus, DMTs need to fulfill the three criteria outlined in Box 2.

7 THE DISEASE-MODIFYING POTENTIAL OF EMERGING TARGETED CSU TREATMENTS USED OFF-LABEL AND/OR UNDER DEVELOPMENT

Mechanisms upstream of MC activation include IgE and IgG autoantibodies, proinflammatory cytokines, and possibly dysbiotic microbiota that compromise the gut barrier.^{10, 28, 50, 51} Some of the targeted treatments currently used off-label for the treatment of CSU and/or under development for CSU aim to disrupt these mechanisms and, therefore, have the potential to be disease-modifying (Table 2 and Figure 8).

8 NON-TARGETED TREATMENTS WITH DISEASE-MODIFYING POTENTIAL

Several non-targeted agents used to treat CSU have shown disease-modifying potential (Table 2). Cyclosporine, the third-line treatment recommended in the urticaria guidelines,¹⁶ has been shown to induce possible lasting remission after treatment is discontinued and has good supporting data.^90-92 This treatment can be especially effective for patients with aiCSU markers, such as low total IgE, elevated levels of anti-thyroid antibodies, and/or a positive BHRA.^{24, 91, 92} However, cyclosporine has potentially serious adverse effects such as hypertension and renal insufficiency, although these are uncommon at the doses used for CSU.⁹³ Cyclosporine acts on MCs, which is unlikely to cause disease-modifying effects, and on T cells, which could be disease-modifying.⁴⁹

Mycophenolate has shown efficacy and possible disease modification in a small study of nine patients with severe CSU over 12 weeks.⁹⁴ Two-thirds of patients experienced markedly improved Urticaria Activity Scores (UAS) during treatment. All patients could discontinue glucocorticoids by the end of the trial, with the improvement persisting for ≥6 months after discontinuation. The disease-modifying mechanism of mycophenolate is unknown, but possible mechanisms include the prevention of lymphocyte and monocyte glycoprotein glycosylation, inhibiting the recruitment of leukocytes to inflammatory sites, and impairing antigen presentation.⁹⁵

Dapsone is another agent that has shown potential disease-modifying effects. A trial involving 22 patients with CSU showed improvement in itch and urticaria scores within the first week, with three patients achieving complete resolution of their CSU.⁹⁶ A larger review of patients with CSU showed that 13% of patients had sustained remission for up to 16 months after tapering down the drug after two months of controlled symptoms.⁹⁷ Close monitoring is required when taking this treatment as it can cause serious adverse effects, such as haematological changes. Additionally, the observed disease-modifying impact may be due to the natural, spontaneous remission of the disease, and there is little other evidence of a true modifying effect.

Sulfasalazine can be useful as an add-on to standard therapies in patients with refractory CSU.⁹⁸ In a retrospective review of 39 patients with CSU refractory to antihistamines and other therapies, sulfasalazine treatment added to existing therapies improved CSU in 84% of patients within three months, and 51% of patients became asymptomatic on sulfasalazine plus antihistamines by six months.⁹⁸ In steroid-treated patients, 90% could discontinue glucocorticoids; sulfasalazine was gradually withdrawn once symptoms were controlled, and 28% remained asymptomatic after sulfasalazine was discontinued, requiring only antihistamine therapy.⁹⁸ A possible disease-modifying mechanism is that sulfasalazine inhibits cytokine release, including IL-1, IL-2, IL-6, IL-12, and TNF, thereby creating an anti-inflammatory environment.⁹⁹

High-dose intravenous immunoglobulins (IVIGs) have the potential to inactivate autoreactive T cells and can downregulate B cell antibody production by neutralizing pathogenic antibodies. On macrophages, dendritic cells, and neutrophils, IVIGs can block FcεR-mediated activity.¹⁰⁰ Clinical benefits were observed in 9/10 patients with severe, recalcitrant chronic urticaria, three of whom had prolonged complete remissions at three years follow-up.¹⁰⁰

9 TARGETED TREATMENTS WITH DISEASE-MODIFYING POTENTIAL THAT SHOULD BE DEVELOPED FOR CSU

Treatments that deplete plasma cells producing MC-activating autoantibodies are more likely to result in long-lasting remission and disease modification than treatments that transiently reduce the secretion of autoantibodies by plasma cells (see Table 2). The challenge lies in creating treatments that specifically target plasma cell-producing autoantibodies responsible for activating MCs while sparing those that have protective antibodies. Treatments that deplete plasma cells, such as bortezomib¹⁰¹ or daratumumab,¹⁰² are effective but also target protective immune functions. Immunoablation procedures followed by autologous stem cell transplantation, wherein immune memory is eradicated, and the immune system is effectively reset, indicate that the loss of pathogenic immune memory can lead to long-term remission or even a cure.^103-106 However, it is important to note that these treatments are typically applied for life-threatening autoimmune conditions and may not be suitable for CSU. A recent study in mice provided promising proof of concept, demonstrating the feasibility of targeting long-lived plasma cells in vivo.¹⁰⁷ This study labelled plasma cells with antibodies containing a known antigen. Subsequently, these antigen-specific plasma cells secreted antibodies targeting the labeled antigen, triggering processes like antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. This approach offers a valuable opportunity for developing therapeutic interventions against autoantibody-mediated diseases, including CSU.

Drugs targeting the lymphocyte surface and adhesion molecules OX40/OX40 ligand and Th2-promoting cytokine IL-13 pathways in CSU could have potential disease-modifying roles, but clinical data is not yet available.^{75, 108}

Anti-IL-25 is another potential DMT. IL-25 can increase Th2 cytokines, resulting in enhanced Th2-type immune responses. Thus, inhibiting IL-25 can dampen Th2-type immune responses.¹⁰⁹ C5a inhibition might lead to disease modification by diminishing the activation of MCs and reducing the inflammatory infiltrate in the skin of CSU patients.

Finally, a novel approach to disease modification that could be further developed is vaccine therapy, such as targeting IgE or type 2 cytokines by inducing endogenous neutralizing antibodies. These techniques have been used successfully in animal models.¹¹⁰

10 CONCLUSION AND OUTLOOK

By treating CSU directly at the immune system level, DMTs could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but future therapies could potentially prevent CSU signs and symptoms and associated comorbidities. Treating the underlying pathophysiology ultimately aims to achieve long-term clinical benefits after discontinuing therapy, thus lowering the need for additional pharmacotherapies. Our proposed definition for disease modification in CSU is a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring.

Regarding the best time to treat patients to achieve the best possible disease-modifying outcome, there is evidence from other chronic conditions that early treatment in patients whose urticaria is not yet chronic, that is, those with ASU, could potentially prevent the disease from becoming chronic. Indeed, this has been demonstrated in plaque psoriasis, another chronic skin condition, where treatment with secukinumab in patients with new-onset disease (≤12 months) resulted in high and sustained skin clearance, indicating that treatment may be more effective if used early in the disease course.¹¹¹ Patients with ASU who progress towards CSU have markers for positive ASST results, thyroid autoimmunity, and basopenia at baseline; these could be used as prognostic biomarkers in patients who would benefit from early treatment interventions.^{112, 113}

The most promising data for disease modification are seen in aiCSU; at least 8% of patients with CSU have aiCSU, and almost all of them also have autoallergy.¹⁴ Cyclosporine, BTK inhibitors and rituximab have all shown good efficacy and indicators of long-term remission in patients with aiCSU.^{52, 79, 91}

Longer-term longitudinal studies are required to assess the impact of each treatment, including follow-up assessments after drug discontinuation to identify DMTs that are effective in CSU. Disease remission of CSU is the absence of signs or symptoms after treatment withdrawal, which should be the aim of any DMT.⁴⁰

AUTHOR CONTRIBUTIONS

All authors contributed to the consensus process that led to this manuscript, reviewed the literature, critically reviewed and revised the article, and proofread and approved the final version. Marcus Maurer, Pavel Kolkhir, Manuel P. Pereira, Frank Siebenhaar, Ellen Witte-Händel, and Martin Metz conceived the project, drafted the article, and coordinated and supervised its finalization.

CONFLICT OF INTEREST STATEMENT

M. Maurer is or recently was a speaker and/or advisor for and/or has received research funds from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL, Behring, FAES, Genentech, GI Innovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB, and Urich. P. Kolkhir has been a speaker for Novartis, ValenzaBio and Roche. M. P. Pereira has received research funding from Almirall; he is an investigator for Allakos, Celldex Therapeutics, Incyte, Sanofi, and Trevi Therapeutics; he has received consulting fees, speaker honoraria and/or travel fees from AbbVie, Beiersdorf, Celltrion, Doctorflix, Eli Lilly, GA2LEN, Galderma, Menlo Therapeutics, Novartis, P.G. Unna Academy, Sanofi, StreamedUP, and Trevi Therapeutics. F. Siebenhaar is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Blueprint, Celldex, Cogent, Escient, Granular, GSK, Invea, Noucor, Novartis, Moxie, Sanofi/Regeneron, and Third Harmonic Bio. H. Bonnekoh was a speaker/consultant and/or advisor for and/or has received research funding AbbVie, Novartis, Sanofi Aventis and ValenzaBio outside of submitted work. T. Buttgereit is or recently was a speaker and/or advisor for Aquestive, AstraZeneca, Biocryst, CSL-Behring, GlaxoSmithKline, Hexal, KalVista, Medac, Novartis, Pharming, Roche, Sanofi, and Takeda. K. Krause has received grants/research support or served as a consultant for Bayer, Beiersdorf, CSL Behring, Moxie, Novartis, Roche/CHUGAI, SOBI, and Takeda. She has no conflicts of interest related to the content of this article. M. Magerl is or recently was a speaker and/or advisor for and/or has received research funding from Biocryst, Pharming, Takeda, CSL Behring, Ionis Pharmaceuticals, KalVista, and Pharvaris. M. Muñoz has received personal fees from AstraZeneca, Celldex Therapeutics, Takeda, and GA²LEN, UNEV, and has received research funding from Roche outside the submitted work. J. Scheffel has conducted studies for, received research funds from and advised Allakos, Ascilion, AstraZeneca, CSL Behring, Escient, Evommune, Novartis, Sanofi, Third Harmonic Bio, Third Rock, and Thermo Fisher. R. Treudler has received honoraria for lectures, advisory boards and/or research funding from AbbVie, ALK-Abello, Almirall, CSL-Behring, Leo Pharma, Novartis, Pfizer, Sanofi-Genzyme, Takeda, Viatris, all outside this paper. K. Weller is or recently was a speaker and/or advisor for and/or has received research funds from Moxie, Novartis, Pharvaris, Shire, Takeda, and Uriach. T. Zuberbier has received institutional funding for research and/or honoraria for lectures and/or consulting from Amgen, AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, L'Oreal, Meda, Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes, Takeda, Teva, UCB, and Uriach. In addition, he is a member of ARIA/WHO, DGAKI, ECARF, GA2LEN, and WAO. M. Metz is or recently was a speaker and/or consultant for Amgen, AstraZeneca, Argenx, Celldex, Celltrion, Escient, Jasper Therapeutics, Novartis, Pharvaris, Regeneron, Sanofi, and Third Harmonic Bio. E. Witte-Händel, J. W. Fluhr, L. Herzog, L. Alice Kiefer, S. Neisinger, P. Pyatilova, N. Nojarov, D. Terhorst-Molawi, K-C. Bergmann, S. Prins, S. Frischbutter, E. Maria Grekowitz, and A. Ramanauskaité declare no conflicts of interest regarding this work.