Perspectives on current and emerging therapies for immunoglobulin G4–related disease

ABSTRACT

Understanding of the pathophysiology of immunoglobulin G4–related disease (IgG4-RD) over the last dozen years has opened the door to a variety of targeted treatment approaches. Glucocorticoids are an effective treatment for IgG4-RD if used at a sufficiently high dose, but disease flares are common during or after glucocorticoid tapers and these medications seldom lead to long-term, treatment-free remissions. Moreover, their long-term use in a disease that frequently affects middle-aged to elderly individuals and often causes major pancreatic damage leads to a narrow therapeutic index. Biological therapies offer the possibility of effective disease control with fewer treatment-associated side effects. Promising avenues of investigation include B-cell depletion, immunomodulation of B-cell subsets, interference with co-stimulation, Bruton’s tyrosine kinase inhibition, and Signaling lymphocytic activation molecule F7-directed treatment.

Overview of IgG4-RD

Immunoglobulin G4–related disease (IgG4-RD), a multi-organ, immune-mediated condition that likely has an autoimmune origin, was recognized as a unified diagnosis only in 2003 [1–4]. Japanese investigators reported the relationship of elevated serum IgG4 concentrations with sclerosing pancreatitis in 2001 [5], and within several years the link had been established between features now recognized to be classic IgG4-RD findings (e.g. major salivary gland enlargement and autoimmune pancreatitis) and elevated serum concentrations of IgG4.

The indolent nature of IgG4-RD has proven to be an advantage in dissecting its pathophysiology. It has often proved possible to make the diagnosis and to capture mechanistic study samples before the institution of broad-spectrum treatment (e.g. glucocorticoids) that would complicate an understanding of the workings of the disease. Investigators have therefore been able to glean insight into key immunological pathways operative in IgG4-RD and to design targeted treatment approaches based on this knowledge. Several mechanism-based approaches to therapy are now under evaluation. Thus, ‘treatment strategy based on disease mechanisms in IgG4-RD’ was intensively discussed in the 4th International Symposium on IgG4-RDs held in Kitakyushu, Japan, on 2–4 December 2021. In this review, we describe perspectives on the current investigative landscape for the treatment of IgG4-RD based on the discussion during the symposium.

The nature of IgG4-RD

IgG4-RD is by its nature a slow disease that has typically been going on for many months and even years before diagnosis. The disease is capable of affecting nearly any organ but has a pronounced predilection for a dozen or so organs or body regions. Moving from the head to the abdomen, these are the pachymeninges and the orbital regions (particularly the extra-ocular muscles); the lacrimal, major salivary glands, and thyroid gland; the pancreas and bile ducts; the lungs and kidneys; and the aorta and retroperitoneum. Disease affecting multiple organs simultaneously is the rule, although patients often appear to have added new organs over time if the diagnosis was not recognized properly at the stage of single-organ involvement. By the time the diagnosis is made, the disease-related pathways have been unfolding for some time and have often led to significant end-organ damage.

Two broad disease subtypes

Two broadly overlapping subtypes of disease have been described [1]. One is referred to as a ‘proliferative’ subtype and the other as a ‘fibrotic’ subtype. These designations are imperfect for a variety of reasons, primarily because the biological differences between these subtypes remain uncertain. In addition, fibrosis to some extent is a part of IgG4-RD across the disease spectrum, so categorization of a patient into one subtype or the other is on some level an issue of the relative balance of fibrosis—a term connoting permanent tissue injury and damage—and proliferative elements of inflammation that typically have greater responsiveness to therapies currently employed as well as those under investigation at this time. Nevertheless, the separation of IgG4-RD into these subtypes appears relevant to broad disease phenotype and responsiveness to therapy. The categories are therefore useful in terms of identifying appropriate patients for clinical trial inclusion.

The glandular and epithelial tissues are primarily affected in patients with the proliferative IgG4-RD subtype. Disease features of patients categorized as having proliferative disease include some combinations of lymphadenopathy, dacryoadenitis, sialadenitis, autoimmune pancreatitis, IgG4-related sclerosing cholangitis, lung disease, tubulointerstitial nephritis, and sinusitis, among others. Patients with proliferative IgG4-RD are typically highly active serologically, having elevated concentrations of IgG4, IgG1 and IgE, low levels of C3 and C4, and peripheral eosinophilia. Multi-organ disease is the rule among patients in the proliferative disease subtype.

In contrast, patients categorized in the fibrotic subtype usually have disease at extra-glandular sites that may involve a body region rather than a specific organ. Disease manifestations typical of the fibrotic subtype are retroperitoneal fibrosis, sclerosing mesenteritis, and fibrosing mediastinitis. However, specific organs such as the thyroid gland (Riedel’s thyroiditis) and meninges (hypertrophic pachymeningitis) can also be involved in the fibrotic subset.

Mechanisms of IgG4-RD

Antigen recognition in the innate immune system

IgG4-RD is a fibrotic disease that often leads to the development of tumour-like mass lesions in various organs. The characteristic histological features observed in all of the affected organs are a dense accumulation of lymphocytes and IgG4-producing plasma cells as well as storiform fibrosis and obliterative phlebitis [1, 2, 6–8].

Activation of the adaptive immune system, which leads to the generation of autoreactive T cells and B cells as well as class switch and differentiation of B cells, is often brought by stimulation of innate immunity involved by dendritic cells, macrophages, innate lymphoid cells, mucosal-associated invariant T cells, and mast cells [9]. Cluster of differentiation (CD) 163⁺ M2 macrophages and dendritic cells play a central role in innate immunity, which might recognize various autoantigens such as laminin 511-E8, galectin-3, annexin A11, prohibitin, and likely others. These cells are activated to produce Type I interferon (IFN), interleukin (IL)-33, B-cell activating factor, and CXCL13 in a large amount (Figure 1) [10].

B-cell differentiation regulated by Tfh and Tph cells

In terms of involvement of the adaptive immune system in IgG-RD, we and others have reported that higher proportions of follicular helper T (Tfh) cells and regulatory T cells (Treg) as well as higher proportions of CD27⁺IgD⁻ class-switched memory B cells and plasmocytes are observed in peripheral blood of patients with IgG4-RD compared to healthy controls (Figure 2) [11–13]. A preponderance of the plasmocytes from the peripheral blood of IgG4-RD patients express IgG4, and these cells proliferate in an oligoclonal manner. The peripheral number of plasmocytes in the circulation correlates highly with serum IgG4 concentrations and the number of organs affected by the disease [14]. In addition, the increased numbers of peripheral plasmocytes are reduced sharply by treatment with rituximab or glucocorticoids, suggesting that cells of the B lymphocyte lineage play important roles in the pathological processes of IgG4-RD.

Tfh cells characteristically express a master regulator Bcl6, an effector cytokine IL-21, and key surface molecules such as programmed cell death-1 (PD-1), C-X-C chemokine receptor type 5 (CXCR5), CD40L, and Inducible T-cell co-stimulator. There is strong evidence that Tfh cells induce the class switch in IgG4-RD and foster the differentiation of B cells into plasmocytes within the follicles of secondary lymphoid organs, through the cognate interaction of CD28 and CD40L. Thus, the interplay between B cells and Tfh cells is a prerequisite to differentiation into the antibody-producing cells in IgG4-RD. Indeed, the number of peripheral plasmocytes correlates not only with serum concentrations of IgG and IgG4 in the IgG4-RD patients but also with the concentration of Tfh cells [11–13]. Furthermore, histopathological examinations of affected organs reveal a markedly increased accumulation of CD3⁺Bcl6⁺ Tfh cells, confirming that the increase of Tfh cells in the peripheral blood reflects the degree of Tfh cell infiltration into the areas of disease [12].

Tfh cells bearing CXCR5 enter into the follicles in lymph nodes in response to CXCL13 produced by dendritic cells, which might recognize antigen/autoantigen. The Tfh cells encounter B cells that also bear CXCR5, form germinal centres within lymph nodes, and induce the differentiation of B cells into plasmocytes. We and others have reported that Tfh cells and B cells form follicular structures in tissues in patients with IgG4-RD [11–16]. These Tfh cells are highly activated, produce large amounts of IL-21, and highly express co-stimulation molecules such as CD28 and CD40L as well as CX₃CR1, a chemokine receptor [17].

An analogous story with some twists is observed with peripheral helper T (Tph) cells. Tph cells are also increased in proportion to serum IgG4 concentrations and the number of involved organs. Tph cells produce an effector cytokine IL-21 and key surface molecules, including PD-1, CCR2, CCR5, and CX₃CR1, thereby stimulating the differentiation of B cells into plasmocytes. However, Tph cells do not express CXCR5 and cannot enter into lymph nodes. Thus, Tph cells activate B cells in peripheral tissue and contribute to the typical pathological findings of tissue injury and ectopic lymphoid structure formation in IgG4-RD. CX₃CR1^high Tph-like cells express abundant levels of cytotoxic mediators such as granzyme A and perforin, leading to pathological tissue damage in patients with IgG4-RD [18].

Fibrosis by CD4⁺ CTL, B cells, and M2 macrophages

Although the mechanisms of fibrosis currently remain unproved, CD4⁺ cytotoxic T lymphocyte (CTL), activated B cells and M2 macrophages are all postulated to play important roles. These cells elaborate pro-fibrotic cytokines that activate fibroblasts, thereby promoting the accumulation of extracellular matrix proteins such as collagen in the tissue as fibrotic lesions [1, 7, 19].

CD4⁺ CTLs are typically present in abundance and indeed sometimes represent the majority of all infiltrating CD4 T cells in tissues from patients with IgG4-RD. The CD4⁺ CTLs, which express Signaling lymphocytic activation molecule F7 (SLAMF7), proliferate in an oligoclonal manner at sites of disease, produce cytotoxic proteins such as perforin, granzyme A/B, and granulysin, and secrete multiple profibrotic molecules, including IL-1β, IFN-γ, and transforming growth factor-β. CD4⁺ CTL may therefore contribute to fibrosis in targeted organs by multiple mechanisms [20–22].

Activated B cells are also involved in tissue fibrosis. Tissue-infiltrating B cells from IgG4-RD patients produce platelet-derived growth factor (PDGF)-B, and PDGF-B mediates the production of collagen by fibroblasts. B cells also secrete lysyl oxidase homologue 2, an enzyme known to cross-link Type IV collagens, suggesting a potential role for activated B cells in tissue remodelling [23, 24].

M2 macrophages accumulate preferentially within fibrotic portions of the diseased tissues and correlated strongly with the degree of tissue fibrosis in patients with IgG4-RD. M2 macrophages abundantly produce IL-33 that acts via the suppression of tumorigenicity 2 receptor (ST2). The IL-33/ST2 pathway contributes to fibrosis not only via trans-differentiation of activated fibroblasts to myofibroblasts but also via epithelial to mesenchymal transition of various cell types [25].

Overall principles of therapy

The goals of therapy in IgG4-RD are to reduce inflammation, induce remission, maintain this remission, and preserve organ function, all while minimizing the unintended consequences of treatment. Patients whose IgG4-RD is both active and symptomatic all require treatment. In addition, patients who demonstrate signs of disease progression also require treatment even if they have few symptoms [2, 26]. Watchful waiting is appropriate only for a minority of patients.

Some asymptomatic patients with single-organ involvement, particularly dacryoadenitis or sialoadenitis, can be monitored without treatment, provided that adequate surveillance to identify all potential sites of disease has been undertaken. Clinical experience suggests that although disease occasionally recedes temporarily in patients with single-organ disease, many such patients eventually develop evidence of disease in major organs. This may not occur for months or even several years later but may lead to significant organ damage when it does, emphasizing the importance of continued follow-up [26–30]. Evaluations of such patients at 6-month intervals are probably appropriate in most patients.

Induction of remission

When the decision is made to start treatment, a realistic goal of therapy is to suppress all signs of active disease within organs completely. IgG4-RD is a highly treatment-responsive disease, and once an effective therapy is begun patients show improvement within days to several weeks. It must be accepted, however, that in some cases, organ damage may already have occurred at the time of diagnosis and that the initiation of treatment is not likely to reverse all baseline damage. A prime example of this is the pancreas. Many patients already have significant exocrine or endocrine dysfunction of that organ at the time treatment begins, and therapy is unlikely to reverse all of these features of tissue injury. Saeki et al. also reported that renal atrophy developed in a considerable proportion of the patients, especially those in whom advanced renal damage had already been evident before glucocorticoid therapy, suggesting that irreversible kidney damage may occur in cases of IgG4-related tubulointerstitial nephritis, even if the response to therapy in terms of achieving disease control is good [31]. Nevertheless, successful remission induction can be expected to resolve any disease symptoms caused by active IgG4-RD, including the normalization of biochemical and radiologic abnormalities.

Glucocorticoids are the cornerstone of treatment for most patients with IgG4-RD. When access to biological agents is limited, glucocorticoids are used nearly exclusively or in combination with a conventional disease-modifying antirheumatic drug (DMARD). The goal of induction therapy at many centres is to discontinue glucocorticoids within 3–6 months, but treatment strategies vary across countries [26]. The value of ongoing glucocorticoids for the maintenance of disease remission in IgG4-related autoimmune pancreatitis has been demonstrated in a systematic review and meta-analysis [32]. DMARDs are used in the hope of reducing glucocorticoid toxicity, but evidence for their efficacy in these patients is limited.

An international consensus guidance document concurred that prednisone at a dosage of 30–40 mg/day is appropriate for initial treatment [26]. In practice, the initial dosage of glucocorticoids varies widely, and some authors have reported the use of higher doses in patients with severe complications (pancreatic, pulmonary, renal, and retroperitoneal involvement) but lower dosages in elderly patients or those with comorbidities. The involvement of vital organs demands aggressive treatment from the outset because of the risk of serious organ dysfunction and failure of the pancreas, liver, kidneys, lungs, and other organs, but starting doses of >40 mg/day are seldom required and lower starting doses of prednisone in the setting of less severe disease are wise (Figure 3) [28, 33].

The starting dose of prednisone is usually maintained for 4 weeks. At some centres, prednisone is then tapered to discontinuation over a total duration of glucocorticoid therapy of not >3 months [26, 34]. At others, prednisone doses are maintained at 5–10 mg/day for up to several years [34–38]. One clinical trial that tapered prednisone generally to between 5 and 10 mg/day and then aimed to maintain those doses for 1 year reported glucose intolerance in 41% of patients, dyslipidemia in 26%, and infections in 18% [37]. Thus, monitoring for glucocorticoid toxicity and proactive interventions to limit such toxicity are important. Despite the toxicity associated with long-term longitudinal glucocorticoid use, ∼40% of the patients are known to either fail to achieve complete remission or relapse within 1 year, even if glucocorticoids are continued at a low dose [2, 3]. For patients with multi-organ disease and high serum IgG4 concentrations, remissions are unlikely to be induced without glucocorticoid courses lengthy enough to cause substantial toxicity.

Maintenance of remission

IgG4-RD is prone to recurrence, and the risk of recurrent disease increases with the number of organs affected at baseline and the baseline serum IgG4 concentration. Azathioprine, mycophenolate mofetil, methotrexate, leflunomide, and cyclophosphamide are commonly used worldwide in combination with glucocorticoids in patients with IgG4-RD. Despite the frequency with which they are used, however, the evidence base for their efficacy remains slim. Most data are derived from retrospective studies in which patients were maintained on some dose of glucocorticoid treatment, as well, complicating efforts to ascribe efficacy to the DMARD alone.

Development of mechanism-based targeted therapies

The consideration of targeted therapies is appropriate even at early stages of treatment in patients with severe involvement of organs such as the lung, kidney, pancreas, liver, bile duct, and retroperitoneum, as well as in patients at risk for severe complications of manifestations such as sclerosing mesenteritis. The combined use of glucocorticoids and immunosuppressive drugs significantly reduces the proportion of Tfh cells and plasmocytes in the peripheral blood and lower serum IgG4 level concentrations, but such combinations of treatments are suboptimal for some patients both in terms of efficacy and adverse effects [11, 39]. In such scenarios, the use of targeted biological therapies makes sense, and there is much room for innovation and drug development in this area [2, 7, 8]. No therapies at all—never mind molecular-targeted therapies—are approved for IgG4-RD at this time.

Nevertheless, there have been exciting developments on this front. Phase 2 trials for a CTLA4-Ig complex abatacept (NCT03669861), an immunomodulatory anti-CD19 monoclonal antibody with a dual specificity for Fc-gamma-RIIb [XmAb5871 (obexelimab)] (NCT02725476), and a Phase 1/2 trial for an anti-CD20 antibody rituximab (NCT01584388) have been completed. In addition, a worldwide Phase 3 trial of an anti-CD19 monoclonal antibody inebilizumab (NCT04540497) is underway. Phase 2 trials for an anti-SLAMF7 monoclonal antibody elotuzumab (NCT04918147) and two Bruton’s tyrosine kinase (Btk)-inhibitors [zanubrutinib (NCT04602598) and rilzabrutinib (NCT04520451)] have been launched. The rapid evolution from conventional treatment approaches to mechanism-based, targeted new potential therapies underscores how quickly insights into the pathophysiology of IgG4-RD have contributed to creative treatment approaches. In the next subsections, we focus on the specific therapies directly addressing IgG4-producing cells and tissue fibrosis that we estimate to be the most relevant treatments across diseases (Figure 4).

Anti-CD20

Rituximab, an anti-CD20 monoclonal antibody, has been a major focus in the off-label treatment of IgG4-RD. A Phase 1/2 trial of rituximab in IgG4-RD was reported in 2015 [40]. Thirty IgG4-RD patients with active disease activity as defined by the IgG4-RD Responder Index (IgG4-RD RI) were enrolled. Disease responses occurred in 97% of the participants, who were either treated with RTX alone (n = 26, two 1000 mg every 2 weeks) or discontinued their baseline glucocorticoids within 2 months (n = 4). The baseline IgG4-RD RI value, 11 ± 7, declined to 1 ± 2 at 6 months. The primary end-point, measured at 6 months, was defined as follows: (1) decline of the IgG4-RD RI ≥2 points compared with baseline, (2) no disease flares before Month 6, and (3) no glucocorticoids use between Months 2 and 6. This end-point was achieved by 23 participants (77%). At 6 months, 14 (47%) were in complete remission, defined as an IgG4-RD RI score of 0 with no glucocorticoid use. Twelve (40%) maintained these complete remissions at 12 months. Among the 19 with elevated baseline serum IgG4, IgG4 concentrations declined from a mean of 911 to 422 mg/dl at Month 6.

This prospective pilot trial lends support to multiple observations from small, retrospective studies, suggesting that B-cell depletion is an effective treatment for IgG4-RD. B-cell depletion with rituximab or another anti-CD20 agent may have a substantial role to play in the treatment of IgG4-RD, especially in patients with inadequate responses to glucocorticoids or comorbidities contraindicating long-term glucocorticoids.

In a systematic review and meta-analysis to estimate the rituximab treatment in pancreato-biliary IgG4-RD, 7 cohort studies and 101 patients were included [41]. During the median follow-up time, 19 months, reasons for rituximab administration were new disease onset (18.5%), disease flare after glucocorticoids (63.5%), and glucocorticoid intolerance (17.9%). The pooled rate of complete response at 6 months was 88.9%, and the pooled estimate of the relapse rate was 21%. The median time to relapse was 10 months, and a higher rate of relapse (35.9%) was reported in studies including patients with multi-organ involvement. Meanwhile, Campochiaro et al. reported that the relapse-free rate during 18 months after induction of remission was significantly higher in patients treated with every 6-month maintenance therapy of rituximab compared with those not treated with repeated rituximab dosing, indicating that the maintenance therapy of rituximab is useful to reduce risk of the disease flare [42].

The pooled estimate of rituximab-related adverse events was 25%. Thus, the meta-analysis provided further evidence on the efficacy and safety of rituximab in pancreato-biliary IgG4-RD. Randomized clinical trials will be necessary to refine the optimal use of rituximab or other anti-CD20 approaches to the treatment of IgG4-RD and to gain regulatory approval.

Anti-CD19

Whereas CD20 is acquired at late stages of B-cell lymphogenesis and is then lost upon differentiation into plasma cells, CD19 expression on developing B cells appears earlier and covers the entire spectrum of early B-cell genesis and the late differentiation stage into plasmocytes. CD19 can therefore be used as a strategy for targeting the full array of B cells in development.

XmAb5871 is a humanized anti-CD19 antibody with an Fc portion that engineered for 400-fold increased affinity for FcγRIIb [43]. FcγRIIb, the only Fcγreceptor on B cells, is a downregulating molecule. The co-ligation of CD19 and FcγRIIb leads to the downregulation and inhibition of B lineage cells—but not to their depletion. Reversible inhibition of B-cell function without B-cell depletion is one potential advantage of this approach. A Phase 2 trial of XmAb5871 demonstrated positive treatment responses in 12 of 15 patients with IgG4-RD. All 12 patients achieved the primary end-point of at least a two-point reduction in the IgG4-RD RI on Day 169 [44]. None of the 12 patients required glucocorticoids after Month 2. Eight patients achieved remission, defined as an IgG4-RD RI of 0 and no glucocorticoids after 2 months. A randomized, double-blind, placebo-controlled trial of Xmab5871, now known as obexelimab, is being launched in the fall of 2022.

Inebilizumab is a humanized, afucosylated IgG1κ monoclonal antibody that binds to the B-cell surface CD19 and depletes B cells. The drug has shown substantial efficacy in neuromyelitis optica and was approved for the disease [45]. A worldwide Phase 3 clinical trial of inebilizumab, currently underway in IgG4-RD, will enrol 160 patients from dozens of countries across several continents. This trial began enrolment in early 2021.

Co-stimulation blockade

Abatacept, a fusion protein composed of the extracellular domain of CTLA-4 and the Fc domain of IgG1, interferes with ligation of the co-stimulatory CD28 molecule on T cells by binding to CD80/86 on antigen-presenting cells. This action prevents the differentiation of naive CD4⁺ T cells to activated helper T cells, thereby limiting ongoing B-cell activation. Tfh cells are increased in the blood and accumulate in the tissues of patients with IgG4-RD, providing a strong mechanistic rationale for targeting co-stimulatory signals needed for T-cell activation as a therapeutic approach in IgG4-RD [11, 12]. Abatacept was approved for rheumatoid arthritis in 2005, and its efficacy and safety have been investigated thoroughly in other diseases.

A Phase 2 prospective, open-label, single-arm, single-centre, proof-of-concept study was performed in 10 IgG4-RD patients to investigate the potential efficacy and safety of abatacept [46]. Three patients achieved remission defined with IgG4-RD RI of 0, no glucocorticoids use beyond Week 4, and no recurrence of disease activity since the baseline. Higher baseline proportions of unswitched memory B cells were associated with responsiveness to abatacept. Three of six participants with a disease response at Week 12 showed a decline in serum IgG4 concentration at Week 24. Reductions from baseline in serum IgE levels, circulating plasmocytes, and activated Type 2 Tfh cells were associated with response to treatment. Abatacept therefore appears to have activity in at least a subset of patients with IgG4-RD, though its efficacy appears to be highest in patients with lower degrees of disease activity. Further studies are required to validate the therapeutic effect of abatacept and to understand the role of this drug in the overall treatment paradigm of IgG4-RD.

CD4⁺ CTL-targeting

CD4⁺ CTLs accumulate in tissues and play a central role in inflammation and fibrosis in IgG4-RD. The expression of SLAMF7 on cells of both the B and T lymphocyte lineages, including CD4⁺ CTL, activated B-cell subsets, and plasmocytes, makes it a highly appealing drug target in IgG4-RD. Elotuzumab, an anti-SLAMF7 monoclonal antibody, is approved for the treatment of refractory multiple myeloma [47]. A Phase 2 proof-of-concept trial with the anti-SLAM7 monoclonal antibody elotuzumab began enrolment in 2021. No further details of the study are currently available.

Bruton’s tyrosine kinase inhibition

Bruton’s tyrosine kinase (Btk) has emerged as an attractive therapeutic target in autoimmunity. Btk is a Tec-family kinase that is most highly expressed in B cells and is of central importance in B-cell receptor–mediated signalling. Its importance in B cells is underscored with X-linked agammaglobulinemia in the inactivating mutations of Btk in humans. Two Btk inhibitors, rilzabrutinib and zanubrutinib, are currently under the Phase 2 trials in patients with IgG4-RD [48]. These small molecules bind ATP-binding sites leading to kinase inactivation and reduction in B-cell receptor–mediated proliferation and autoantibody secretion. These agents offer the considerable potential advantages of being oral agents that do not deplete B cells. No additional details of these trials are available at this time.

Conclusion and future perspectives

The study of IgG4-RD, a disease described only over the past two decades, offers remarkable insights into human immunology. The condition, particularly its proliferative subtype, is typically highly responsive to currently available therapies. Moreover, the disease appears to be strongly amenable to targeted biological and small-molecule treatment approaches. Ongoing clinical trials and future studies are poised to lead to a new era of treatment and improved patient outcomes for patients with this disease.

Authors’ contribution

Y.T. and J.H.S participated in substantial contributions to review conception, interpretation of reviewed literature, drafting the article or revising it critically for important intellectual content, and final approval of the version of the article to be published.

Conflict of interest

Y.T. received speaking fees and/or honoraria from Behringer Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, Bristol Myers, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, and GlaxoSmithKline and received research grants from Asahi Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi Sankyo, and Behringer Ingelheim. J.H.S. reports consulting for Bristol Myers Squib, Sanofi, and Horizon.

Funding

This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan (20FC1040).

References