Elsevier

The Lancet Rheumatology

Volume 1, Issue 1, September 2019, Pages e55-e65
The Lancet Rheumatology

Review
Management of IgG4-related disease

https://doi.org/10.1016/S2665-9913(19)30017-7Get rights and content

Summary

IgG4-related disease was unrecognised as a unified disease entity until this century, yet in a short period of time the disease has been appreciated to have a worldwide distribution, and its clinical, pathological, and radiological features have been described in considerable detail. The disease has strong organ predilections, and many of the clinical presentations of disease are increasingly familiar to both generalists and specialists. Early recognition of IgG4-related disease is crucial because although the disease is highly treatable, it can lead to serious organ damage and even death if undiagnosed until advanced stages. Its indolent nature often makes diagnosis challenging, and IgG4-related disease is one of the great mimickers of other diseases in the current era. Glucocorticoids are an effective treatment for IgG4-related disease, but their long-term use is problematic in a disease that frequently affects middle-aged to elderly individuals and often leads to pancreatic dysfunction. Our understanding of the pathophysiology of the disease is surprisingly advanced given the relatively recent recognition of this condition. Insights into disease pathophysiology offer the possibility of a variety of targeted treatment approaches. Looking ahead, biological therapies could profoundly alter the way in which IgG4-related disease is managed, permitting the use of specific therapies that are tailored to patients' clinical phenotypes.

Introduction

IgG4-related disease is a multi-organ, immune-mediated condition that was recognised as a unified disease only in 2003.1, 2 However, clinical presentations now known to be classic features of IgG4-related disease appeared in the medical literature much earlier, with descriptions in the late 1800s of Mikulicz disease (simultaneous enlargement of the lacrimal and major salivary glands);3 Küttner's tumour (isolated submandibular gland enlargement);4 and Riedel's thyroiditis.5 Many of the other organ system manifestations now linked to IgG4-related disease were identified during the 1900s, but these were thought to be manifestations of single-organ diseases'6 or processes restricted to single-body regions,7 rather than parts of a systemic inflammatory disease. The connection between clinical features of disease and elevated serum concentrations of IgG4 was established in 2000, when Hamano and colleagues8 reported the utility of elevated serum IgG4 concentrations in distinguishing between sclerosing pancreatitis—now known as type 1 IgG4-related autoimmune pancreatitis—and other hepatobiliary conditions.

In the past decade, there has been an extraordinary expansion in knowledge about IgG4-related disease. Furthermore, the indolent nature of the disease and the use of targeted treatment approaches have provided major insights into its pathophysiology. These insights, in turn, suggest the possibility of several mechanism-based approaches to therapy. In this review, we discuss the pathology and pathophysiology of IgG4-related disease and provide an overview of the clinical management of patients with the disease.

Section snippets

Pathology and pathophysiology

The organs affected by IgG4-related disease all share similar histopathological and immunostaining features.9 The hallmark findings include a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells (figure 1A). This cellular infiltrate is enmeshed in fibrosis with an irregular, whorled appearance termed storiform fibrosis (figure 1B).10 Obliterative phlebitis and eosinophilic infiltration are observed in approximately half of patients with IgG4-related disease. By contrast,

Clinical characteristics of disease

IgG4-related disease affects nearly every organ, but particularly the meninges, orbits (extraocular muscles and retrobulbar masses), lacrimal glands, salivary glands, thyroid gland, pancreas, bile ducts, lungs, kidneys, aorta, and retroperitoneum. Approximately 40% of patients present with clinically-evident disease in a single organ, but presentations involving five or six organs are not uncommon. Moreover, the disease can evolve over time, with new organs becoming involved in a metachronous

Disease classification and subsets

Classifying IgG4-related disease into distinct subsets is intuitively appealing because the identification of disease subsets and their corresponding biological features might lead to insights that guide treatment. The ultimate utility of identifying disease subsets is to discover meaningful biological differences between subsets that offer insights into prognosis or guide therapy.

The American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) have produced a

Biomarkers

Studies in IgG4-related disease benefit from a wealth of good potential biomarkers, some of which are useful in clinical management. Serum IgG4 concentrations—which are elevated in most patients—have proven particularly useful. In many patients with elevated serum IgG4 concentrations at baseline, trends in IgG4 concentrations over time constitute a reliable biomarker of disease activity and an indicator of when re-treatment should be considered. Moreover, serum IgG4 concentrations reflect the

Risk factors for relapse

Risk factors for disease relapse can be divided into five main categories: demographic features, organ involvement, serological findings, medications, and changes in peripheral blood cell populations. Reported risk factors for relapse are shown in figure 3, organised according to their frequency as reported in the literature.

Being male has been implicated as a risk factor for disease flare in some studies, with a hazard ratio of 3·14 (p=0·003) reported in one study.74 This is interesting in

Special situations

In selected situations, surgical treatment or other mechanical interventions (eg, stent placement) are complementary approaches to medical therapy. Surgical biliary drainage, now rare, was common before IgG4-related disease was recognised as a specific disease entity. Surgical resection of some organs that are severely damaged is occasionally necessary. The placement of biliary stents, ureteral stents, or nephrostomy tubes are sometimes required at the start of medical therapy, but ideally, the

Future Steps

In less than 15 years, IgG4-related disease has gone from being an unrecognised disease to one that is recognised around the world. The disease has certain strong organ predilections, and clinicians from nearly every specialty now recognise the complications of IgG4-related disease within their fields. IgG4-related disease is one of the great mimickers of other diseases in the current era, and early recognition and treatment is crucial. Areas of uncertainty, ongoing controversy, and intense

Search strategy and selection criteria

We based our review on a narrative rather than systematic literature search. We searched MEDLINE for papers published in the English language before March 31, 2019, on treatment and stratification of therapies in IgG4-related disease. We identified key abstracts from the European League Against Rheumatism and American College of Rheumatology annual meetings in 2016–18. Search terms were “IgG4-related disease”, “autoimmune pancreatitis”, “tubulointerstitial nephritis”, “complement”, “SLAMF7”, “B

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