John Stone, MD, MPH

Suppose you had a new patient in your practice, whose clinical presentation included swelling under the chin caused by enlargement of the submandibular glands. Following a biopsy, you see storiform fibrosis, obliterative phlebitis, a lymphoplasmacytic infiltrate, and mild-to-moderate tissue eosinophilia, similar to what is seen in the pancreas during autoimmune pancreatitis. If diagnosing such a patient seems challenging, you are not alone. I saw this precise patient more than 15 years ago. The encounter with that patient, a 26-year-old woman from Casablanca, single-handedly changed the trajectory and focus of my entire career. It was also the turning point for patients with a rare disease struggling with a medical mystery, nearly all of whom were unaware of the nature of their diagnosis at that time.

In 2007, when I evaluated my “first” patient (who knows how many I’d missed before then), literature had already started to emerge from Japanese investigators, who had reported finding the same type of pathology in autoimmune pancreatitis and in other organs that seemed to be affected by the same condition. Since then, physicians have recognized that there is a common disease pathogenesis occurring across a wide variety of organ systems, leading to consistent phenotypes and similar disease expressions with regard to clinical, serological, and pathological findings. The community of physicians and investigators across the world focusing on this “new” condition eventually came to believe that this was a single disease capable of affecting essentially any organ. In 2011, and the First International Symposium on IgG4-RD, they agreed to term it “IgG4-Related Disease”, or IgG4-RD.

A lot has happened since then. Fast-forward to today, a new International Classification of Diseases (ICD) diagnosis code has been assigned specifically to IgG4-RD, which has the potential to significantly decrease the time-to-diagnosis and treatment, and improve access to care, tracking, and disease management efforts.

IgG4-RD is a rare systemic disease with a debilitating impact

IgG4-RD is a chronic, systemic, immune-mediated, fibroinflammatory disease characterized by an infiltration of IgG4-bearing plasma cells.¹ The disease has been reported in nearly every organ, but it is most commonly seen in the aorta, kidneys, lacrimal glands, lungs, pancreas, abdominal retroperitoneal tissue, and salivary glands.^1,2 The inflammation and development of pseudotumors caused by IgG4-RD can prevent normal organ/tissue function and may lead to fibrosis and permanent organ damage.¹

The indolent nature and heterogeneous presentations of IgG4-RD make the diagnosis challenging for healthcare providers (HCPs).^2,3 However, early recognition of the disease is crucial because, it can progress to serious multi-organ damage and even death if undiagnosed until advanced stages.³ 

The journey to diagnosis of IgG4-RD may be complex and lead to delays in treatment

Patients frequently report that it takes many years and multiple HCPs to receive an accurate IgG4-RD diagnosis. This often leads to enormous emotional distress as patients confront the deeply troubling uncertainty about what is going on, not to mention frustrations stemming from delays in treatment. I have personally seen intervals between symptom onset and diagnosis as long as 30 years.

Misdiagnosis of IgG4-RD can result in a cascade of cataclysmic events. For example, patients may be faced with unnecessary surgery because the disease has been misdiagnosed as cancer (eg, pancreatic cancer, cholangiocarcinoma, lung adenocarcinoma, prostate cancer, and lymphoma). This is especially true when the disease appears to affect only a single organ. All too often, the diagnosis is suspected for the first time only when a surgical specimen is examined under the microscope or an “incidental finding” of major importance is detected on a radiology study.^1,4

Conversely, multiorgan IgG4-RD may mimic lymphoma or a metastatic cancer, with manifestations of weight loss and lymphadenopathy.¹ IgG4-RD is a remarkable mimicker of other autoimmune diseases (eg, granulomatosis with polyangiitis, lupus) and infection.^4,5 Overall, there is a pressing, unmet need to educate HCPs, including rheumatologists, gastroenterologists, neurologists, nephrologists, and pulmonologists about the ways that IgG4-RD presents.

As its name implies, measuring serum IgG4 levels is often helpful in diagnosing IgG4-RD. It can also be misleading, however, because elevated serum IgG4 levels are not specific for IgG4-RD. Such findings may be present in a host of other conditions.⁶ To establish the diagnosis correctly, clinicians must not only refer to the serum IgG4 concentration, they must also pay careful attention to the patients’ clinical presentation as well as consider the information available from radiology studies and pathology findings, when available. In short, they have to put together an entire picture of the patient in front of them, rather than focusing only on a single aspect of the patient’s story.

Data from biopsies can be similarly tricky to interpret. Conditions other than IgG4-RD can be associated with increased numbers of IgG4+ plasma cells in tissue. It is often helpful to ask the pathologist to assess the ratio of IgG4+ to IgG+ plasma cells within a biopsy as well as the number of IgG4+ plasma cells per high-power field. Even with that information in hand, however, careful clinicopathologic correlation is required to understand and correctly interpret the information from a biopsy.⁷

Fortunately, if diagnosed early, IgG4-RD is highly treatable. Glucocorticoids are an effective first-line treatment for IgG4-RD³, but they are by no means a “cure-all”. A significant number of patients will experience a “flare” or re-emergence of the disease when attempting to reduce the use of steroids. Moreover, prolonged use of steroids is problematic in a disease that frequently affects middle-aged to elderly individuals and often leads to pancreatic dysfunction.⁷ Further research into the pathophysiology of the disease offers the possibility of more targeted and specific therapies to treat the disease.

The call to action: Use IgG4-RD’s new ICD-10 code for a more accurate diagnosis

Given the variation in IgG4-RD symptom onset and HCP awareness, both providers and patients face a significant burden that can be relieved with proper disease classification and appropriate coding.

ICD codes are a set of designations used by HCPs to classify morbidity data, including the extent, causes, and consequences of human diseases, in a way that is globally accepted. The tenth and most recent edition is known as ICD-10.⁸

Previously, disease coding for a patient with IgG4-RD was nonspecific and varied enormously by physician and specialty. Most frequently, patients are coded according to the affected organ and as a nonspecific inflammatory issue, which has limited the HCP's ability to truly understand and track the disease resulting in a limited understanding of the disease epidemiology and long-term impact on patients. All of these together can lengthen the time-to-diagnosis and treatment of IgG4-RD.

The new ICD-10 code specific to IgG4-RD will greatly reduce both patient and healthcare system burdens by improving access to care, tracking, and disease management efforts. Specific coding will potentially revolutionize the current understanding of IgG4-RD and unify HCP specialties, allowing for more accurate diagnoses and therefore more accurate treatment plans, thereby improving patient outcomes.

The future of IgG4-RD

We will soon begin to realize that IgG4-RD is much more common than we once believed. Those first patients that began to be recognized more than 15 years ago were in fact, I’m sure, just the tip of the iceberg. IgG4-RD may still be classified as an orphan disease over time, but with the new ICD-10 code, we will see an increase in correct diagnoses, be able to better understand the disease epidemiology and demographics, and better support our patients.

Stone is professor of medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at the Massachusetts General Hospital. He has treated IgG4-RD since its emergence in recent years and is passionate about educating patients and fellow HCPs about the indolent and systemic nature of this disease. Stone is also launching the IgG4ward platform, the first and only organization solely dedicated to IgG4-RD advocacy, research, and support.

­­References

1. ^{Stone JH, Brito-Zerón P, Bosch X, Ramos-Casals M. Diagnostic Approach to the Complexity of}
2. ^{IgG4-Related Disease. Mayo Clin Proc. 2015;90(7):927-939. doi:10.1016/j.mayocp.2015.03.020}
3. ^{Katz G, Stone JH. Clinical Perspectives on IgG4-Related Disease and Its Classification. Annu Rev Med. 2022;73:545-562. doi:10.1146/annurev-med-050219-034449}
4. ^{Zhang W, Stone JH. Management of IgG4-related disease. Lancet. 2019;1(1):E55-E65.}
5. ^{doi:10.1016/S2665-9913(19)30017-7}
6. ^{Martín-Nares E, Hernández-Molina G, Baenas DF, Paira S. IgG4-Related Disease: Mimickers and Diagnostic Pitfalls. J Clin Rheumatol. 2022;28(2):e596-e604. doi:10.1097/RHU.0000000000001787}
7. ^{Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet. 2015;385(9976):1460-1471. doi:10.1016/S0140-6736(14)60720-0}
8. ^{Culver EL, Sadler R, Simpson D, et al. Elevated Serum IgG4 Levels in Diagnosis, Treatment Response, Organ Involvement, and Relapse in a Prospective IgG4-Related Disease UK Cohort. Am J Gastroenterol. 2016;111(5):733-743. doi:10.1038/ajg.2016.40}
9. ^{Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62(6):1755-1762. doi:10.1002/art.27435}
10. ^{World Health Organization. 2023. International Statistical Classification of Diseases and Related Health Problems.}