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Evaluating, Diagnosing, and Managing IgG4-RD in Rheumatology

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Released: October 14, 2026

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IgG4-related disease (IgG4-RD) is a rare, multisystem immune-mediated condition that can cause progressive inflammation, fibrosis, and irreversible organ damage. Diagnosing and managing IgG4-RD requires a systematic and multidisciplinary approach to patient care. Learn how IgG4-RD generally presents in rheumatology, the importance of ruling out key mimicking diseases and assessing multiorgan involvement, and evidence-based treatment strategies to prevent relapse and irreversible organ damage.

Guy Katz
Guy Katz, MD, MS
IgG4 RD in rheumatology

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IgG4-related disease (IgG4-RD) is a systemic, autoimmune disease that can affect nearly any organ, with some patients presenting with isolated organ involvement and others with disease affecting multiple organs. Therefore, it is essential that healthcare professionals (HCPs) in rheumatology recognize its systemic nature, not only to establish an accurate diagnosis, but also to assess multiorgan involvement and tailor evidence-based treatment to reduce the risk of long-term organ damage.

The first step is recognizing the common manifestations of IgG4-RD. One of the most characteristic presentations is painless, symmetric enlargement and inflammation of the salivary and lacrimal glands, particularly the submandibular, lacrimal, and parotid glands. Although patients may experience gland dysfunction and dry eyes or mouth, sicca symptoms are generally less prominent. In my experience, facial swelling is often a more noticeable feature than sicca symptoms, which can help distinguish IgG4-RD from other conditions with similar glandular involvement.

Another characteristic manifestation is autoimmune pancreatitis, a potential source of irreversible organ damage. The pancreas does not tolerate inflammation well, and the resulting damage generally includes exocrine pancreatic dysfunction, weight loss, malabsorption, maldigestion, steatorrhea, diarrhea, and vitamin deficiencies. Active autoimmune pancreatitis also presents with characteristic findings on imaging like diffuse pancreatic enlargement and narrowing of the pancreatic and bile ducts. Furthermore, patients may experience abdominal pain, nausea, vomiting, and anorexia, although many are asymptomatic.

A particularly concerning presentation is focal or mass-forming autoimmune pancreatitis, which can look similar, if not identical, to pancreatic adenocarcinoma. Therefore, it is critical to order a biopsy to confirm the diagnosis before completing a full or modified Whipple procedure. Patients with a pancreatic mass and type 1 autoimmune pancreatitis should be treated with the appropriate pharmacotherapy, not chemotherapy, radiation, or surgery.

Other common manifestations of IgG4-RD are retroperitoneal fibrosis, which can obstruct the ureters, orbital inflammation, pachymeningitis, Riedel’s thyroiditis, interstitial lung disease, organizing pneumonia, airway inflammation, paravertebral masses, fibrosing mediastinitis, and large-vessel vasculitis. Determining whether patients with IgG4-RD have coronary artery involvement is vital because it can lead to large coronary artery aneurysms.

Cholangitis, sclerosing mesenteritis, kidney disease, and prostate involvement are additional manifestations of IgG4-RD. The most common kidney manifestation is tubulointerstitial nephritis, which can eventually progress to chronic kidney disease. In addition, prostate involvement can cause symptoms resembling benign prostatic hyperplasia, but one striking difference is that it can respond well to immunosuppression in IgG4-RD.

Diagnosing IgG4-RD Requires a Complete Clinical Picture:
A persistent challenge in diagnosing IgG4-RD is the lack of a single diagnostic test to confirm the disease. There is no test with 100% specificity nor one that can reliably rule out the disease. Rather, healthcare professionals (HCPs) must incorporate all the available clinical information they have to make an IgG4-RD diagnosis.

My approach mirrors the widely recognized classification criteria, but I strongly emphasize that these should not be used as diagnostic criteria. Patients can have IgG4-RD without fulfilling the necessary criteria, and rarely, some can fulfill the classification criteria without having the disease.

Regardless, the first criterion to meet is to identify a typical clinical or radiologic manifestation in an organ. The second is to look systematically for supportive features. At this step, I obtain CT imaging of the chest, abdomen, and pelvis because a substantial proportion of multiorgan involvement can be asymptomatic. I also complete a physical examination, where I pay particular attention to patients’ eyes and salivary glands. Here I look for lacrimal or salivary gland enlargement, proptosis, or abnormalities in extraocular movements.

Additional diagnostics include biopsy and lab tests. My lab evaluation for IgG4-RD generally includes a complete blood count with differential, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, serum protein electrophoresis, free light chains, IgG subclasses, IgE, C3 and C4, lipase, urinalysis, and urine protein-to-creatinine ratio. Although serum IgG4 is an important biomarker, it is not the only one. Some patients with IgG4-RD have normal serum IgG4 concentrations, and an elevated IgG4 by itself does not establish a diagnosis.

The third—and most important—group of criteria asks HCPs to look for features that are not consistent with IgG4-RD. The exclusion criteria highlighted within the larger list of the IgG4-RD classification criteria are useful for identifying which findings should make HCPs strongly consider an alternative diagnosis. Using all this information is necessary to confidently diagnose patients with IgG4-RD.

Treatment Strategies for IgG4-RD
Monitoring those off treatment is an appropriate approach for select patients. I often reserve this strategy for patients with extremely mild, essentially asymptomatic disease who have a very low likelihood of developing damage. These cases most commonly consist of isolated glandular disease that is not bothersome.

A second group of patients may be treated with a brief course of glucocorticoid therapy alone for approximately 1-2 months. These folks should have relatively mild disease without significant risk factors for relapse or organ damage.

However, I use steroid-sparing therapy and sometimes together with glucocorticoids at induction for most of my patients. Determining whether to include concomitant glucocorticoid therapy depends on the severity of patients’ symptoms and their immediate risk of organ damage. If I am worried about something happening over the next 2 or 3 months, I will prescribe prednisone to provide more rapid control while waiting for the longer-term therapy to take effect.

Conventional steroid-sparing immunosuppressive therapy, such as mycophenolate mofetil, methotrexate, and azathioprine, can reduce the risk of flares in some. But many patients treated with these agents cannot fully stop their glucocorticoid therapy, which should be the goal whenever possible. Another steroid-sparing approach is to use B-cell–depleting therapy, which has become central to my practice. I routinely used rituximab for many patients before inebilizumab became available. Now inebilizumab is the only FDA-approved agent to treat IgG4-RD in adults as of October 2026, and it has become my standard approach for almost all patients who require systemic treatment.

Regardless of which approach is best, IgG4-RD treatment must be individualized. This means HCPs should use shared decision-making to determine whether glucocorticoid therapy is needed initially and if patients’ relapse risk makes them a good candidate for systemic therapy.

Recognizing and Addressing Relapse Risk:
Moving on to the long-term management of IgG4-RD, one important aspect of your care is to identify and address patients’ relapse risk. In doing so, I monitor the same biomarkers used during my initial evaluation every 3-4 months. Sometimes I monitor these as frequently as every 2 months in patients with severe relapsing disease.

Of note, IgG4 is the biomarker that tracks best with disease activity in many patients, but not all. Some never have an elevated IgG4 concentration, and others will have complement, IgE, or another IgG subclass level that correlates better with disease activity. Therefore, I use each patient as their own control when personalizing their maintenance and monitoring approach.

Of more importance, a rising IgG4 concentration does not automatically mean that treatment should be started. Biomarkers can help determine how closely HCPs need to watch patients. HCPs should look for clinical evidence of relapse—gland swelling, pulmonary symptoms, abdominal symptoms, or changes on imaging—to inform their treatment and monitoring strategies.

Tips for Improving Timely Recognition and Intervention:
One of the most useful changes rheumatology and other HCPs can make today is to simply become more familiar with the typical manifestations of IgG4-RD. Patients can present with imaging and/or physical examination findings for years before IgG4-RD is recognized because HCPs do not make the correct associations.

Bilateral submandibular gland enlargement is a good example of this. IgG4-RD should be high on HCPs’ list of differential diagnoses when patients present with this finding. HCPs should also know where the major salivary and lacrimal glands are, recognize their enlargement, and remember that IgG4-RD is a systemic disease.

Finally, HCPs must remember that a normal serum IgG4 concentration does not exclude IgG4-RD. Those with painless bilateral submandibular gland enlargement and a normal serum IgG4 may still warrant further evaluation and biopsy.

Your Thoughts:
How often do you consider IgG4-RD as a diagnosis in patients who present with gland enlargement, autoimmune pancreatitis, or retroperitoneal fibrosis? You can get involved in the discussion by answering the poll question and posting a comment below.

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How often do you consider IgG4-RD as a diagnosis in patients who present with gland enlargement, autoimmune pancreatitis, or retroperitoneal fibrosis?

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