IgG4 may be ‘innocent bystander’ in IgG4 disease
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DESTIN, Fla. — The role of IgG4 itself in IgG4 disease remains unclear, one of the many unexplained components of the condition, according to data presented at the Congress of Clinical Rheumatology East.
“We really do not understand the role of IgG4 in this disease,” Zachary S. Wallace, MD, MSc, of Massachusetts General Hospital, said in his presentation. “It may just be an innocent bystander. We are still trying to understand better what is driving the symptoms in these patients.”
Another complicating factor is that serum IgG4 concentrations are not necessarily abnormal in all patients.
“Serum IgG4 concentrations can be elevated, but they are not diagnostic,” Wallace said.
He added that the disease can often be confused with malignancy as it can cause unexplained masses.
“If it is not recognized and treated, it can lead to damage, including pancreatic insufficiency and end-stage renal disease,” Wallace said.
Looking to the future, Wallace noted researchers are currently attempting to understand the etiology of IgG4 disease.
“There is some evidence to support that this is an autoimmune disease,” Wallace said. However, data are only beginning to accrue supporting that theory, he added. There is some evidence that there is a genetic component, but this, too, is uncertain at the moment.
“We are still trying to fully understand this disease and what causes it,” he said.
According to Wallace, patients with IgG4 disease come from diverse racial and ethnic backgrounds, typically ranging in age from their 50s to their 70s.
“There is a slight male predominance when you look at various cohorts from around the world,” Wallace said.
Diagnosis is commonly delayed by around 2 years. However, that is improving as recognition and understanding of the disease is growing, according to Wallace.
The disease can manifest in myriad ways. In general terms, the pancreas, salivary glands, bile ducts, eye, kidney, lung, aorta, retroperitoneum, pachymeninges and thyroid may be involved.
Dry mouth is commonly seen early in the disease, but it can also be marked by painless GI symptoms or jaundice, biliary involvement, kidney disease or prostate involvement.
“The findings in the lymph nodes are often non-specific,” Wallace added.
Although approximately 40% of patients have single organ disease, the majority of patients experience multiple-organ involvement, according to Wallace. He noted that patients can present with multiple comorbidities at once — for example, salivary and pancreatic involvement concurrently — or have the manifestations appear in succession.
“Then it all comes together later on,” he said.
Attempts are being made to categorize and cluster patients based on how the disease presents and progresses. Although patients can be grouped into a pancreatic and hepatobiliary group, a head and neck group, a retroperitoneum and aorta group, and a Mikulicz syndrome and systemic disease group, individuals may not fall into these easy categories.
Regarding treatment, the aim is not necessarily to normalize IgG4, according to Wallace.
Glucocorticoids are generally considered first line.
“When you look at cohorts around the world, the vast majority are just getting steroids,” Wallace said. “Not responding to glucocorticoids is a red flag.”
Although dosing varies, patients are usually treated with 40 mg to 60 mg of steroids per day. Importantly, attempts should be made to taper patients off of steroids around the 3-month mark. However, efforts to taper can vary greatly depending on how patients are responding.
“This is largely because patients who are on high doses of steroids are still seeing frequent relapses,” Wallace said.
Turning to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), mycophenolate mofetil and leflunomide have been studied, alone and in combination with steroids. Although they may show some benefit in combination with glucocorticoids in terms of remission induction, the more quantifiable benefit of these drugs is in maintenance of remission, according to Wallace.
“Despite DMARD therapy, these patients still require substantial doses of steroids,” he said.
In addition, rituximab (Rituxan, Genentech) monotherapy may have some efficacy in remission induction, but the evidence for this is currently accruing.
“Our goal, as it is in all of our diseases, is complete remission,” Wallace said. “But this is complicated.”
As for future directions of therapeutic research, experts are looking at other B-cell depleting drugs like rituximab.
“Additional studies are needed to really understand how we use these B-cell drugs both for remission induction and remission maintenance,” Wallace said.
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Wallace ZS. What’s new in IgG4 disease? An approach to the diagnosis and management of IgG4-RD. Presented at: The Congress of Clinical Rheumatology East; May 12-15, 2022; Destin, Fla.
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