‘Landmark’ B-cell depletion data offer hope to patients with IgG4-related disease
Last November, results from the MITIGATE trial made headlines at ACR Convergence 2024 with positive phase 3 trial data for inebilizumab, an IgG1 monoclonal antibody targeting CD19, in patients with IgG4-related disease.
That trial, the first randomized, double-blind, placebo-controlled study ever conducted in IgG4-RD, confirmed “beyond doubt” that B-cell depletion is an effective treatment strategy for the disease, John H. Stone, MD, MPH, lead author and professor of medicine at Harvard Medical School, told Healio prior to his ACR presentation. Now, this and other studies are offering hope that B-cell depletion, in its various forms, could be leveraged for patients with this complicated condition.
“The unmet need in IgG4-related disease is multifaceted,” Matthew C. Baker, MD, MS, associate division chief and assistant professor of medicine in the division of immunology and rheumatology at Stanford University, told Healio. “Relative to other rheumatic diseases, IgG4-related disease is still a new disease.”
With that newness comes specific clinical challenges, according to Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic.
“IgG4-related disease is under-diagnosed, largely because the pace of defining it pathologically and clinically, and the development of diagnostic classification criteria, came so rapidly,” Calabrese said. “Many people are left in a void because they have not been exposed to it.”
The condition, first described in Japan in 2003, did not gain real recognition in the United States until 2008, according to Baker.
“For this reason, awareness of the disease among both patients and physicians has been relatively low,” he said. “However, education is increasing rapidly.”
However, challenges even in this regard remain, according to Calabrese. Describing IgG4-related disease as “remarkably protean,” he added it may affect a single organ or be marked by an asymptomatic enlargement of a gland in the head or neck, or demonstrate widespread, multiorgan involvement.
“There are still gaps diagnostically,” Calabrese said. “Therapeutically, there are still many who do not know how to initiate and maintain therapy.”
Of particular concern is the fact that glucocorticoids — with all of their associated toxic knock-on effects — have long been the mainstay of treatment.
“There are currently no FDA-approved treatments for IgG4-related disease, and as a result, many patients are treated with off-label medications such as rituximab,” Baker said. “Rituximab is typically quite effective, however it too has potential side effects when used repeatedly over the long term. There are also challenges in the short term, as coverage for the medication may be denied by insurance companies.”
This is why inebilizumab (Uplizna, Amgen) may be a paradigm-changing drug.
“Based on current clinical experience and multiple case series of treatment with rituximab, we know that B-cell depletion is a great therapeutic approach in IgG4-related disease,” Arezou Khosroshahi, MD, associate professor of medicine and director of clinical trials in the rheumatology division at the Emory University School of Medicine, said in an interview.
“Inebilizumab depletes B cells through CD19, which is expressed on a wider range of B-cell population than CD20, which is the target of rituximab,” she added. “Plasmablasts that are identified as key pathogenic players in IgG4-related disease can be targeted and depleted by inebilizumab. This can lead to better and more durable remission.”
MITIGATE demonstrated exactly that result, and may be the forerunner to more medications in the class for this patient population.
‘Landmark study’
Published in the New England Journal of Medicine, the MITIGATE trial examined the efficacy and safety of inebilizumab to reduce flare risk in adults with IgG4-related disease. Stone and colleagues included 135 adults with IgG4-related disease from 80 sites across 22 countries. Randomly assigned treatment regimens included 300 mg of inebilizumab (n = 68) or a placebo (n = 67) administered on day 1, day 15, and week 26 of the 52-week study.
“The design of the MITIGATE study included patients with active IgG4-related disease who were put into remission with glucocorticoids during the screening period,” Baker said.
According to Khosroshahi, steroid sparing is critical among this population, as IgG4-related disease is characterized by recurrent flares, often requiring repeated courses of corticosteroids to control them.
“Reducing flare, which leads to reduced use of corticosteroids, can spare patients from significant side effects of steroid treatment, including diabetes, osteoporosis and obesity,” she said.
The study drug significantly improved on placebo in terms of flare risk (HR = 0.13; 95% CI, 0.06-0.28), according to the findings. Inebilizumab was also superior to placebo in terms of annualized flare rate, the proportion of patients who achieved flare- and treatment-free complete remission, or corticosteroid-free complete remission, at week 52.
“The goal of treatment is to prevent flares, and this was significantly achieved with inebilizumab treatment,” Baker said.
Safety data demonstrated comparable adverse event profiles in the treatment and placebo arms, with COVID-19, lymphopenia and urinary tract infections as the most common events. There were no fatalities.
“The MITIGATE trial is a landmark study that demonstrates in a robust way that B cell depletion using an antibody targeting CD19 is highly effective for the treatment of IgG4-related disease,” Baker said. “We believe this treatment is so effective because the B cells play a key role in driving the disease pathogenesis, both by activating harmful T cells and by directly secreting cytokines that cause inflammation and fibrosis.”
The MITIGATE results may also portend long-term benefit for these patients, according to Khosroshahi.
“Another important reason that flare prevention is the key in this condition is that each relapse contributes to cumulative organ damage, leading to fibrosis and permanent dysfunction of the organs,” she said.
B-cell depletion ‘cannot be reversed’
According to Baker, the biggest concern with B-cell depletion as a treatment modality in general is that once it is administered, the effect is long-lasting and cannot be reversed.
This, of course, leads to an accompanying concern — infection risk.
“Patients receiving back-to-back infusions are particularly prone to developing hypogammaglobulinemia, further increasing infection risk,” Khosroshahi said.
Despite these risks, B-cell depletion has become more widespread across the rheumatology spectrum. That experience may provide rheumatologists more tools for understanding and preventing infections in patients who undergo treatment with these therapies.
“Although there are some known risks such as reactivation of dormant viral infections or the very rare risk of a disease called progressive multifocal leukoencephalopathy, in practice it is actually quite uncommon to observe significant issues after treatment with B-cell depletion,” Baker said.
Infections aside, Khosroshahi explained the other fear associated with this treatment approach.
“Another key drawback is the reduced response to vaccinations during B-cell depletion,” she said.
Although rheumatologists have improved their understanding of vaccine timing in the context of B-cell depletion, this is just one question that must be answered when considering current and future treatments for IgG4-related disease.
One such question: Is something better on the horizon?
‘Durable remission, or even a cure’
Although there has been much talk regarding the potentially curative nature of chimeric antigen receptor T-cell therapy in autoimmune rheumatic diseases, Khosroshahi said she believes it may be too early to discuss such possibilities within the context of IgG4-related disease.
“To cure any autoimmune disease, we need to eliminate the underlying immune dysregulation,” she said. “Most current treatments only suppress the immune system to control the autoimmune disease.”
According to Baker, CAR T-cell therapy is the closest rheumatology has reached to anything resembling a “cure.” However, he cautioned that patients who have received these therapies have not yet experienced a long enough follow-up to determine if they will indeed provide such a long-lasting impact.
“Given the key role that B cells play in IgG4-related disease and the benefit seen with treatments targeting B cells, it is conceivable that in the future CAR T-cell or T-cell engagers will be used in IgG4-related disease and could provide long-lasting durable remission, or even cure,” Baker said.
To reach that goal, Khosroshahi offered a possible ongoing direction for research.
“B-cell inhibition, rather than completely depleting them, or targeting plasma cells more directly, can be some of the other mechanisms to consider,” she said.
In the meantime, the strong results with inebilizumab should be a boon to physicians managing this complicated disease.
“Now that we have one highly effective therapy in inebilizumab, which will hopefully be approved for use in IgG4-related disease, we are looking forward to studying additional therapies that target B cells without depleting them,” Baker said. “If equally effective, such treatments may provide a safer long-term option for patients.”
As that research continues, Calabrese stressed the need for more, and better, experience in managing this multisystemic condition among clinicians — particularly those outside rheumatology.
“We need to build up diagnostic and treatment confidence of practitioners who will see these patients,” he said. “We need to educate ENTs who will deal with lymph node involvement, ophthalmologists who will manage double vision, gastroenterologists who will deal with pancreatitis or hepatobiliary complications, along with nephrologists and urologists. There is a big gap in meeting educational needs.”
References:
Stone JH, et al. NEJM. 2024;doi:10.1056/NEJMoa2409712.
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