Although ongoing research continues to advance our understanding of IgG4-related disease (IgG4-RD), the epidemiology and downstream consequences of this relatively rare and complex autoimmune condition remain poorly understood. This makes managing the disease and its impact on patients and healthcare systems far more difficult than it should be. Fortunately, this picture is changing, as epidemiologists begin to mine previously untapped data sources to gain a more comprehensive picture of the comorbidities and healthcare utilization associated with IgG4-RD and its treatment.
Both IgG4-RD and its treatment have significant consequences for patients
IgG4-RD is a fibroinflammatory condition that can affect nearly every organ in the body. Its variable nature and ability to masquerade as a variety of other disorders make it challenging to diagnose and treat. This is further complicated by first-line treatment with glucocorticoids, which can lead to steroid dependency and organ damage over time.
Zachary S Wallace, MD MSC is a rheumatologist and clinical epidemiologist at Massachusetts General Hospital (MGH) in Boston, and a member of its Center for IgG4-Related Disease. In his rheumatology practice, he's seen first-hand the complications that can arise and the life-changing impact that this disease can have on patients and their families.
"We know that IgG4-RD can have a variety of significant consequences. For instance, if someone has pancreatitis from IgG4-RD, they can be left with endocrine pancreatic insufficiency and go on to develop diabetes, or they can be left with exocrine pancreatic insufficiency which leads to malnutrition, chronic diarrhea, and other complications. Patients with renal disease can develop chronic kidney disease, and so on.
"At the same time, the most frequently used treatment for IgG4-RD is steroids, and those have numerous effects that we also need to monitor and manage. These include weight gain, diabetes, hypertension, heart disease, and susceptibility to infections, to name just a few.”
Translating clinical experience into quantitative research
Gaining an accurate picture of the total comorbidity burden and healthcare utilization associated with IgG4-RD in the United States is an important step toward better management of patients and healthcare resources. It may also encourage investment in the development of new therapeutic options.
“At our Center, we see more cases of IgG4-RD than most other centers in the country. That puts us in a strong position to take what we learn at the point of care and translate it into research questions–and eventually answers–that can give us more insight into this disease.”
One stumbling block has been the limited availability of large patient cohorts that are representative of the general population in the United States.
“While we are fortunate at our Center to see so many cases of IgG4-RD, that doesn’t necessarily give us insights into the experience that patients are having around the country. That requires a different source of data than we have at our disposal.”
To tackle this problem, Dr Wallace and his team had to think outside the box. They developed an algorithm that could trawl through mountains of commercial insurance claims data to identify patients with IgG4-RD.
“Our algorithm works very well and has allowed us to assemble a large cohort of 524 IgG4-RD patients and 5,240 matched comparators who did not have the disease. This cohort is much more representative of what’s going on across the United States. Not just at a single center of excellence like ours, and not just in rheumatology, but in other specialties like gastroenterology.”
Valuable insights hidden in claims data: high burden of steroid-toxicity
With this large and more representative cohort, the first thing Wallace and team did was to describe the incidence and prevalence of IgG4-RD in the US. These findings were published earlier this year.[1]
“Among other things, we found the incidence of IgG4-RD is rising, which is to be expected since we’re getting better at recognizing this disease. Even more importantly, we found that patients with IgG4-RD are dying more often than patients who don’t have the disease.”
Compared with non-IgG4-RD comparators, the risk of death in people with IgG4-RD was 2.5 times greater.
“That finding motivated us to dig deeper, to start to piece together why that should be so, and to try to understand the experience of those patients.”
Toward that end, the researchers conducted another investigation with the same cohort, with the aim of describing the comorbidity burdens that patients with IgG4-RD experience.
They assessed the frequency of 21 clinical outcomes associated with IgG4-RD or its treatment in the 12 months prior to, and over the 36 months following, the earliest IgG4-RD-related claim. They also assessed healthcare-associated visits and costs over this period.
The study, which has been presented at rheumatology meetings and is being prepared for publication, produced some striking findings.
“By analyzing treatments and procedures recorded in the claims database, we could see that 85% of IgG4-RD patients received some form of glucocorticoid therapy. When we then looked at clinical outcomes, we found that patients with IgG-RD had substantially higher rates of hypertension, hyperlipidemia, gastroesophageal reflux disease (GERD), diabetes, osteoporosis and other conditions commonly associated with steroid-toxicity.
"We also found that IgG4-RD patients had a four-fold higher burden of infection (22%) compared to the general population (5%), and we know infections are a common cause of mortality in patients.”
The analysis also painted a sobering picture of the high burden of healthcare resource utilization among IgG4-RD patients, including much higher hospitalization rates and nearly twice as many emergency room visits compared to the general population.
“In addition to the costs and logistics of healthcare provision, when we think about the toll this takes on patients—having to go to the hospital, step away from work and family—it’s a heavy burden all around. And presumably some of those hospitalizations were due to the consequences of steroid-toxicity: high blood sugar levels, fractures related to osteoporosis, and so on.
"One clear take-home message is that we need to be cognizant of our steroid use, and try to spare patients steroids as much as possible, because it’s obviously contributing to a lot of the comorbidities they experience.”
What’s on the horizon?
“I think that our work so far might generate as many questions as it answers, if not more,” says Wallace. “An obvious avenue for further investigation is to better understand the factors driving comorbidity and the relative contribution of steroid-toxicity versus complications stemming from the disease itself.”
In that regard, one thought is whether the algorithm for identifying cases of IgG4-RD could be applied to claims data that are connected to electronic health records.
“Provided the health records contained the right data domains, a tool like the Steritas GTI-MD might enable us to score the degree of steroid-toxicity in patients and see whether that is associated with different outcomes,” says Wallace.
Another important message is that the medical community needs to consider how we can care for patients more comprehensively, he adds.
“Patients aren’t suffering from the consequences of IgG4-RD alone, they have all these other comorbidities as well. So, how do we make sure that we’re addressing all of their medical problems and connecting them with the resources and specialists that they need?”
On a final note, Wallace comments: “It’s exciting to know that we have two Phase 3 trials of steroid-sparing drugs for IgG4-RD right now, so there’s a lot of optimism for having effective alternative therapies in the near future. And, even while we wait for the results of these trials, our research highlights the opportunity to act now – to taper steroid use as much as possible and reach for some of the existing alternatives that we’re comfortable using, to try and spare people some of these steroid-toxicities.”
From Boston to Beijing. IgG4-RD and Steroid-toxicity
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References
- Wallace ZS, Miles G, Smolkina E, et al. Incidence, prevalence and mortality of IgG4-related disease in the USA: a claims-based analysis of commercially insured adults. Ann Rheum Dis (2023) 82:957–962.