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ACR guidelines on HBV screening called inadequate
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
SNOWMASS, COLO. – The ACR guidelines for hepatitis B virus screening prior to starting immunosuppressive therapy are sorely in need of an overhaul, Leonard H. Calabrese, MD, asserted at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We need to do better,” declared Dr. Calabrese, professor of medicine and head of the section of clinical immunology at the Cleveland Clinic.
The current ACR guidelines on hepatitis B virus (HBV) screening in rheumatoid arthritis patients (Arthritis Rheumatol. 2016 Jan;68[1]:1-26) are unchanged since 2008. The recommendation is for selective screening confined to patients who are going to go on methotrexate or leflunomide or who state they have an HBV risk factor.
He recommended that his fellow rheumatologists skip the ACR guidance and instead do what he does, which is to follow the American Association for the Study of Liver Diseases (AASLD) guidelines that have been in place for the past 8 years (Hepatology. 2009 Sep;50[3]:661-2).
The AASLD screening algorithm is simple and straightforward: Screen everyone who is going to go on any form of immunosuppressive therapy or cancer therapy by testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc).
The highest-risk group for HBV reactivation are patients who are HBsAg positive. They have an active infection and should be referred to a hepatologist for antiviral therapy. Depending upon the patient’s HBV DNA level and liver function test results, the antiviral therapy will be started either prior to or simultaneously with the immunosuppressive therapy.
The AASLD guidelines rank immunosuppressive agents in terms of their associated risk of HBV reactivation based upon the best available evidence. It’s a tricky business. Patients with a history of HBV are excluded from clinical trials of immunosuppressants, so the evidence is sketchy.
Nevertheless, the consensus is that among HBsAg-positive patients the risk associated with methotrexate and other antimetabolites is considered low. The tumor necrosis factor inhibitors are deemed to pose a moderate risk, as does cyclosporine. The risk of other cytokine inhibitors, including ustekinumab (Stelara) and abatacept (Orencia), is uncertain, but thought to be moderate to high. The use of corticosteroids at more than 20 mg/day for longer than 4 weeks is considered high-risk therapy. And rituximab (Rituxan), which carries a black box warning regarding HBV reactivation, is rated very-high-risk, as is cancer chemotherapy and hematopoietic stem cell transplantation.
An HBV screen that comes back HBsAg negative but anti-HBc positive indicates past HBV infection. This places a patient at intermediate risk for reactivation during immunosuppressive therapy. If Dr. Calabrese plans to put that patient on rituximab, he’ll make a referral to a hepatologist for consideration of antiviral therapy. If he’s going to use any other form of immunosuppressive therapy in a patient who is HBsAg negative/anti-HBc positive, he tests for HBV DNA every 1-3 months while the patient is on treatment. If HBV DNA becomes detectable, it’s time to start antiviral therapy.
No further action is required if a rheumatology patient’s HBV screen comes back negative for both HBsAg and anti-HBc.
“There are six approved drugs for HBV. They don’t have the power of the direct-acting antiviral agents used for hepatitis C. Cures are very infrequent. But lifelong viral suppression is readily achievable with these drugs, which are well tolerated and have low potential for drug-drug interactions. If patients have undetectable HBV DNA on antiviral therapy, I believe we can treat them with any of our rheumatologic regimens, including rituximab,” Dr. Calabrese said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Rituximab is dramatically effective in IgG4-related disease
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
IgG4-related disease can strike any organ system
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM