Lupus & Connective Tissue Diseases

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

WASHINGTON — A new guideline for management of lupus nephritis (LN) was unveiled at the annual meeting of the American College of Rheumatology (ACR), updating the 2012 LN guideline to recommend a more aggressive first-line approach to treating the disease.

“The biggest differences are that we are recommending what we’re calling triple therapy, where we incorporate the glucocorticoid therapy with baseline conventional immunosuppressants, usually mycophenolate with cyclophosphamide, and the addition of one of the newer agents more recently approved by the FDA [Food and Drug Administration] — belimumab, voclosporin, or another CNI [calcineurin inhibitor],” said Lisa Sammaritano, MD, director of the Rheumatology Reproductive Health Program of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College, both in New York City.

“This is a bit of a change from not only our previous guideline but some of the other guidelines out there, and it is based on the fact that we have very convincing evidence that starting with triple therapy yields to better long-term outcomes for our patients than starting with only two agents and waiting to see if they respond before escalating therapy,” she said. Other key updates include recommending use of pulse glucocorticoid therapy with a lower dose and more rapid steroid taper and treating patients with the recommended therapy for 3-5 years.

The guiding principles of the guideline are not only to preserve kidney function and minimize morbidity and mortality but also to ensure collaborative care with nephrology, to utilize shared decision-making that includes patients’ values and preferences, to reduce healthcare disparities, and to consider pediatric and geriatric populations. The guidelines are based on a quantitative synthesis of 105 studies that yielded 7 strong recommendations, 21 conditional recommendations, and 13 good practice statements — those commonly accepted as beneficial or practical advice even if there is little direct evidence to support them. The voting panel of 19 members included not only 3 nephrologists and 2 pediatric rheumatologists but also 2 patient representatives with LN.

The recommendations are just that, “a recommendation, not an order,” Sammaritano said, and strong recommendations are those “where we think, unequivocally, almost everybody should follow that recommendation. When we feel that we cannot make a strong recommendation, then we call our recommendation conditional, and it is conditional on looking at different things,” she said.

“Patients are different, especially lupus patients, and so one lupus nephritis patient may have different clinical characteristics, different thoughts about what therapy will work for them in their lives, or what therapy they really do not want to pursue,” Sammaritano said. “Maybe they can’t conceive of coming to the hospital once a month for intravenous therapy. Maybe they’re concerned about pill burden, which is something that our patient panel really emphasized to us. So, conditional recommendation means this voting panel thought that this was the best overall for most patients and most circumstances, recognizing there will still be a significant number of people, clinicians and patients, who may feel differently for that particular situation. So, that’s where you know the patient-clinician discussion can help with decision-making.”

 

What Are the Recommendations?

All patients with systemic lupus erythematosus (SLE) are strongly recommended to undergo proteinuria screening every 6-12 months or at the time of a flare. Those suspected of having LN should receive a prompt kidney biopsy and treatment with glucocorticoids while awaiting the biopsy and results. Two conditional recommendations for kidney biopsy include patients with SLE with unexplained impaired kidney function or a protein to creatinine ratio > 0.5 g/g, and patients with LN with a suspected flare after initial response or a lack of response or worsening after 6 months of therapy.

The guidelines include a strong recommendation for all patients with SLE to receive hydroxychloroquine and a conditional recommendation for all patients with elevated proteinuria (> 0.5 g/g) to receive renin-angiotensin-aldosterone system inhibitors (RAAS-I). Dosages in patients with LN with decreased glomerular filtration rate (GFR) should be adjusted as needed.

Sammaritano then reviewed the specifics on medication treatment. The glucocorticoid therapy in all patients with LN should begin with Pulse IV Therapy at 250-1000 mg/d for 1-3 days, followed by oral prednisone ≤ 0.5 mg/kg per day up to 40 mg/d, then tapered to a target dose > 5 mg/d within 6 months. The justification for this course comes from a 2024 systematic review finding pulse followed by oral glucocorticoids maximized complete renal response while minimizing toxicities, Sammaritano said.

“We have all become acutely aware of the very high risk of prolonged high dose of glucocorticoids for our patients,” she said, “and importantly, our patient panel participants strongly emphasized their preference for minimizing glucocorticoids dose.”

In addition to the recommendation of all patients receiving hydroxychloroquine and RAAS-I, first-line treatment of active, new-onset, or flaring LN should begin with triple therapy — glucocorticoids with two additional immunosuppressive agents. For patients with class III/IV LN, triple therapy includes the glucocorticoids course with a mycophenolic acid analog (MPAA) and either belimumab or a CNI. Conditional recommendations support MPAA with belimumab for significant extrarenal manifestations and MPAA with CNI for proteinuria ≥ 3 g/g.

An alternative triple therapy for class III/IV is glucocorticoids with low-dose cyclophosphamide and belimumab, but MPAA at 2-3 g/d is preferred over cyclophosphamide. The preferred regimen for cyclophosphamide is derived from the Euro-Lupus Nephritis Trial: Intravenous 500 mg every 2 weeks for six doses and then MPAA. Sammaritano noted that there are some limited data on using cyclophosphamide with belimumab, but “we do not specifically recommend cyclophosphamide with a CNI as one of our options because this combination has not been studied in randomized controlled trials.”

There are less data supporting class V recommendations, Sammaritano said, but for those with proteinuria of at least 1 g/g, the panel still recommends triple therapy with glucocorticoids, a MPAA, and a CNI. A CNI is preferred over belimumab because of its stabilizing effects on the podocyte cytoskeleton. Two alternative triple therapies for class V–only patients are glucocorticoids with belimumab and either low-dose cyclophosphamide or MPAA.

Dual therapy is only recommended if triple therapy is not available or not tolerated. The voting panel chose to recommend triple therapy over dual therapy with escalation for two reasons. First, the BLISS-LN and AURORA 1 trials showed improved outcomes with initial triple therapy over initial dual therapies.

Second, “nephron loss proceeds throughout a person’s lifetime even for those who do not have lupus nephritis, and every case of lupus nephritis or every period of time with uncontrolled lupus nephritis changes the course of that decline for the worse,” Sammaritano said. “So, we feel we can’t wait for nephron loss to implement what has been shown to be the most efficacious therapy. We want to gain rapid control of inflammation using the most effective regimen to prevent further damage and flare and maintain survival.”

Therapy is conditionally recommended for at least 3-5 years because “not only do we want to gain rapid control of disease activity [but we also] want to maintain control of disease activity until there’s sustained inactive disease,” Sammaritano said. “Repeat kidney biopsies show that immunologic activity persists in the kidneys for several years, and the withdrawal of immunosuppression when there is histologic activity predisposes patients to flare.” But immunosuppressive therapy can be tapered over time as determined by renal disease activity and medication tolerability.

For patients with refractory disease, consider additional factors that could be affecting the disease, such as adherence, the presence of other diagnoses, or advanced chronicity.

“If true refractory nephritis is present,” she said, “we recommend escalation to a more intensive regimen,” including the addition of anti-CD20 agents, combination therapy with three immunosuppressives, or referral for investigational therapy.

“We also emphasize the importance of other adjunctive therapies preventing comorbidities, such as cardiovascular disease, changes in bone health, or infection risk,” she said. In older patients, avoid polypharmacy as much as possible and be mindful of age-related GFR, she added.

A strong recommendation supported monitoring patients with LN and proteinuria at least every 3 months if they have not achieved complete renal response and every 3-6 months after sustained complete renal response.

Last, in patients with LN and end-stage kidney disease (ESKD), the voting panel strongly recommends transplant over dialysis and conditionally recommends proceeding to the transplant without requiring a complete clinical or serologic remission as long as no other organs are involved. In patients with LN at risk for ESKD, the guideline conditionally recommends consideration of a preemptive transplant, and patients on dialysis or post transplant are strongly recommended to regularly follow up with rheumatology.

Gabriel Kirsch, MD, a resident rheumatologist at the University of Florida College of Medicine, Jacksonville, said he found the guidelines helpful, “especially the guidance on the dichotomy between using belimumab and voclosporin and the clinical and patient preference that help you make that decision.”

Kirsch had hoped, however, to hear more about the impact of therapeutic drug monitoring of hydroxychloroquine on LN outcomes. He also noted a clinical scenario he’s come across that wasn’t addressed.

“When you’re checking GFR on these folks, a lot of our eGFR calculators are creatinine based, and creatinine at the extremes of muscle mass can be inaccurate,” such as getting artificially low creatinine readings from pediatric patients because of their low muscle mass or from patients with muscle atrophy caused by a lot of glucocorticoid exposure. “I was hoping for some more guidance on that,” he said.

Ellen Ginzler, MD, MPH, chief of rheumatology at SUNY Health Science Center in Brooklyn, New York, said the guidelines were pretty much what she expected them to be. She agreed with the panel’s advice that, when deciding between belimumab or voclosporin, “if it’s pure proteinuria, then you add voclosporin. If the patient has extra renal manifestations, you go with belimumab first.” 

“They really made it quite clear that, despite the fact that people really want to reduce the amount of immunosuppression — and I agree you should taper steroids quickly — you really need to keep the immunosuppression for a prolonged period of time because all of the studies that have been done for years show that the longer you’re on immunosuppression after you achieve remission or a low disease activity state, the better your chance of not flaring,” Ginzler said. “Rapid tapering or discontinuation really increases the risk of flare.”

Sammaritano, Kirsch, and Ginzler had no disclosures. No external funding was used.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — Glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications appear beneficial for people with systemic lupus erythematosus (SLE) and lupus nephritis, two new studies suggest. 

“The risk of cardiovascular disease is thought to be at least double that for people with lupus ... and we know the risk of progressing to end-stage renal disease [ESKD] for patients with lupus nephritis can be as high as 10%-30%, so there’s clearly a major unmet need for new treatments and approaches to improve these outcomes, perhaps with adjunctive treatment beyond our typical immunosuppressive therapy,” April Jorge, MD, of Massachusetts General Hospital, Boston, said at the annual meeting of the American College of Rheumatology (ACR). 

The GLP-1 RAs are approved for the treatment of type 2 diabetes (T2D) and obesity. They also have proven cardiovascular benefit, along with emerging data suggesting kidney protection independent of glucose lowering. Jorge presented findings from a study using data from the US multicenter electronic health record database TriNetX, showing that, among patients who had both T2D and SLE, those using GLP-1 RAs had lower risks for major adverse cardiac events (MACE), venous thrombosis, kidney disease progression, and all-cause mortality, compared with those using a different class of T2D medication. 

A second study using TriNetX, presented at the same ACR meeting session by Anna-Kay Palmer, MD, a third-year internal medicine resident at Jefferson Einstein Hospital, Philadelphia, Pennsylvania, showed that GLP-1 RAs reduced the risk of progression to ESKD in patients with lupus nephritis, possibly caused by reductions in pro-inflammatory mediators.

Asked to comment, session moderator Diane L. Kamen, MD, professor of medicine at the Medical University of South Carolina Division of Rheumatology, Charleston, said in an interview that she definitely supports the use of GLP-1 RAs for patients who have SLE and/or lupus nephritis and also a drug label indication, either T2D or obesity. “[The GLP-1 RA prescriber] will usually run it by rheumatology to make sure that it doesn’t conflict with any of their other medical treatment, and it’s very reassuring to know that they could actually get a win-win.” 

But as far as prescribing off-label for those with SLE/lupus nephritis who don’t have other GLP-1 RA indications, Kamen said, “that’s a black hole at this point. We need to do those prospective studies. But if they have another indication, yes.”

 

Cardiovascular, Kidney Benefits of GLP-1 RAs

Jorge noted that patients with lupus were excluded from the randomized clinical trials of GLP-1 RAs, so the current study was designed to investigate the potential impact of these medications on cardiovascular and kidney outcomes in patients with SLE and lupus nephritis. 

From TriNetX data for 46 healthcare organizations nationwide, a total of 96,511 patients with both SLE and T2D but not ESKD had initiated either a GLP-1 RA or another diabetes drug class, dipeptidyl peptidase 4 inhibitors (DPP4i), between October 2006 and August 2021. Of those, 29,177 had lupus nephritis. 

Propensity score matching for factors such as demographics, lupus severity, comorbidities, and medication use was used to emulate a randomized trial. This yielded 25,838 with SLE and T2D, of whom 910 initiated a GLP-1 RA and 1004 started a DPP4i, and 12,387 with lupus nephritis and T2D, including 267 on a GLP-1 RA and 324 on a DPP4i. After matching, the mean age was 55 years, more than 90% were women, and just under half were White individuals. About one third had chronic kidney disease stages ≥ 3, and about 15% had heart failure. 

Over an average follow-up time of 1.2-1.4 years among those with SLE, the hazard ratio (HR) for MACE (a composite of myocardial infarction, stroke, and heart failure) for those taking a GLP-1 RA vs a DPP4i was 0.66, a significant difference. And for venous thrombosis, the HR was also significant at 0.49.

Kidney disease progression, defined as an estimated glomerular filtration rate decline of 30% or more or new ESKD, was significantly less likely in the GLP-1 RA group, with a HR of 0.77. All-cause mortality also was dramatically reduced (HR, 0.26). As expected, there was no difference in control outcome, genital infections (HR, 1.02). 

In the subgroup with lupus nephritis, there were also lower risks for both MACE (HR, 0.64) and for renal progression (HR, 0.70). “The findings suggest similar cardiac and kidney benefits among patients with SLE and lupus nephritis as have been observed in other populations,” Jorge concluded. 

Kamen commented that the study design “was pretty brilliant, because you wouldn’t be able to do a placebo-controlled trial since the indication was diabetes ... but the fact is you do see that the GLP-1 RA gets the benefit whereas the other drug does not.”

Next steps, Jorge said, will be mechanistic studies to better understand the effects of GLP-1 RAs in lupus and other rheumatic diseases, prospective studies of GLP-1 RAs in SLE and lupus nephritis without diabetes, and clarification of ideal timing for GLP-1 RA use in SLE and lupus nephritis. 

“Ideally, with our prospective studies with these patients we can try to isolate the effect on patients with lupus and also better understand whether there might be an impact on disease activity through the anti-inflammatory effects of these medications, rather than just the cardioprotective and nephroprotective benefits,” she said. 

 

In Those With Lupus Nephritis, Kidney Protection Seen

In her presentation, Palmer noted that, despite immunosuppressive therapies for SLE, 10%-20% of patients who develop lupus nephritis will progress to ESKD within 5 years of diagnosis. 

She added that GLP-1 RAs have been shown to reduce albuminuria in people with diabetes and have been hypothesized to reduce inflammation through multiple pathways, thereby potentially reducing kidney disease independently of the presence of diabetes or weight loss. These pathways include modulating immune cell signaling and reducing pro-inflammatory cytokines. 

Based on all this, Palmer and colleagues used International Classification of Diseases – 10th edition diagnostic codes in TriNetX to identify 839 patients who had been diagnosed with lupus nephritis between 2014 and 2024 and who were prescribed liraglutide, dulaglutide, semaglutide, or exenatide for any time after the lupus nephritis diagnosis. Another 29,840 patients with lupus nephritis had not used GLP-1 RAs. 

After 1:1 propensity score matching for age, sex, race, ethnicity, presence of hypertension, diabetes, use of immunosuppressive and diabetes medication, smoking, obesity, and statin use, there were 735 individuals in each group. About two thirds in each had diabetes, whereas the rest had been prescribed the GLP-1 RAs for other indications. 

Patients who were not on GLP-1 RAs were twice as likely to develop ESKD or dialysis (8.88% vs 3.971%; odds ratio, 2.35; P = .001). 

Kamen pointed out that not including the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was a study flaw. On the other hand, the fact that not everyone in this study had diabetes was an advantage.

Jorge received grant/research support from Bristol-Myers Squibb, Cabaletta Bio, and the Lupus Clinical Investigator Network. Kamen is an adviser/review panel member for Alpine Immune Sciences. Palmer had no disclosures.

A version of this article appeared on Medscape.com.

WASHINGTON — The investigational anti-CD40 ligand agent dapirolizumab pegol (DZP) outperformed placebo in improving disease activity and reducing high-dose corticosteroid use in patients with systemic lupus erythematosus (SLE) in the phase 3 PHOENYCS GO trial.

“We really think that dapirolizumab pegol may represent a novel treatment for lupus, particularly given its broad immune modulatory effects,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She presented the study in a late-breaking poster session at the American College of Rheumatology (ACR) 2024 Annual Meeting.

There is a “huge unmet need” for drugs for lupus, Clowse told this news organization. Patients with SLE continue to have high disease burden, including ongoing symptoms often driven by inflammation. Corticosteroids are often the best medications to control disease activity, she said, but they can result in long-term toxicity.

 

What Makes DZP Unique?

Through CD40 ligand signaling, DZP has been shown to reduce B- and T-cell activation and to downregulate interferon pathways. Previous antibodies targeting the CD40 ligand have been associated with an increased risk for thromboembolic events. However, DZP lacks the Fc portion of the antibody, which can bind to platelets and cause clotting. Data from phase 1, 2, and 3 trials thus far do not show an elevated risk for these events, Clowse explained. In fact, safety signals were strong enough that patients with antiphospholipid antibodies — a key driver for blood clots in patients with SLE — were included in the trial.

In PHOENYCS GO, investigators enrolled 321 patients with moderate to severe SLE with persistently active or frequently flaring/relapsing-remitting disease activity despite stable standard of care (SOC) medications such as antimalarials, corticosteroids, and immunosuppressants.

Patients were randomized 2:1 to receive intravenous DZP (24 mg/kg) plus SOC or intravenous placebo plus SOC every 4 weeks, with patients and investigators blinded to treatment assignments.

Patients taking a corticosteroid dose > 7.5 mg/day began a mandatory steroid taper by week 8 of the trial, with the goal of reducing that to < 7.5 mg/day. The tapering regimen was at the discretion of providers and was adapted to each patient’s individual disease activity.

The primary endpoint was British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response at week 48.

Patients in the DZP and placebo groups were on average 43.5 and 41.5 years old, respectively. More than 90% of patients were women, all on concomitant SLE medications. About half of the participants took a daily corticosteroid dose > 7.5 mg.

At 48 weeks, half of the DZP group (49.5%) achieved BICLA response compared with 34.6% in the placebo group (P = .0110). A higher proportion of patients taking DZP achieved SLE Responder Index-4 response than those taking placebo (60.1% vs 41.1%, respectively; P = .0014), and the rate of severe British Isles Lupus Assessment Group flares in the DZP group was half that of the placebo group (11.6% vs 23.4%; P = .0257). In the subgroup of patients who underwent corticosteroid tapering, 72.4% receiving DZP and 52.9% taking placebo reduced their dose to < 7.5 mg/day by 48 weeks (P = .0404).

DZP was generally well tolerated. Over 48 weeks, 82.6% of the DZP group and 75% of the placebo group reported treatment-emergent adverse events, but serious occurrences were more common in the placebo group (14.8%) than in the DZP group (9.9%). Herpes viral infections were higher in the placebo group, although there were three ophthalmic herpes cases in the DZP group. There was one case of acute myocardial infarction and one death linked to gangrene-related sepsis in patients receiving DZP.

 

A ‘Mild to Moderate’ Response

Although these are definitely positive results, they show a “mild to moderate response” to DZP, commented Gregory Gardner, MD, an emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, and chair of the American College of Rheumatology’s annual meeting planning committee. He moderated the session where the research was presented. Although DZP showed efficacy among some patients, he noted, “there were still 51% patients that it didn’t work for.” 

The drug uses an alternative pathway to current lupus drugs, Gardner added, and more research is needed to understand how best to use this medication in practice.

Clowse noted that DZP could be particularly beneficial for patients with SLE who want to get pregnant. Many drugs used to treat the disease are teratogenic; however, “because of the lack of Fc portion on this drug, it very likely does not cross the placenta in any kind of significant amount,” she said. Although there are not yet any reproductive safety data on DZP, she added, “that is a great potential niche.”

Biogen and UCB, which are jointly developing DZP, aim to start a second phase 3 trial of DZP in patients with SLE, called PHOENYCS FLY, in 2024.

The trial was sponsored by UCB. Clowse is a consultant and has received grant/research support from GSK and UCB. Gardner had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

WASHINGTON — The investigational anti-CD40 ligand agent dapirolizumab pegol (DZP) outperformed placebo in improving disease activity and reducing high-dose corticosteroid use in patients with systemic lupus erythematosus (SLE) in the phase 3 PHOENYCS GO trial.

“We really think that dapirolizumab pegol may represent a novel treatment for lupus, particularly given its broad immune modulatory effects,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She presented the study in a late-breaking poster session at the American College of Rheumatology (ACR) 2024 Annual Meeting.

There is a “huge unmet need” for drugs for lupus, Clowse told this news organization. Patients with SLE continue to have high disease burden, including ongoing symptoms often driven by inflammation. Corticosteroids are often the best medications to control disease activity, she said, but they can result in long-term toxicity.

 

What Makes DZP Unique?

Through CD40 ligand signaling, DZP has been shown to reduce B- and T-cell activation and to downregulate interferon pathways. Previous antibodies targeting the CD40 ligand have been associated with an increased risk for thromboembolic events. However, DZP lacks the Fc portion of the antibody, which can bind to platelets and cause clotting. Data from phase 1, 2, and 3 trials thus far do not show an elevated risk for these events, Clowse explained. In fact, safety signals were strong enough that patients with antiphospholipid antibodies — a key driver for blood clots in patients with SLE — were included in the trial.

In PHOENYCS GO, investigators enrolled 321 patients with moderate to severe SLE with persistently active or frequently flaring/relapsing-remitting disease activity despite stable standard of care (SOC) medications such as antimalarials, corticosteroids, and immunosuppressants.

Patients were randomized 2:1 to receive intravenous DZP (24 mg/kg) plus SOC or intravenous placebo plus SOC every 4 weeks, with patients and investigators blinded to treatment assignments.

Patients taking a corticosteroid dose > 7.5 mg/day began a mandatory steroid taper by week 8 of the trial, with the goal of reducing that to < 7.5 mg/day. The tapering regimen was at the discretion of providers and was adapted to each patient’s individual disease activity.

The primary endpoint was British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response at week 48.

Patients in the DZP and placebo groups were on average 43.5 and 41.5 years old, respectively. More than 90% of patients were women, all on concomitant SLE medications. About half of the participants took a daily corticosteroid dose > 7.5 mg.

At 48 weeks, half of the DZP group (49.5%) achieved BICLA response compared with 34.6% in the placebo group (P = .0110). A higher proportion of patients taking DZP achieved SLE Responder Index-4 response than those taking placebo (60.1% vs 41.1%, respectively; P = .0014), and the rate of severe British Isles Lupus Assessment Group flares in the DZP group was half that of the placebo group (11.6% vs 23.4%; P = .0257). In the subgroup of patients who underwent corticosteroid tapering, 72.4% receiving DZP and 52.9% taking placebo reduced their dose to < 7.5 mg/day by 48 weeks (P = .0404).

DZP was generally well tolerated. Over 48 weeks, 82.6% of the DZP group and 75% of the placebo group reported treatment-emergent adverse events, but serious occurrences were more common in the placebo group (14.8%) than in the DZP group (9.9%). Herpes viral infections were higher in the placebo group, although there were three ophthalmic herpes cases in the DZP group. There was one case of acute myocardial infarction and one death linked to gangrene-related sepsis in patients receiving DZP.

 

A ‘Mild to Moderate’ Response

Although these are definitely positive results, they show a “mild to moderate response” to DZP, commented Gregory Gardner, MD, an emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, and chair of the American College of Rheumatology’s annual meeting planning committee. He moderated the session where the research was presented. Although DZP showed efficacy among some patients, he noted, “there were still 51% patients that it didn’t work for.” 

The drug uses an alternative pathway to current lupus drugs, Gardner added, and more research is needed to understand how best to use this medication in practice.

Clowse noted that DZP could be particularly beneficial for patients with SLE who want to get pregnant. Many drugs used to treat the disease are teratogenic; however, “because of the lack of Fc portion on this drug, it very likely does not cross the placenta in any kind of significant amount,” she said. Although there are not yet any reproductive safety data on DZP, she added, “that is a great potential niche.”

Biogen and UCB, which are jointly developing DZP, aim to start a second phase 3 trial of DZP in patients with SLE, called PHOENYCS FLY, in 2024.

The trial was sponsored by UCB. Clowse is a consultant and has received grant/research support from GSK and UCB. Gardner had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

WASHINGTON — The investigational anti-CD40 ligand agent dapirolizumab pegol (DZP) outperformed placebo in improving disease activity and reducing high-dose corticosteroid use in patients with systemic lupus erythematosus (SLE) in the phase 3 PHOENYCS GO trial.

“We really think that dapirolizumab pegol may represent a novel treatment for lupus, particularly given its broad immune modulatory effects,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She presented the study in a late-breaking poster session at the American College of Rheumatology (ACR) 2024 Annual Meeting.

There is a “huge unmet need” for drugs for lupus, Clowse told this news organization. Patients with SLE continue to have high disease burden, including ongoing symptoms often driven by inflammation. Corticosteroids are often the best medications to control disease activity, she said, but they can result in long-term toxicity.

 

What Makes DZP Unique?

Through CD40 ligand signaling, DZP has been shown to reduce B- and T-cell activation and to downregulate interferon pathways. Previous antibodies targeting the CD40 ligand have been associated with an increased risk for thromboembolic events. However, DZP lacks the Fc portion of the antibody, which can bind to platelets and cause clotting. Data from phase 1, 2, and 3 trials thus far do not show an elevated risk for these events, Clowse explained. In fact, safety signals were strong enough that patients with antiphospholipid antibodies — a key driver for blood clots in patients with SLE — were included in the trial.

In PHOENYCS GO, investigators enrolled 321 patients with moderate to severe SLE with persistently active or frequently flaring/relapsing-remitting disease activity despite stable standard of care (SOC) medications such as antimalarials, corticosteroids, and immunosuppressants.

Patients were randomized 2:1 to receive intravenous DZP (24 mg/kg) plus SOC or intravenous placebo plus SOC every 4 weeks, with patients and investigators blinded to treatment assignments.

Patients taking a corticosteroid dose > 7.5 mg/day began a mandatory steroid taper by week 8 of the trial, with the goal of reducing that to < 7.5 mg/day. The tapering regimen was at the discretion of providers and was adapted to each patient’s individual disease activity.

The primary endpoint was British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response at week 48.

Patients in the DZP and placebo groups were on average 43.5 and 41.5 years old, respectively. More than 90% of patients were women, all on concomitant SLE medications. About half of the participants took a daily corticosteroid dose > 7.5 mg.

At 48 weeks, half of the DZP group (49.5%) achieved BICLA response compared with 34.6% in the placebo group (P = .0110). A higher proportion of patients taking DZP achieved SLE Responder Index-4 response than those taking placebo (60.1% vs 41.1%, respectively; P = .0014), and the rate of severe British Isles Lupus Assessment Group flares in the DZP group was half that of the placebo group (11.6% vs 23.4%; P = .0257). In the subgroup of patients who underwent corticosteroid tapering, 72.4% receiving DZP and 52.9% taking placebo reduced their dose to < 7.5 mg/day by 48 weeks (P = .0404).

DZP was generally well tolerated. Over 48 weeks, 82.6% of the DZP group and 75% of the placebo group reported treatment-emergent adverse events, but serious occurrences were more common in the placebo group (14.8%) than in the DZP group (9.9%). Herpes viral infections were higher in the placebo group, although there were three ophthalmic herpes cases in the DZP group. There was one case of acute myocardial infarction and one death linked to gangrene-related sepsis in patients receiving DZP.

 

A ‘Mild to Moderate’ Response

Although these are definitely positive results, they show a “mild to moderate response” to DZP, commented Gregory Gardner, MD, an emeritus professor in the Division of Rheumatology at the University of Washington, Seattle, and chair of the American College of Rheumatology’s annual meeting planning committee. He moderated the session where the research was presented. Although DZP showed efficacy among some patients, he noted, “there were still 51% patients that it didn’t work for.” 

The drug uses an alternative pathway to current lupus drugs, Gardner added, and more research is needed to understand how best to use this medication in practice.

Clowse noted that DZP could be particularly beneficial for patients with SLE who want to get pregnant. Many drugs used to treat the disease are teratogenic; however, “because of the lack of Fc portion on this drug, it very likely does not cross the placenta in any kind of significant amount,” she said. Although there are not yet any reproductive safety data on DZP, she added, “that is a great potential niche.”

Biogen and UCB, which are jointly developing DZP, aim to start a second phase 3 trial of DZP in patients with SLE, called PHOENYCS FLY, in 2024.

The trial was sponsored by UCB. Clowse is a consultant and has received grant/research support from GSK and UCB. Gardner had no relevant disclosures.

 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Home spirometry shows potential for early detection of pulmonary function decline in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD). It shows good cross-sectional correlation with hospital tests, along with 60% sensitivity and 87% specificity for detecting progressive ILD.

METHODOLOGY:

• Researchers conducted a prospective, observational study to examine the validity of home spirometry for detecting a decline in pulmonary function in patients with SSc-ILD.
• They included 43 patients aged 18 years or older with SSc-ILD from two tertiary referral centers in the Netherlands who received treatment with immunosuppressives for a maximum duration of 8 weeks prior to baseline.
• All participants were required to take weekly home spirometry measurements using a handheld spirometer for 1 year, with 35 completing 6 months of follow-up and 31 completing 12 months.
• Pulmonary function tests were conducted in the hospital at baseline and semiannual visits.
• The primary outcome was the κ (kappa statistic) agreement between home and hospital measurements after 1 year to detect a decline in forced vital capacity (FVC) of 5% or more; the sensitivity and specificity of home spirometry were also evaluated to detect an absolute decline in FVC%, using hospital tests as the gold standard.

TAKEAWAY:

• Home spirometry showed a fair agreement with the pulmonary function tests conducted at the hospital (κ, 0.40; 95% CI, 0.01-0.79).
• Home spirometry showed a sensitivity of 60% and specificity of 87% in detecting a decline in FVC% predicted of 5% or more.
• The intraclass correlation coefficient between home and hospital FVC measurements was moderate to high, with values of 0.85 at baseline, 0.84 at 6 months, and 0.72 at 12 months (P < .0001 for all).
• However, the longitudinal agreement between home and hospital measurements was lower with a correlation coefficient of 0.55.

IN PRACTICE:

“These findings suggest that home spirometry is both feasible and moderately accurate in patients with systemic sclerosis–associated ILD. However, where home spirometry fell short was the low sensitivity in detecting a decline in FVC% predicted,” experts wrote in an accompanying editorial.

“The results of this study support further evaluation of the implementation of home spirometry in addition to regular healthcare management but do not endorse relying solely on home monitoring to detect a decline in pulmonary function,” study authors wrote.

SOURCE:

The study was led by Arthiha Velauthapillai, MD, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands, and was published online November 8, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study might have been underpowered because of inaccuracies in initial assumptions, with a lower-than-anticipated prevalence of progressive ILD and a higher dropout rate. The study included only Dutch patients, which may have limited the generalizability of its findings to other settings with lower internet access or literacy rates.

DISCLOSURES:

This study was partly supported by grants from Galapagos and Boehringer Ingelheim. Some authors received grants or consulting or speaker fees from Boehringer Ingelheim, AstraZeneca, and other pharmaceutical companies.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Home spirometry shows potential for early detection of pulmonary function decline in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD). It shows good cross-sectional correlation with hospital tests, along with 60% sensitivity and 87% specificity for detecting progressive ILD.

METHODOLOGY:

• Researchers conducted a prospective, observational study to examine the validity of home spirometry for detecting a decline in pulmonary function in patients with SSc-ILD.
• They included 43 patients aged 18 years or older with SSc-ILD from two tertiary referral centers in the Netherlands who received treatment with immunosuppressives for a maximum duration of 8 weeks prior to baseline.
• All participants were required to take weekly home spirometry measurements using a handheld spirometer for 1 year, with 35 completing 6 months of follow-up and 31 completing 12 months.
• Pulmonary function tests were conducted in the hospital at baseline and semiannual visits.
• The primary outcome was the κ (kappa statistic) agreement between home and hospital measurements after 1 year to detect a decline in forced vital capacity (FVC) of 5% or more; the sensitivity and specificity of home spirometry were also evaluated to detect an absolute decline in FVC%, using hospital tests as the gold standard.

TAKEAWAY:

• Home spirometry showed a fair agreement with the pulmonary function tests conducted at the hospital (κ, 0.40; 95% CI, 0.01-0.79).
• Home spirometry showed a sensitivity of 60% and specificity of 87% in detecting a decline in FVC% predicted of 5% or more.
• The intraclass correlation coefficient between home and hospital FVC measurements was moderate to high, with values of 0.85 at baseline, 0.84 at 6 months, and 0.72 at 12 months (P < .0001 for all).
• However, the longitudinal agreement between home and hospital measurements was lower with a correlation coefficient of 0.55.

IN PRACTICE:

“These findings suggest that home spirometry is both feasible and moderately accurate in patients with systemic sclerosis–associated ILD. However, where home spirometry fell short was the low sensitivity in detecting a decline in FVC% predicted,” experts wrote in an accompanying editorial.

“The results of this study support further evaluation of the implementation of home spirometry in addition to regular healthcare management but do not endorse relying solely on home monitoring to detect a decline in pulmonary function,” study authors wrote.

SOURCE:

The study was led by Arthiha Velauthapillai, MD, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands, and was published online November 8, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study might have been underpowered because of inaccuracies in initial assumptions, with a lower-than-anticipated prevalence of progressive ILD and a higher dropout rate. The study included only Dutch patients, which may have limited the generalizability of its findings to other settings with lower internet access or literacy rates.

DISCLOSURES:

This study was partly supported by grants from Galapagos and Boehringer Ingelheim. Some authors received grants or consulting or speaker fees from Boehringer Ingelheim, AstraZeneca, and other pharmaceutical companies.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Home spirometry shows potential for early detection of pulmonary function decline in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD). It shows good cross-sectional correlation with hospital tests, along with 60% sensitivity and 87% specificity for detecting progressive ILD.

METHODOLOGY:

• Researchers conducted a prospective, observational study to examine the validity of home spirometry for detecting a decline in pulmonary function in patients with SSc-ILD.
• They included 43 patients aged 18 years or older with SSc-ILD from two tertiary referral centers in the Netherlands who received treatment with immunosuppressives for a maximum duration of 8 weeks prior to baseline.
• All participants were required to take weekly home spirometry measurements using a handheld spirometer for 1 year, with 35 completing 6 months of follow-up and 31 completing 12 months.
• Pulmonary function tests were conducted in the hospital at baseline and semiannual visits.
• The primary outcome was the κ (kappa statistic) agreement between home and hospital measurements after 1 year to detect a decline in forced vital capacity (FVC) of 5% or more; the sensitivity and specificity of home spirometry were also evaluated to detect an absolute decline in FVC%, using hospital tests as the gold standard.

TAKEAWAY:

• Home spirometry showed a fair agreement with the pulmonary function tests conducted at the hospital (κ, 0.40; 95% CI, 0.01-0.79).
• Home spirometry showed a sensitivity of 60% and specificity of 87% in detecting a decline in FVC% predicted of 5% or more.
• The intraclass correlation coefficient between home and hospital FVC measurements was moderate to high, with values of 0.85 at baseline, 0.84 at 6 months, and 0.72 at 12 months (P < .0001 for all).
• However, the longitudinal agreement between home and hospital measurements was lower with a correlation coefficient of 0.55.

IN PRACTICE:

“These findings suggest that home spirometry is both feasible and moderately accurate in patients with systemic sclerosis–associated ILD. However, where home spirometry fell short was the low sensitivity in detecting a decline in FVC% predicted,” experts wrote in an accompanying editorial.

“The results of this study support further evaluation of the implementation of home spirometry in addition to regular healthcare management but do not endorse relying solely on home monitoring to detect a decline in pulmonary function,” study authors wrote.

SOURCE:

The study was led by Arthiha Velauthapillai, MD, Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands, and was published online November 8, 2024, in The Lancet Rheumatology.

LIMITATIONS:

The study might have been underpowered because of inaccuracies in initial assumptions, with a lower-than-anticipated prevalence of progressive ILD and a higher dropout rate. The study included only Dutch patients, which may have limited the generalizability of its findings to other settings with lower internet access or literacy rates.

DISCLOSURES:

This study was partly supported by grants from Galapagos and Boehringer Ingelheim. Some authors received grants or consulting or speaker fees from Boehringer Ingelheim, AstraZeneca, and other pharmaceutical companies.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

WASHINGTON — A diagnostic test to predict preeclampsia does not effectively rule in or out this pregnancy complication in women with systemic lupus erythematosus (SLE) and proteinuria, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“If you have a patient who has proteinuria during pregnancy, I’m not sure we know what to do with this test,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She led the research and presented the work.

The results “are probably a step in the right direction to understanding that we need more biochemical markers for differentiating preeclampsia [in this patient population],” Leanna Wise, MD, of the Keck School of Medicine at the University of Southern California, Los Angeles, said in an interview. She comoderated the session where the research was presented. “It exposed that we have a lot of gray areas in which we need to do more research.”

The test is a ratio of two biomarkers that measure spiral artery and placental health: Soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). In the general population, a sFlt-1/PlGF ratio ≤ 38 effectively rules out the short-term risk for preeclampsia, whereas a ratio ≥ 85 is moderately predictive of preeclampsia. However, it was not known how this test would fare in pregnant women with SLE who are already at a higher risk for the complication.

To answer this question, Clowse and colleagues pulled patient data from an ongoing prospective registry of lupus pregnancies. The analysis included patients with a confirmed SLE diagnosis who had enrolled in the registry prior to 30 weeks’ gestation. All participants had provided a serum sample prior to 16 weeks’ gestation and had singleton pregnancies.

In an extensive chart review, preeclampsia was determined by a roundtable of six experts: Two rheumatologists, two maternal-fetal medicine doctors, and two nephrologists.

The analysis included 79 pregnancies, of which 30% developed preeclampsia. Nearly half (47%) of the participants identified as Black or African American. About 30% had a history of lupus nephritis, and half of these patients had active disease during their pregnancy. About half of the women reported that this was their first pregnancy, and an additional 17% of women reported a prior episode of preeclampsia. Most patients were on aspirin (92%) and hydroxychloroquine (87%), and another 43% were prescribed prednisone and 37% were taking azathioprine.

Researchers assessed whether a low sFlt-1/PlGF ratio (≤ 38) was associated with the absence of preeclampsia at 4- and 8-weeks post–blood draw, as well as during the entire pregnancy. They also tested if a high ratio (≥ 85) was associated with the development of preeclampsia within 4- and 8-weeks post–blood draw and through the entire pregnancy.

Across all pregnancies in the cohort, those with sFlt-1/PlGF ≤ 38 were unlikely to develop preeclampsia at 4 weeks post draw (negative predictive value [NPV], 98%) and 8 weeks post draw (NPV, 96%). Still, 20% of patients with this low ratio went on to develop preeclampsia at some point during their pregnancy.

Similar to the general population, sFlt-1/PlGF ≥ 85 was only moderately predictive of preeclampsia. Over half of all patients with this high ratio developed preeclampsia, but more than 40% did not.

Researchers also stratified patients by urine protein:creatinine ratio (UPCR) at the time of their rheumatology visit, defining proteinuria as a UPCR ≥ 300 mg/g.

In patients without proteinuria (n = 63), a low sFlt-1/PlGF ratio ruled out preeclampsia over the next 8 weeks, but a high sFlt-1/PlGF ratio was not usefully predictive of preeclampsia.

 

Low Ratio to Rule Out Preeclampsia ‘Reassuring’

The high reliability in ruling out preeclampsia in this subset of patients with a low sFlt-1/PlGF ratio is “reassuring,” Wise said, and suggests that these patients are “relatively safe moving forward,” given regular follow-up.

In the small group of patients with proteinuria (n = 16), 44% ultimately developed preeclampsia. One third of patients with sFlt-1/PlGF ≤ 38 developed preeclampsia in 8 weeks, and half experienced preeclampsia at some point during their pregnancy. Among the patients with sFlt-1:PlGF ≥ 85, 56% developed preeclampsia during their pregnancy.

“The negative predictive values are not really great, and the positive predictive values are not really very useful,” Clowse said. For a pregnant patient with proteinuria, “I don’t think that a high [ratio] is going to tell us that she definitely has preeclampsia today or tomorrow. I also am not convinced yet that a low [ratio] tells us that she’s out of the woods. So, I think we definitely need more research on what to do with this test in patients with proteinuria.”

Clowse is a consultant and has received research support/grants from GSK and UCB. She also reported consulting for AstraZeneca. Wise is a consultant for Aurinia Pharmaceuticals and has received honoraria from AstraZeneca, Aurinia Pharmaceuticals, and GSK.

A version of this article first appeared on Medscape.com.

WASHINGTON — A diagnostic test to predict preeclampsia does not effectively rule in or out this pregnancy complication in women with systemic lupus erythematosus (SLE) and proteinuria, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“If you have a patient who has proteinuria during pregnancy, I’m not sure we know what to do with this test,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She led the research and presented the work.

The results “are probably a step in the right direction to understanding that we need more biochemical markers for differentiating preeclampsia [in this patient population],” Leanna Wise, MD, of the Keck School of Medicine at the University of Southern California, Los Angeles, said in an interview. She comoderated the session where the research was presented. “It exposed that we have a lot of gray areas in which we need to do more research.”

The test is a ratio of two biomarkers that measure spiral artery and placental health: Soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). In the general population, a sFlt-1/PlGF ratio ≤ 38 effectively rules out the short-term risk for preeclampsia, whereas a ratio ≥ 85 is moderately predictive of preeclampsia. However, it was not known how this test would fare in pregnant women with SLE who are already at a higher risk for the complication.

To answer this question, Clowse and colleagues pulled patient data from an ongoing prospective registry of lupus pregnancies. The analysis included patients with a confirmed SLE diagnosis who had enrolled in the registry prior to 30 weeks’ gestation. All participants had provided a serum sample prior to 16 weeks’ gestation and had singleton pregnancies.

In an extensive chart review, preeclampsia was determined by a roundtable of six experts: Two rheumatologists, two maternal-fetal medicine doctors, and two nephrologists.

The analysis included 79 pregnancies, of which 30% developed preeclampsia. Nearly half (47%) of the participants identified as Black or African American. About 30% had a history of lupus nephritis, and half of these patients had active disease during their pregnancy. About half of the women reported that this was their first pregnancy, and an additional 17% of women reported a prior episode of preeclampsia. Most patients were on aspirin (92%) and hydroxychloroquine (87%), and another 43% were prescribed prednisone and 37% were taking azathioprine.

Researchers assessed whether a low sFlt-1/PlGF ratio (≤ 38) was associated with the absence of preeclampsia at 4- and 8-weeks post–blood draw, as well as during the entire pregnancy. They also tested if a high ratio (≥ 85) was associated with the development of preeclampsia within 4- and 8-weeks post–blood draw and through the entire pregnancy.

Across all pregnancies in the cohort, those with sFlt-1/PlGF ≤ 38 were unlikely to develop preeclampsia at 4 weeks post draw (negative predictive value [NPV], 98%) and 8 weeks post draw (NPV, 96%). Still, 20% of patients with this low ratio went on to develop preeclampsia at some point during their pregnancy.

Similar to the general population, sFlt-1/PlGF ≥ 85 was only moderately predictive of preeclampsia. Over half of all patients with this high ratio developed preeclampsia, but more than 40% did not.

Researchers also stratified patients by urine protein:creatinine ratio (UPCR) at the time of their rheumatology visit, defining proteinuria as a UPCR ≥ 300 mg/g.

In patients without proteinuria (n = 63), a low sFlt-1/PlGF ratio ruled out preeclampsia over the next 8 weeks, but a high sFlt-1/PlGF ratio was not usefully predictive of preeclampsia.

 

Low Ratio to Rule Out Preeclampsia ‘Reassuring’

The high reliability in ruling out preeclampsia in this subset of patients with a low sFlt-1/PlGF ratio is “reassuring,” Wise said, and suggests that these patients are “relatively safe moving forward,” given regular follow-up.

In the small group of patients with proteinuria (n = 16), 44% ultimately developed preeclampsia. One third of patients with sFlt-1/PlGF ≤ 38 developed preeclampsia in 8 weeks, and half experienced preeclampsia at some point during their pregnancy. Among the patients with sFlt-1:PlGF ≥ 85, 56% developed preeclampsia during their pregnancy.

“The negative predictive values are not really great, and the positive predictive values are not really very useful,” Clowse said. For a pregnant patient with proteinuria, “I don’t think that a high [ratio] is going to tell us that she definitely has preeclampsia today or tomorrow. I also am not convinced yet that a low [ratio] tells us that she’s out of the woods. So, I think we definitely need more research on what to do with this test in patients with proteinuria.”

Clowse is a consultant and has received research support/grants from GSK and UCB. She also reported consulting for AstraZeneca. Wise is a consultant for Aurinia Pharmaceuticals and has received honoraria from AstraZeneca, Aurinia Pharmaceuticals, and GSK.

A version of this article first appeared on Medscape.com.

WASHINGTON — A diagnostic test to predict preeclampsia does not effectively rule in or out this pregnancy complication in women with systemic lupus erythematosus (SLE) and proteinuria, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“If you have a patient who has proteinuria during pregnancy, I’m not sure we know what to do with this test,” said Megan Clowse, MD, MPH, associate professor of medicine and chief of the Division of Rheumatology and Immunology at Duke University School of Medicine in Durham, North Carolina. She led the research and presented the work.

The results “are probably a step in the right direction to understanding that we need more biochemical markers for differentiating preeclampsia [in this patient population],” Leanna Wise, MD, of the Keck School of Medicine at the University of Southern California, Los Angeles, said in an interview. She comoderated the session where the research was presented. “It exposed that we have a lot of gray areas in which we need to do more research.”

The test is a ratio of two biomarkers that measure spiral artery and placental health: Soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). In the general population, a sFlt-1/PlGF ratio ≤ 38 effectively rules out the short-term risk for preeclampsia, whereas a ratio ≥ 85 is moderately predictive of preeclampsia. However, it was not known how this test would fare in pregnant women with SLE who are already at a higher risk for the complication.

To answer this question, Clowse and colleagues pulled patient data from an ongoing prospective registry of lupus pregnancies. The analysis included patients with a confirmed SLE diagnosis who had enrolled in the registry prior to 30 weeks’ gestation. All participants had provided a serum sample prior to 16 weeks’ gestation and had singleton pregnancies.

In an extensive chart review, preeclampsia was determined by a roundtable of six experts: Two rheumatologists, two maternal-fetal medicine doctors, and two nephrologists.

The analysis included 79 pregnancies, of which 30% developed preeclampsia. Nearly half (47%) of the participants identified as Black or African American. About 30% had a history of lupus nephritis, and half of these patients had active disease during their pregnancy. About half of the women reported that this was their first pregnancy, and an additional 17% of women reported a prior episode of preeclampsia. Most patients were on aspirin (92%) and hydroxychloroquine (87%), and another 43% were prescribed prednisone and 37% were taking azathioprine.

Researchers assessed whether a low sFlt-1/PlGF ratio (≤ 38) was associated with the absence of preeclampsia at 4- and 8-weeks post–blood draw, as well as during the entire pregnancy. They also tested if a high ratio (≥ 85) was associated with the development of preeclampsia within 4- and 8-weeks post–blood draw and through the entire pregnancy.

Across all pregnancies in the cohort, those with sFlt-1/PlGF ≤ 38 were unlikely to develop preeclampsia at 4 weeks post draw (negative predictive value [NPV], 98%) and 8 weeks post draw (NPV, 96%). Still, 20% of patients with this low ratio went on to develop preeclampsia at some point during their pregnancy.

Similar to the general population, sFlt-1/PlGF ≥ 85 was only moderately predictive of preeclampsia. Over half of all patients with this high ratio developed preeclampsia, but more than 40% did not.

Researchers also stratified patients by urine protein:creatinine ratio (UPCR) at the time of their rheumatology visit, defining proteinuria as a UPCR ≥ 300 mg/g.

In patients without proteinuria (n = 63), a low sFlt-1/PlGF ratio ruled out preeclampsia over the next 8 weeks, but a high sFlt-1/PlGF ratio was not usefully predictive of preeclampsia.

 

Low Ratio to Rule Out Preeclampsia ‘Reassuring’

The high reliability in ruling out preeclampsia in this subset of patients with a low sFlt-1/PlGF ratio is “reassuring,” Wise said, and suggests that these patients are “relatively safe moving forward,” given regular follow-up.

In the small group of patients with proteinuria (n = 16), 44% ultimately developed preeclampsia. One third of patients with sFlt-1/PlGF ≤ 38 developed preeclampsia in 8 weeks, and half experienced preeclampsia at some point during their pregnancy. Among the patients with sFlt-1:PlGF ≥ 85, 56% developed preeclampsia during their pregnancy.

“The negative predictive values are not really great, and the positive predictive values are not really very useful,” Clowse said. For a pregnant patient with proteinuria, “I don’t think that a high [ratio] is going to tell us that she definitely has preeclampsia today or tomorrow. I also am not convinced yet that a low [ratio] tells us that she’s out of the woods. So, I think we definitely need more research on what to do with this test in patients with proteinuria.”

Clowse is a consultant and has received research support/grants from GSK and UCB. She also reported consulting for AstraZeneca. Wise is a consultant for Aurinia Pharmaceuticals and has received honoraria from AstraZeneca, Aurinia Pharmaceuticals, and GSK.

A version of this article first appeared on Medscape.com.

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

WASHINGTON — Patients with granulomatosis with polyangiitis (GPA) completely tapered off prednisone have a more than fourfold risk of relapse by 6 months, compared with those tapered to 5 mg/day of prednisone; however, this benefit was only seen in patients not on rituximab, according to new research presented at the annual meeting of the American College of Rheumatology (ACR).

“For patients treated with rituximab, fully tapering off glucocorticoids is reasonable to consider as the first approach,” said Peter Merkel, MD, MPH, chief of the division of rheumatology at the University of Pennsylvania, Philadelphia, during his presentation of the findings.

Although a low dose of glucocorticoids can prevent some minor relapses in patients on other treatment regimens such as methotrexate or azathioprine, “fully tapering off prednisone presents relatively little risk of major relapse, and that major relapse can be treated rather quickly,” Merkel added.

The Assessment of Prednisone in Remission (TAPIR) trial enrolled 143 patients with GPA who were in remission (defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis [BVAS/WG] of 0) within 1 year of treatment to induce remission for active disease and who were taking 5-10 mg of prednisone per day. After all patients tapered to 5 mg/day of prednisone, 71 patients completely tapered off prednisone over 4 weeks and remained off glucocorticoids until month 6. The remaining patients maintained a 5-mg/day dose over the study period. Placement in either treatment group was randomized, and patients continued other immunosuppressive therapy during the study.

Researchers evaluated the rate of relapse by 6 months, defined as a physician’s decision to increase the dose of glucocorticoids to treat GPA, in both groups.

Across all participants, the median age was 58 years, and 52% of patients were male. Most patients were White, and 47% of all patients were prescribed rituximab. 

At 6 months, 15.5% of participants who completely tapered off prednisone experienced a relapse of GPA, compared with 4.2% of those taking low-dose prednisone. Time to relapse was also shorter in the 0-mg prednisone group (P = .026), and relapses occurred continually over 6 months, Merkel said.

When stratified by rituximab use, relapse rates at 6 months between the 5-mg and 0-mg prednisone groups in patients taking rituximab showed no difference. Among patients not taking rituximab, those who completely stopped prednisone were nine and a half times as likely to experience relapse as those in the low-dose group. 

Despite these differences in relapse rates, “surprisingly, there were no differences in patient-reported outcomes [such as pain interference, physical function, and fatigue],” Merkel said. 

Across all patients, all but one relapse was characterized as minor. There were five serious adverse events and 10 infections in the 0-mg group versus one adverse event and 4 infections in the 5-mg group, but these differences were not statistically significant. 

In patients who relapsed, musculoskeletal and ear, nose, and throat manifestations of GPA were most common, and these are “the kind of stuff we see that is helped by low-dose glucocorticoids,” Merkel said.

It’s a good sign that for patients who were completely weaned off glucocorticoids, nearly all relapses were minor, Galina Marder, MD, a rheumatologist and associate professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, said in an interview. She was not involved with the research. 

The study “can reinforce the message [of] trying to get them off steroids completely [when possible],” she said.

The findings also provide insight for future clinical trials, Merkel noted. For patients taking non–rituximab-based regimens, completely tapering off glucocorticoids or maintaining a low dose can affect study outcomes.

“[These data are] even more important for clinical trials because they are [reinforcing] the fact that you can have a diminishing signal if you allow some patients to stay on 5 mg prednisone” when GPA flares are the primary outcome, Marder added.

The Vasculitis Clinical Research Consortium received funding for this research through grants from the National Institutes of Health. Merkel has disclosed financial relationships with AbbVie/Abbott, Amgen, argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, ChemoCentryx, CSL Behring, Dynacure, Eicos, Electra, EMD Serono, Forbius, Genentech/Roche, Genzyme/Sanofi, GSK, HI-Bio, Inmagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sanofi, Sparrow, Takeda, Talaris, UpToDate, and Visterra. Marder consults for Amgen and Boehringer Ingelheim.

A version of this article first appeared on Medscape.com.

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

A version of this article first appeared on Medscape.com.

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

A version of this article first appeared on Medscape.com.

WASHINGTON — The B cell–depleting agent inebilizumab (Uplizna) dramatically reduced the risk of flares and increased year-long remission of IgG4-related disease (RD), new research has found.

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial of 135 adults with active IgG4-RD, treatment with inebilizumab resulted in a significant 87% reduction in flare risk and nearly fivefold greater likelihood of flare-free remission at 1 year. The results were published online November 14 in The New England Journal of Medicine and were presented at the annual meeting of the American College of Rheumatology (ACR).

The drug’s manufacturer, Amgen, released top-line results of the trial, called MITIGATE, in June 2024.

 

Until now, the mainstay of management for the chronic multiorgan disease IgG4-RD has been glucocorticoids, which can cause numerous adverse effects. “It is hoped that inebilizumab can be used as an important steroid-sparing medication in this disease to reduce steroid toxicity,” lead author John H. Stone, MD, professor of medicine at Harvard Medical School, Boston, Massachusetts, said in an interview, noting that it may not entirely eliminate the need for steroid treatment, but for many, it appears to work after the remission induction period as a monotherapy without steroids. 

Asked to comment, Leonard H. Calabrese, DO, head of the Section of Clinical Immunology and manager of the Clinical Immunology Clinic at the Cleveland Clinic, Ohio, said: “There has been anecdotal or observational evidence for some effect with other immunosuppressive agents, including rituximab, but no robust clinical trial until this study. This clearly has demonstrated efficacy by reducing the risk of flares. And most importantly, putting people into remission means no active disease in any given organ. ... This gives us another tool in the toolbox to attack B cell–directed diseases, and I think it really makes a lot of sense.”

Calabrese cautioned, though, that “this is a disease that extends over many years. This is just a 1-year study. Label extensions will be important.”

 

And several questions remain, Calabrese noted: “How long do patients need to remain on drug? What will happen when the drug is stopped? Can they be retreated? These are the natural questions that arise in any sentinel study like this. But this is extremely encouraging. And I think it’s great for patients. I also think it’s a clarion call to increase awareness about this disease since there’s now strong evidence of effective treatment.” 

 

Underrecognized, Often Misdiagnosed as Cancer

Indeed, IgG4-RD, a chronic, relapsing, autoimmune, fibro-inflammatory multiorgan disease, was only first described in Japan in 2003. Since then, it has been reported all over the world yet remains vastly underrecognized. It is often misdiagnosed as cancer because it produces lesions in multiple organs. It received an ICD-10 code only about a year ago. A previous study estimated a prevalence of about 5.3 persons per 100,000 but that is likely to be a three- to fourfold underestimate, said Stone, who is also executive chairman of the IgG4ward! Foundation. 

“Nobody had heard of the disease until about 20 years ago. ... And there are many people in the world who have still not heard of it despite the fact that it is a multiorgan autoimmune disease and is probably as common, or more common, than many other diseases that rheumatologists spend a lot of time thinking about, such as scleroderma.”

While knowledge about the disease is increasing in rheumatology circles, it’s less well-recognized among many of the specialties where patients present, depending on the location of their lesions. These include gastroenterology, ophthalmology, pulmonary medicine, neurology, and nephrology. “All would be likely to see this disease,” Stone said. 

The disease can be mistaken for tumors in many of those locations and even as metastatic cancer, he noted, adding that “any time a patient has a mass lesion in a typical organ, the pancreas, the major salivary glands, the lungs, or the kidneys, this should be on the differential diagnosis.” 

The diagnosis of IgG4-RD is a clinical one, involving “quadrangulation between clinical features, serological findings, IgG4 levels in the blood, radiology studies, and then pathology biopsies when those are available,” Stone said. 

Calabrese characterized the current situation as “we’re all blind men on the elephant. To the neurologist or the neurosurgeon, it’s a mass in the brain. It could present to the ophthalmologist as an [eye] tumor. It can be thyroid gland failure, pulmonary disease, retroperitoneal fibrosis, hepatobiliary disease, and beyond. So, whoever sees that patient, there’s often a long lag time in recognizing it.”

And interestingly, Stone noted that unlike other autoimmune diseases, IgG4-RD primarily affects middle-aged men rather than younger-to-middle-aged women. And when IgG4-RD is diagnosed, glucocorticoid treatment can be particularly toxic when the pancreas is involved, heightening the risk for hyperglycemia and potentially causing diabetes. 

 

Dramatic Improvement in Flares, Remission Achievement

MITIGATE is a phase 3, multicenter, double-blind, randomized, placebo-controlled trial in which 135 adults (mean age 58.2 years, 88 men) with active IgG4-RD were randomized 1:1 to receive 300-mg intravenous infusions of inebilizumab or placebo on days 1 and 15, and again at week 26. At baseline, 62 (45.9%) participants had newly diagnosed IgG4-RD and 73 (54.1%) had recurrent disease. 

Both groups received identical glucocorticoid tapers. Overall, 127 (94.1%) completed the 52 weeks of treatment. 

By 52 weeks, only seven patients in the inebilizumab group (10%) had experienced disease flares vs 40 (60%) in the placebo group, a significant difference with a hazard ratio of 0.13 (P < .001). 

The percentage of participants achieving flare-free, treatment-free complete remission was 59 with inebilizumab (57%), compared with just 15 (22%) in the placebo group (odds ratio [OR], 4.68; P < .001). And for flare-free, glucocorticoid-free complete remission, those proportions were 40 (59%) vs 15 (22%), respectively (OR, 4.96; P < .001). 

Excluding the 8-week glucocorticoid taper period, mean total glucocorticoid use was 1264.2 mg less in the inebilizumab than the placebo group, a significant reduction. Overall, 61 participants (90%) were able to entirely discontinue glucocorticoids during the trial, compared with just 25 (37%) in the placebo group. 

Adverse events of grade 3 or higher occurred in 12 participants (18%) in the inebilizumab group and 8 (12%) in the placebo group; serious adverse events occurred in 12 (18%) and 6 (9%), respectively. However, no serious adverse event occurred in more than one participant, and there were no deaths. Adverse events led to withdrawal from the trial in six patients (9%) in the inebilizumab group and three patients (4%) in the placebo group. 

Adverse events that occurred in more than 10% of participants in the inebilizumab group were COVID-19 in 16 participants (24%), lymphopenia in 11 (16%), and urinary tract infection in 8 (12%). 

Importantly, Stone noted, B-cell depletion can reduce responses to vaccines, so patients should receive all recommended vaccinations, including COVID-19, influenza, respiratory syncytial virus, and others, prior to initiating therapy. 

Uplizna (inebilizumab-cdon) was approved by the Food and Drug Administration (FDA) for the treatment of neuromyelitis optica spectrum disorder in 2020. In October 2024, the FDA granted Amgen breakthrough therapy designation for use in IgG4-RD. The company is also developing the drug for use in myasthenia gravis.

The study was funded by Amgen. Stone has reported being a consultant for Amgen, Zenas, Argenx, Bristol Myers Squibb, Novartis, Sanofi, and Horizon Pharma. Calabrese has reported being a consultant and/or speaker for Amgen, AstraZeneca, Jansen, Sanofi, and UCB.

A version of this article first appeared on Medscape.com.