Lupus & Connective Tissue Diseases

The heterogeneity of lupus and the subsequent lack of a clear disease definition have been identified by an international group of experts as the primary barriers hindering timely diagnosis, improved treatment options, and appropriate access to care.

A report published in Lupus Science & Medicine titled “Global Consensus Building and Prioritization of Fundamental Lupus Challenges: The ALPHA Project” describes the results of a first-ever global consensus on key barriers to advances in lupus care, including a lack of validated biomarkers and flawed clinical trial design.

A lack of access to medical professionals familiar with lupus, challenges in managing lupus because of social determinants, and lack of treatment adherence were also considered to be barriers to improving the outcomes of people living with lupus.

First author Susan Manzi, MD, codirector of the Lupus Center of Excellence at Allegheny Health Network, Pittsburgh, and her colleagues said that, in contrast to other autoimmune diseases such as rheumatoid arthritis and psoriasis, the field of lupus has struggled with establishing a clear pathway for lupus drug development because of “persistent challenges in understanding the biology of the disease, defining clinical trial entry criteria and end points, developing instruments to measure changes in clinical activity, and controlling background medications.”

The authors noted that the intention of the Addressing Lupus Pillars for Health Advancement (ALPHA) Project was to build on the work of other initiatives, including some that were international in scope or were still ongoing.

“The ALPHA project was founded as the first step in an ongoing commitment to identify, prioritize, and implement strategies to address the most pressing challenges that limit progress in lupus across the continuum,” they wrote. In a joint initiative, the Lupus Foundation of America (LFA) and the Tufts Center for the Study of Drug Development (Tufts CSDD) set up a Global Advisory Committee (GAC) that included 13 lupus experts from the United States, Australia, United Kingdom, Germany, and South Korea to guide and oversee the study. Members had extensive knowledge of the disease, with specific expertise in rheumatology, dermatology, immunology, nephrology, and pediatrics.

Next, in-depth interviews were conducted with 17 experts who were well respected in the lupus scientific and care communities and represented all stakeholders. Using information garnered from these interviews, the LFA, Tufts CSDD, and GAC collaborated to develop a survey that included 23 questions addressing attitudes and perceptions about lupus as well as the prioritization of the most pressing challenges to improving diagnosis, care, treatment, and research.

The online survey was sent to 366 candidates, from whom the researchers received 127 completed responses. Of these, 82 (65%) were clinician-researcher-scientists and 14 (11%) worked in industry/biotechnology, 13 (10%) were researcher-scientists, and 12 (9%) were clinicians; 5% marked “other.”

The research team used a weighting system to prioritize barriers ranked by respondents, whereby higher ratings represented the challenges of highest impact (a score of 9 was highest rating, with 1 the lowest).

Survey respondents ranked the following as the top barriers to improving outcomes in lupus:
 

• A lack of diagnostic, predictive, and prognostic biomarkers for lupus (weighted prioritization score of 7.294) and lack of biomarkers to predict drug response in clinical trials (weighted prioritization score of 6.614).
• Flawed clinical trial design (weighted prioritization score of 6.370).
• Lack of access to clinicians familiar with lupus (weighted prioritization score of 6.873), and limited awareness of lupus among nonexpert medical professionals (weighted prioritization score of 5.800).
• Barriers to effective management of lupus because of social determinants of care in predominantly lower socioeconomic status areas (weighted prioritization score of 6.937).
• A lack of treatment adherence (weighted prioritization score of 6.717).

“A strong consensus built throughout the study, as themes and insights gathered from the in-depth interviews were highly consistent with those collected in the survey,” the researchers noted.

They said it was not surprising that the development of biomarkers had received a high ranking, as advances in this area would help accelerate drug development and precision medicine as well as more practical aspects of clinical care.

The research team acknowledged that substantial funds would be needed to address the top priorities identified in the study, and some of the issues may be more easily addressed than others.

“In the past decade, the overall funding landscape for lupus has been on a decline, particularly through the National Institutes of Health – the largest public funder of lupus research in the world – during a time in which arguably, lupus research has been prolific,” they wrote.

They concluded that comprehensive measures were needed to transform the lupus research and health care landscape.

“Lupus experts must convene to determine feasible and coordinated approaches for addressing long-standing barriers across the global lupus community,” they stressed.

The next part of the project will involve an international stakeholder meeting to develop a global road map of specific recommendations to address identified barriers, which “may include multipronged strategies using regulatory and advocacy approaches, scientific consensus building, communication efforts, among other possible tactics,” they added.

The ALPHA Project was launched in partnership with founding partner EMD Serono Research & Development (a business of Merck KGaA) and through additional support by GlaxoSmithKline. Many authors of the report had financial connections to the pharmaceutical industry.

SOURCE: Manzi S et al. Lupus Sci Med. 2019;6:e000342. doi: 10.1136/lupus-2019-000342.

The heterogeneity of lupus and the subsequent lack of a clear disease definition have been identified by an international group of experts as the primary barriers hindering timely diagnosis, improved treatment options, and appropriate access to care.

A report published in Lupus Science & Medicine titled “Global Consensus Building and Prioritization of Fundamental Lupus Challenges: The ALPHA Project” describes the results of a first-ever global consensus on key barriers to advances in lupus care, including a lack of validated biomarkers and flawed clinical trial design.

A lack of access to medical professionals familiar with lupus, challenges in managing lupus because of social determinants, and lack of treatment adherence were also considered to be barriers to improving the outcomes of people living with lupus.

First author Susan Manzi, MD, codirector of the Lupus Center of Excellence at Allegheny Health Network, Pittsburgh, and her colleagues said that, in contrast to other autoimmune diseases such as rheumatoid arthritis and psoriasis, the field of lupus has struggled with establishing a clear pathway for lupus drug development because of “persistent challenges in understanding the biology of the disease, defining clinical trial entry criteria and end points, developing instruments to measure changes in clinical activity, and controlling background medications.”

The authors noted that the intention of the Addressing Lupus Pillars for Health Advancement (ALPHA) Project was to build on the work of other initiatives, including some that were international in scope or were still ongoing.

“The ALPHA project was founded as the first step in an ongoing commitment to identify, prioritize, and implement strategies to address the most pressing challenges that limit progress in lupus across the continuum,” they wrote. In a joint initiative, the Lupus Foundation of America (LFA) and the Tufts Center for the Study of Drug Development (Tufts CSDD) set up a Global Advisory Committee (GAC) that included 13 lupus experts from the United States, Australia, United Kingdom, Germany, and South Korea to guide and oversee the study. Members had extensive knowledge of the disease, with specific expertise in rheumatology, dermatology, immunology, nephrology, and pediatrics.

Next, in-depth interviews were conducted with 17 experts who were well respected in the lupus scientific and care communities and represented all stakeholders. Using information garnered from these interviews, the LFA, Tufts CSDD, and GAC collaborated to develop a survey that included 23 questions addressing attitudes and perceptions about lupus as well as the prioritization of the most pressing challenges to improving diagnosis, care, treatment, and research.

The online survey was sent to 366 candidates, from whom the researchers received 127 completed responses. Of these, 82 (65%) were clinician-researcher-scientists and 14 (11%) worked in industry/biotechnology, 13 (10%) were researcher-scientists, and 12 (9%) were clinicians; 5% marked “other.”

The research team used a weighting system to prioritize barriers ranked by respondents, whereby higher ratings represented the challenges of highest impact (a score of 9 was highest rating, with 1 the lowest).

Survey respondents ranked the following as the top barriers to improving outcomes in lupus:
 

• A lack of diagnostic, predictive, and prognostic biomarkers for lupus (weighted prioritization score of 7.294) and lack of biomarkers to predict drug response in clinical trials (weighted prioritization score of 6.614).
• Flawed clinical trial design (weighted prioritization score of 6.370).
• Lack of access to clinicians familiar with lupus (weighted prioritization score of 6.873), and limited awareness of lupus among nonexpert medical professionals (weighted prioritization score of 5.800).
• Barriers to effective management of lupus because of social determinants of care in predominantly lower socioeconomic status areas (weighted prioritization score of 6.937).
• A lack of treatment adherence (weighted prioritization score of 6.717).

“A strong consensus built throughout the study, as themes and insights gathered from the in-depth interviews were highly consistent with those collected in the survey,” the researchers noted.

They said it was not surprising that the development of biomarkers had received a high ranking, as advances in this area would help accelerate drug development and precision medicine as well as more practical aspects of clinical care.

The research team acknowledged that substantial funds would be needed to address the top priorities identified in the study, and some of the issues may be more easily addressed than others.

“In the past decade, the overall funding landscape for lupus has been on a decline, particularly through the National Institutes of Health – the largest public funder of lupus research in the world – during a time in which arguably, lupus research has been prolific,” they wrote.

They concluded that comprehensive measures were needed to transform the lupus research and health care landscape.

“Lupus experts must convene to determine feasible and coordinated approaches for addressing long-standing barriers across the global lupus community,” they stressed.

The next part of the project will involve an international stakeholder meeting to develop a global road map of specific recommendations to address identified barriers, which “may include multipronged strategies using regulatory and advocacy approaches, scientific consensus building, communication efforts, among other possible tactics,” they added.

The ALPHA Project was launched in partnership with founding partner EMD Serono Research & Development (a business of Merck KGaA) and through additional support by GlaxoSmithKline. Many authors of the report had financial connections to the pharmaceutical industry.

SOURCE: Manzi S et al. Lupus Sci Med. 2019;6:e000342. doi: 10.1136/lupus-2019-000342.

The heterogeneity of lupus and the subsequent lack of a clear disease definition have been identified by an international group of experts as the primary barriers hindering timely diagnosis, improved treatment options, and appropriate access to care.

A report published in Lupus Science & Medicine titled “Global Consensus Building and Prioritization of Fundamental Lupus Challenges: The ALPHA Project” describes the results of a first-ever global consensus on key barriers to advances in lupus care, including a lack of validated biomarkers and flawed clinical trial design.

A lack of access to medical professionals familiar with lupus, challenges in managing lupus because of social determinants, and lack of treatment adherence were also considered to be barriers to improving the outcomes of people living with lupus.

First author Susan Manzi, MD, codirector of the Lupus Center of Excellence at Allegheny Health Network, Pittsburgh, and her colleagues said that, in contrast to other autoimmune diseases such as rheumatoid arthritis and psoriasis, the field of lupus has struggled with establishing a clear pathway for lupus drug development because of “persistent challenges in understanding the biology of the disease, defining clinical trial entry criteria and end points, developing instruments to measure changes in clinical activity, and controlling background medications.”

The authors noted that the intention of the Addressing Lupus Pillars for Health Advancement (ALPHA) Project was to build on the work of other initiatives, including some that were international in scope or were still ongoing.

“The ALPHA project was founded as the first step in an ongoing commitment to identify, prioritize, and implement strategies to address the most pressing challenges that limit progress in lupus across the continuum,” they wrote. In a joint initiative, the Lupus Foundation of America (LFA) and the Tufts Center for the Study of Drug Development (Tufts CSDD) set up a Global Advisory Committee (GAC) that included 13 lupus experts from the United States, Australia, United Kingdom, Germany, and South Korea to guide and oversee the study. Members had extensive knowledge of the disease, with specific expertise in rheumatology, dermatology, immunology, nephrology, and pediatrics.

Next, in-depth interviews were conducted with 17 experts who were well respected in the lupus scientific and care communities and represented all stakeholders. Using information garnered from these interviews, the LFA, Tufts CSDD, and GAC collaborated to develop a survey that included 23 questions addressing attitudes and perceptions about lupus as well as the prioritization of the most pressing challenges to improving diagnosis, care, treatment, and research.

The online survey was sent to 366 candidates, from whom the researchers received 127 completed responses. Of these, 82 (65%) were clinician-researcher-scientists and 14 (11%) worked in industry/biotechnology, 13 (10%) were researcher-scientists, and 12 (9%) were clinicians; 5% marked “other.”

The research team used a weighting system to prioritize barriers ranked by respondents, whereby higher ratings represented the challenges of highest impact (a score of 9 was highest rating, with 1 the lowest).

Survey respondents ranked the following as the top barriers to improving outcomes in lupus:
 

• A lack of diagnostic, predictive, and prognostic biomarkers for lupus (weighted prioritization score of 7.294) and lack of biomarkers to predict drug response in clinical trials (weighted prioritization score of 6.614).
• Flawed clinical trial design (weighted prioritization score of 6.370).
• Lack of access to clinicians familiar with lupus (weighted prioritization score of 6.873), and limited awareness of lupus among nonexpert medical professionals (weighted prioritization score of 5.800).
• Barriers to effective management of lupus because of social determinants of care in predominantly lower socioeconomic status areas (weighted prioritization score of 6.937).
• A lack of treatment adherence (weighted prioritization score of 6.717).

“A strong consensus built throughout the study, as themes and insights gathered from the in-depth interviews were highly consistent with those collected in the survey,” the researchers noted.

They said it was not surprising that the development of biomarkers had received a high ranking, as advances in this area would help accelerate drug development and precision medicine as well as more practical aspects of clinical care.

The research team acknowledged that substantial funds would be needed to address the top priorities identified in the study, and some of the issues may be more easily addressed than others.

“In the past decade, the overall funding landscape for lupus has been on a decline, particularly through the National Institutes of Health – the largest public funder of lupus research in the world – during a time in which arguably, lupus research has been prolific,” they wrote.

They concluded that comprehensive measures were needed to transform the lupus research and health care landscape.

“Lupus experts must convene to determine feasible and coordinated approaches for addressing long-standing barriers across the global lupus community,” they stressed.

The next part of the project will involve an international stakeholder meeting to develop a global road map of specific recommendations to address identified barriers, which “may include multipronged strategies using regulatory and advocacy approaches, scientific consensus building, communication efforts, among other possible tactics,” they added.

The ALPHA Project was launched in partnership with founding partner EMD Serono Research & Development (a business of Merck KGaA) and through additional support by GlaxoSmithKline. Many authors of the report had financial connections to the pharmaceutical industry.

SOURCE: Manzi S et al. Lupus Sci Med. 2019;6:e000342. doi: 10.1136/lupus-2019-000342.

MILAN – A novel synthetic cannabinoid helped reduce the severity of dermatomyositis and improved patient-reported outcomes in early clinical trials, according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.

Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.

Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.

In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.

Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.

However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.

Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.

Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.

“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.

Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.

[email protected]

MILAN – A novel synthetic cannabinoid helped reduce the severity of dermatomyositis and improved patient-reported outcomes in early clinical trials, according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.

Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.

Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.

In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.

Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.

However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.

Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.

Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.

“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.

Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.

[email protected]

MILAN – A novel synthetic cannabinoid helped reduce the severity of dermatomyositis and improved patient-reported outcomes in early clinical trials, according to Victoria Werth, MD, who presented early-stage findings at the World Congress of Dermatology.

Lenabasum – previously known as anabasum – is a synthetic cannabinoid that binds to the CB2 receptor present on a variety of cells, including lymphocytes, explained Dr. Werth, professor of medicine at the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Administration Hospital. The nonpsychoactive compound’s mechanism of action helps prevent tissue thickening and fibrosis. In addition to its potential for dermatomyositis treatment, it is also being investigated as a treatment for cystic fibrosis, scleroderma, and lupus.

Dr. Werth added that earlier in vitro work with peripheral blood mononuclear cells of patients with dermatomyositis showed that lenabasum markedly suppressed the cells’ secretion of tumor necrosis factor–alpha, interferon-alpha, and interferon-beta (J Invest Dermatol. 2017 Nov;137[11]:2445-7). A randomized, placebo-controlled trial tested lenabasum, known in the trial as JBT-101, in 22 patients with skin-predominant myositis. The study was structured so patients took a half dose of lenabasum for 1 month, followed by 2 months of taking a full dose, and finally 1 month with no lenabasum dosing. Compared with placebo, scores on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) were significantly improved with full dosing of lenabasum (P = .02), Dr. Werth said.

In this 16-week trial, the mean change in CDASI score dropped for participants in both the lenabasum and placebo groups for the first 4 weeks. After that, however, those taking lenabasum saw an improvement of about 8 points from baseline CDASI score at 8 weeks, while those taking placebo had a decline of 3 points (P = .05). The differences remained significant at trial’s end.

Patient-reported outcomes for pain were significantly better with lenabasum, with patients on lenabasum recording a decrease on the Patient-Reported Outcomes Measurement Information System–29 pain interference scale, while patients on placebo reported an increase in pain by the end of the study period (P = .026). Scores on two other patient-reported dermatomyositis scales were numerically improved for patients taking lenabasum, but the differences from the patients on placebo were not statistically significant, Dr. Werth said.

However, patients in the initial clinical trial were given the opportunity to continue in a long-term extension arm, and that group has seen the clinician-rated CDASI scores continue to fall, with a mean decrease of 22 points from baseline (about 12 further points from the mean for those on lenabasum in the initial trial) at the 68-week mark, she added.

Itch scores continued to drop as well, with a reduction of 3.7 points on the 5-D Itch scale by 68 weeks; at 16 weeks, the reduction for the lenabasum arm had been 1.3 points.

Skin samples taken from trial participants showed many fewer CD4 cells in those taking lenabasum, compared with placebo at week 12 of the initial study. Interferon-beta and -gamma levels also dropped in those taking lenabasum, but not in the placebo arm.

“Lenabasum has effects on cytokine signatures and inflammatory cells correlating with response to therapy,” Dr. Werth said, adding that the findings gave support for a planned global phase 3 clinical trial of lenabasum in dermatomyositis.

Dr. Werth reported receiving grants from Pfizer and Corbus, and consulting fees from Pfizer, Janssen, Neovacs, Idera Pharmaceuticals, Octapharma, CSL Behring, and Corbus Pharmaceuticals. The study was funded by Corbus, the National Institutes of Health, and the University of Pennsylvania.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.

FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.

The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.


Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.

“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.

[email protected]

The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.

FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.

The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.


Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.

“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.

[email protected]

The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.

FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.

The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.


Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.

“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.

[email protected]

MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).

Sara Freeman/MDEdge News

Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.

The recommendations, which are the first evidence-based guidelines for adult APS to be produced by EULAR, also cover the secondary prevention of APS and how to manage individuals with recurrent episodes.

The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.

The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”

Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.

The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.

Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.

“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.

Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.

Sara Freeman/MDEdge News

With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.

Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
 

New treatment guidelines for catastrophic APS

During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.

The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.

The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.

“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”

The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.

SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.

MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).

Sara Freeman/MDEdge News

Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.

The recommendations, which are the first evidence-based guidelines for adult APS to be produced by EULAR, also cover the secondary prevention of APS and how to manage individuals with recurrent episodes.

The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.

The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”

Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.

The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.

Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.

“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.

Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.

Sara Freeman/MDEdge News

With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.

Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
 

New treatment guidelines for catastrophic APS

During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.

The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.

The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.

“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”

The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.

SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.

MADRID – Low-dose aspirin is recommended for the primary prevention of antiphospholipid syndrome (APS) in patients at high risk for developing the condition, according to new recommendations developed by the European League Against Rheumatism (EULAR).

Sara Freeman/MDEdge News

Indeed, the NSAID should be given at a dose of between 75 mg and 100 mg per day, in patients with a “high risk” antiphospholipid (aPL) antibody profile, including asymptomatic aPL antibody carriers, patients with systemic lupus erythematosus (SLE) without APS, and in women who are not pregnant but who have a history of obstetric APS.

The recommendations, which are the first evidence-based guidelines for adult APS to be produced by EULAR, also cover the secondary prevention of APS and how to manage individuals with recurrent episodes.

The recommendations aim to help guide practice and ultimately to improve the quality of care for patients and their outcomes following treatment, Maria G. Tektonidou, MD, PhD, said at the European Congress of Rheumatology.

The guidance is necessary as “clinical practice in APS remains highly variable,” said Dr. Tektonidou of the National and Kapodistrian University of Athens. This is perhaps because APS is a “rare disease and also because it’s a newly recognized disease – it’s only 35 years old – and knowledge about the clinical spectrum, classification, and management is continuously advancing.”

Dr. Tektonidou, who was the convener of the EULAR Task Force that wrote the recommendations, noted that they were now published in Annals of the Rheumatic Diseases and considered three main groups of patients: those with thrombotic APS, those with obstetric APS, and those with catastrophic APS (CAPS). There are three overarching principles, 12 recommendations, and 29 graded statements, she said.

The three overarching principles concerned risk stratification, general measures for managing patients who test positive for aPL antibodies, and patient education and counseling on various topics, such as treatment adherence, therapeutic drug monitoring, contraceptive use, and lifestyle interventions.

Dr. Tektonidou highlighted how risk stratification was important and that a high-risk aPL profile was defined as the presence of lupus anticoagulant (LA) on at least two occasions, measured 12 weeks apart according to International Society on Thrombosis and Haemostasis guidelines, or the presence of two or even three aPL antibodies, or persistently high aPL antibody titers. By contrast, a low-risk aPL profile was defined as the isolated presence of anticardiolipin (aCL) or anti–beta-2 glycoprotein I antibodies at low-medium titers, particularly if transiently positive.

“Risk stratification should include the determination of the high-risk aPL profile; a prior history of thrombotic or obstetric [APS]; the coexistence of other systemic autoimmune diseases, and the presence of traditional cardiovascular risk factors,” Dr. Tektonidou said.

Four of the recommendations focus on the secondary prevention of APS, giving guidance on anticoagulant treatment with definite APS, first provoked or unprovoked venous thrombosis, and how to manage recurrent venous thrombosis. There also is a recommendation for the management of patients with definite APS and a first arterial thrombosis, outlining the type and intensity of anticoagulant therapy that should be given. Another four of the recommendations focus on the management of obstetric APS, with a focus on how to manage the various types of complications seen in pregnant women. Then the final recommendation concerns CAPS, it’s prevention and first-line treatment, and how to manage refractory patients.

Sara Freeman/MDEdge News

With regards to CAPS, Ricard Cervera, MD, PhD, of the Hospital Clinic of Barcelona, this is “terrible” but “thankfully rare” form of APS that was first described in the early 1990s.

Although fewer than 1% of the APS adult population have CAPS (Arthritis Rheum. 2002;46[4]:1019-27), it’s a condition in which several thrombotic events occur simultaneously, affecting multiple systems or organs and which can be life threatening if not treated quickly.
 

New treatment guidelines for catastrophic APS

During a separate clinical science session at the conference, Dr. Cervera discussed the development of treatment guidelines for CAPS, noting that this had been one of the focus points of the McMaster RARE-Bestpractices project group in 2016. The group selected CAPS for a pilot exercise in guideline development for a rare disease and published their recommendations in 2018 (J Thromb Haemost. 2018;16:1656-64). Ten recommendations were developed, most of which were conditional, Dr. Cervera said, due to the lack of, or very low certainty, of the evidence.

The new EULAR 2019 adult APS recommendations now include CAPS and recommendation number 12 is split into two parts. The first, part A, states that prompt treatment of infections is needed in all patients positive for aPL antibodies and that anticoagulation should have minimal interruption or be used at level to help prevent the development of CAPS.

The second, part B, states that the first-line treatment of CAPS should be a triple combination therapy of glucocorticoids, heparin, and plasma exchange, or intravenous immunoglobulins, rather than single-agent treatment. Plus, it says that any triggering factor should be treated accordingly.

“Finally,” Dr. Cervera said, “in patients with refractory CAPS, B-cell depletion with rituximab or complement inhibitors, for example eculizumab, may be considered.”

The adult APS recommendations project was funded by EULAR. Dr. Tektonidou and Dr. Cervera reported having no relevant conflicts of interest.

SOURCES: Tektonidou M. Ann Rheum Dis. Jun 2019;78(Suppl 2):59-60. Abstract SP0191, doi: 0.1136/annrheumdis-2019-eular.8601; and Cervera R et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):62. Abstract SP0201. doi: 10.1136/annrheumdis-2019-eular.8444.

Pregnancy management and outcomes have improved markedly for women with SLE over the past 2 decades, but there’s still progress to be made, research shows.

A retrospective cohort study led by rheumatologist Bella Mehta, MBBS, of the Hospital for Special Surgery in New York, and colleagues looked at data from the National Inpatient Sample database involving 93,820 pregnant women with SLE and 78,045,054 without SLE who were hospitalized in the United States between 1998 and 2015.

The results showed that over the 18-year study period, in-hospital maternal deaths per 100,000 admissions declined among patients with as well as those without SLE (442 vs. 13 for 1998-2000 and less than 50 vs. 10 for 2013-2015), although the decrease was greater in women with SLE (difference in trends, P less than .002).

Fetal mortality declined both for patients with SLE (268 deaths per 10,000 deliveries in 1998-2000 vs. 153 in 2013-2015) and those without SLE (72 deaths per 10,000 deliveries in 1998-2000 vs. 66 in 2013-2015).

“Although the decrease in fetal mortality seems somewhat greater in patients with SLE than those without it, the difference in trends is not statistically significant (P = .064),” the study authors noted in their paper, published in Annals of Internal Medicine.

Although patients with SLE in their study showed greater progress in rates of preeclampsia or eclampsia and length of stay, they still had worse outcomes in all measures when compared against women without SLE, the authors noted.

“Our study provides nationwide evidence that SLE pregnancy outcomes have become markedly better in the past 2 decades and continue to improve. However, SLE pregnancy risks remain high, and more work is needed to ensure good pregnancy outcomes among women with SLE,” they concluded.

Writing in an accompanying editorial, Megan E.B. Clowse, MD, of Duke University, Durham, N.C., noted that although the study findings of a progressive reduction in maternal mortality seemed very likely, the absolute decrease seen – from 140 maternal deaths per 100,000 births to fewer than 50 in 2013-2015 – warranted some reflection (Ann Intern Med. 2019;171:212-3. doi: 10.7326/M19-1667).

“SLE pregnancy management has not advanced within the past 5 years to an extent great enough to explain such a large drop in mortality,” she wrote.

There were also question marks around whether the NIS data should be used to analyze very rare events, such as maternal deaths in women with SLE. The SLE diagnosis in the database may also have included pregnancies in women who did not have SLE but instead had an elevated level of antinuclear antibody or lupus anticoagulant, which “may have diluted the frequency of poor outcomes,” Dr. Clowse wrote.

“For these reasons, I am concerned that the observed decline in maternal mortality may be an artifact, underestimating the ongoing risk of pregnancy for women with SLE,” Dr. Clowse wrote.

She added that recent analyses demonstrated that the use of hydroxychloroquine and aspirin in SLE pregnancy was not widespread.

“The inaugural reproductive health guidelines soon to be published by the American College of Rheumatology will have the potential to help expand state-of-the-art approaches to the management of pregnant women with SLE seen in everyday practice,” she concluded.

The study had no primary funding source and no conflicts of interest were declared. Dr. Mehta is supported by the C. Ronald MacKenzie Young Scientist Endowment Award. Dr. Clowse reported grants from GlaxoSmithKline and personal fees from UCB, both outside the submitted work.

SOURCE: Mehta B et al. Ann Intern Med. 2019;171:164-71. doi: 10.7326/M19-0120.

Pregnancy management and outcomes have improved markedly for women with SLE over the past 2 decades, but there’s still progress to be made, research shows.

A retrospective cohort study led by rheumatologist Bella Mehta, MBBS, of the Hospital for Special Surgery in New York, and colleagues looked at data from the National Inpatient Sample database involving 93,820 pregnant women with SLE and 78,045,054 without SLE who were hospitalized in the United States between 1998 and 2015.

The results showed that over the 18-year study period, in-hospital maternal deaths per 100,000 admissions declined among patients with as well as those without SLE (442 vs. 13 for 1998-2000 and less than 50 vs. 10 for 2013-2015), although the decrease was greater in women with SLE (difference in trends, P less than .002).

Fetal mortality declined both for patients with SLE (268 deaths per 10,000 deliveries in 1998-2000 vs. 153 in 2013-2015) and those without SLE (72 deaths per 10,000 deliveries in 1998-2000 vs. 66 in 2013-2015).

“Although the decrease in fetal mortality seems somewhat greater in patients with SLE than those without it, the difference in trends is not statistically significant (P = .064),” the study authors noted in their paper, published in Annals of Internal Medicine.

Although patients with SLE in their study showed greater progress in rates of preeclampsia or eclampsia and length of stay, they still had worse outcomes in all measures when compared against women without SLE, the authors noted.

“Our study provides nationwide evidence that SLE pregnancy outcomes have become markedly better in the past 2 decades and continue to improve. However, SLE pregnancy risks remain high, and more work is needed to ensure good pregnancy outcomes among women with SLE,” they concluded.

Writing in an accompanying editorial, Megan E.B. Clowse, MD, of Duke University, Durham, N.C., noted that although the study findings of a progressive reduction in maternal mortality seemed very likely, the absolute decrease seen – from 140 maternal deaths per 100,000 births to fewer than 50 in 2013-2015 – warranted some reflection (Ann Intern Med. 2019;171:212-3. doi: 10.7326/M19-1667).

“SLE pregnancy management has not advanced within the past 5 years to an extent great enough to explain such a large drop in mortality,” she wrote.

There were also question marks around whether the NIS data should be used to analyze very rare events, such as maternal deaths in women with SLE. The SLE diagnosis in the database may also have included pregnancies in women who did not have SLE but instead had an elevated level of antinuclear antibody or lupus anticoagulant, which “may have diluted the frequency of poor outcomes,” Dr. Clowse wrote.

“For these reasons, I am concerned that the observed decline in maternal mortality may be an artifact, underestimating the ongoing risk of pregnancy for women with SLE,” Dr. Clowse wrote.

She added that recent analyses demonstrated that the use of hydroxychloroquine and aspirin in SLE pregnancy was not widespread.

“The inaugural reproductive health guidelines soon to be published by the American College of Rheumatology will have the potential to help expand state-of-the-art approaches to the management of pregnant women with SLE seen in everyday practice,” she concluded.

The study had no primary funding source and no conflicts of interest were declared. Dr. Mehta is supported by the C. Ronald MacKenzie Young Scientist Endowment Award. Dr. Clowse reported grants from GlaxoSmithKline and personal fees from UCB, both outside the submitted work.

SOURCE: Mehta B et al. Ann Intern Med. 2019;171:164-71. doi: 10.7326/M19-0120.

Pregnancy management and outcomes have improved markedly for women with SLE over the past 2 decades, but there’s still progress to be made, research shows.

A retrospective cohort study led by rheumatologist Bella Mehta, MBBS, of the Hospital for Special Surgery in New York, and colleagues looked at data from the National Inpatient Sample database involving 93,820 pregnant women with SLE and 78,045,054 without SLE who were hospitalized in the United States between 1998 and 2015.

The results showed that over the 18-year study period, in-hospital maternal deaths per 100,000 admissions declined among patients with as well as those without SLE (442 vs. 13 for 1998-2000 and less than 50 vs. 10 for 2013-2015), although the decrease was greater in women with SLE (difference in trends, P less than .002).

Fetal mortality declined both for patients with SLE (268 deaths per 10,000 deliveries in 1998-2000 vs. 153 in 2013-2015) and those without SLE (72 deaths per 10,000 deliveries in 1998-2000 vs. 66 in 2013-2015).

“Although the decrease in fetal mortality seems somewhat greater in patients with SLE than those without it, the difference in trends is not statistically significant (P = .064),” the study authors noted in their paper, published in Annals of Internal Medicine.

Although patients with SLE in their study showed greater progress in rates of preeclampsia or eclampsia and length of stay, they still had worse outcomes in all measures when compared against women without SLE, the authors noted.

“Our study provides nationwide evidence that SLE pregnancy outcomes have become markedly better in the past 2 decades and continue to improve. However, SLE pregnancy risks remain high, and more work is needed to ensure good pregnancy outcomes among women with SLE,” they concluded.

Writing in an accompanying editorial, Megan E.B. Clowse, MD, of Duke University, Durham, N.C., noted that although the study findings of a progressive reduction in maternal mortality seemed very likely, the absolute decrease seen – from 140 maternal deaths per 100,000 births to fewer than 50 in 2013-2015 – warranted some reflection (Ann Intern Med. 2019;171:212-3. doi: 10.7326/M19-1667).

“SLE pregnancy management has not advanced within the past 5 years to an extent great enough to explain such a large drop in mortality,” she wrote.

There were also question marks around whether the NIS data should be used to analyze very rare events, such as maternal deaths in women with SLE. The SLE diagnosis in the database may also have included pregnancies in women who did not have SLE but instead had an elevated level of antinuclear antibody or lupus anticoagulant, which “may have diluted the frequency of poor outcomes,” Dr. Clowse wrote.

“For these reasons, I am concerned that the observed decline in maternal mortality may be an artifact, underestimating the ongoing risk of pregnancy for women with SLE,” Dr. Clowse wrote.

She added that recent analyses demonstrated that the use of hydroxychloroquine and aspirin in SLE pregnancy was not widespread.

“The inaugural reproductive health guidelines soon to be published by the American College of Rheumatology will have the potential to help expand state-of-the-art approaches to the management of pregnant women with SLE seen in everyday practice,” she concluded.

The study had no primary funding source and no conflicts of interest were declared. Dr. Mehta is supported by the C. Ronald MacKenzie Young Scientist Endowment Award. Dr. Clowse reported grants from GlaxoSmithKline and personal fees from UCB, both outside the submitted work.

SOURCE: Mehta B et al. Ann Intern Med. 2019;171:164-71. doi: 10.7326/M19-0120.

MADRID – Repeated antinuclear antibody testing after a negative result has limited use for the diagnosis of ANA-associated rheumatologic conditions, according to data from a multicenter, retrospective analysis that considered a 7-year period.

Sara Freeman/MDEdge News

Considering more than 7,875 repeated ANA tests in 4,887 patients, “the vast majority of results didn’t change,” Ai Li Yeo, MBBS, a PhD candidate, rheumatologist, and infectious disease fellow at Monash University, Melbourne, reported at the European Congress of Rheumatology.

ANA tests were repeated between 2 and as many as 45 times in individual patients, she reported, but the results of 79% of these tests remained unchanged – 45% of tests were persistently negative and 34% persistently positive using a cutoff titer of 1:160.

“Our study showed that there was a very low yield in repeating an ANA test for the diagnosis of ANA-associated rheumatological conditions unless there was evidence of evolving multisystem clinical features,” Dr. Yeo said.

Indeed, the positive predictive value was just 0.01. “So for a hundred patients staring off with a negative ANA results that on repeat testing became positive, the probability is that one patient will have a new ANA-associated rheumatological condition diagnosis,” Dr. Yeo said.

“ANA testing is frequently performed and is part of the classification criteria for autoimmune conditions such as lupus and scleroderma,” she observed. However, the test provides no information on the severity or activity of the disease, and the value of serial monitoring for such conditions is unclear.

“Minimizing unnecessary tests is a global health economic priority,” Dr. Yeo said. She noted that there are multiple initiatives in place to try to open a dialog about using health care resources most effectively, such as ‘Choosing Wisely’ set up by the American Board of Internal Medicine (ABIM) Foundation.

The aim of the present analysis was to calculate the cost of repeated ANA testing and to see if any change in the ANA result was associated with new diagnoses of ANA-associated rheumatological conditions.

The analysis considered more than 36,700 tests that were performed on samples from more than 28,800 patients within the Monash Health tertiary health network between 2011 and 2018. Of these, 22,657 (62%) had given a negative result and 14,058 (38%) had given a positive result.

“Not surprisingly, the age of those who tested positive was significantly higher than those who tested negative,” Dr. Yeo said (52.6 vs. 48.9 years; P less than .001). There was also a higher number of women than men tested, and women more often tested positive.

Around one-fifth of tests performed were repeat tests, of which 511 (6.5%) changed from being negative to positive over a median of 1.71 years.

“A small percentage of people alternated between results,” Dr. Yeo acknowledged, with 9.4% of people going from a positive to a negative result; 10.5% moving from a negative to a positive result, and 1.9% going from positive to negative to positive.

With repeated tests, just five new diagnoses of ANA-associated rheumatologic conditions were made: two cases of systemic lupus erythematosus (SLE), one case of scleroderma, and two cases of undifferentiated connective tissue disease. There was a range of ANA titers and patterns and evolving clinical features of a multisystem disease.

Based on the direct costs of ANA testing in her health care system, not performing repeated tests could yield significant savings, Dr. Yeo said, a 21.4% reduction, in fact, based on this analysis. The cost of an ANA test in Australia ranges from 15 to 46 euros, making the cost of all tests in this analysis 564,745 euros. Taking away the cost of all the single ANA tests performed (443,209 euros) gives a potential cost saving of more than 121,000 euros, she said.

“We now have an opportunity to prevent unnecessary ANA testing, Dr. Yeo said. “Ultimately, our aim is to change behavior at the start of the ordering cycle by educating medical students and doctors about inappropriate test ordering.”

The majority of repeated tests had been ordered by nonrheumatologists (82% of cases), and Dr. Yeo said that rheumatologists ordered repeat tests in 11% of cases. However, there was little information available in this retrospective analysis as to why the tests had been repeated.

The research was picked as one of the six best clinical abstracts at the meeting, out of a total of almost 5,000 submitted abstracts.

Dr. Yeo reported having no conflicts of interest.

SOURCE: Yeo AL et al. Ann Rheum Dis. Jun 2019;78(suppl 2):76-7, Abstract OP0020. doi: 10.1136/annrheumdis-2019-eular.4517.

MADRID – Repeated antinuclear antibody testing after a negative result has limited use for the diagnosis of ANA-associated rheumatologic conditions, according to data from a multicenter, retrospective analysis that considered a 7-year period.

Sara Freeman/MDEdge News

Considering more than 7,875 repeated ANA tests in 4,887 patients, “the vast majority of results didn’t change,” Ai Li Yeo, MBBS, a PhD candidate, rheumatologist, and infectious disease fellow at Monash University, Melbourne, reported at the European Congress of Rheumatology.

ANA tests were repeated between 2 and as many as 45 times in individual patients, she reported, but the results of 79% of these tests remained unchanged – 45% of tests were persistently negative and 34% persistently positive using a cutoff titer of 1:160.

“Our study showed that there was a very low yield in repeating an ANA test for the diagnosis of ANA-associated rheumatological conditions unless there was evidence of evolving multisystem clinical features,” Dr. Yeo said.

Indeed, the positive predictive value was just 0.01. “So for a hundred patients staring off with a negative ANA results that on repeat testing became positive, the probability is that one patient will have a new ANA-associated rheumatological condition diagnosis,” Dr. Yeo said.

“ANA testing is frequently performed and is part of the classification criteria for autoimmune conditions such as lupus and scleroderma,” she observed. However, the test provides no information on the severity or activity of the disease, and the value of serial monitoring for such conditions is unclear.

“Minimizing unnecessary tests is a global health economic priority,” Dr. Yeo said. She noted that there are multiple initiatives in place to try to open a dialog about using health care resources most effectively, such as ‘Choosing Wisely’ set up by the American Board of Internal Medicine (ABIM) Foundation.

The aim of the present analysis was to calculate the cost of repeated ANA testing and to see if any change in the ANA result was associated with new diagnoses of ANA-associated rheumatological conditions.

The analysis considered more than 36,700 tests that were performed on samples from more than 28,800 patients within the Monash Health tertiary health network between 2011 and 2018. Of these, 22,657 (62%) had given a negative result and 14,058 (38%) had given a positive result.

“Not surprisingly, the age of those who tested positive was significantly higher than those who tested negative,” Dr. Yeo said (52.6 vs. 48.9 years; P less than .001). There was also a higher number of women than men tested, and women more often tested positive.

Around one-fifth of tests performed were repeat tests, of which 511 (6.5%) changed from being negative to positive over a median of 1.71 years.

“A small percentage of people alternated between results,” Dr. Yeo acknowledged, with 9.4% of people going from a positive to a negative result; 10.5% moving from a negative to a positive result, and 1.9% going from positive to negative to positive.

With repeated tests, just five new diagnoses of ANA-associated rheumatologic conditions were made: two cases of systemic lupus erythematosus (SLE), one case of scleroderma, and two cases of undifferentiated connective tissue disease. There was a range of ANA titers and patterns and evolving clinical features of a multisystem disease.

Based on the direct costs of ANA testing in her health care system, not performing repeated tests could yield significant savings, Dr. Yeo said, a 21.4% reduction, in fact, based on this analysis. The cost of an ANA test in Australia ranges from 15 to 46 euros, making the cost of all tests in this analysis 564,745 euros. Taking away the cost of all the single ANA tests performed (443,209 euros) gives a potential cost saving of more than 121,000 euros, she said.

“We now have an opportunity to prevent unnecessary ANA testing, Dr. Yeo said. “Ultimately, our aim is to change behavior at the start of the ordering cycle by educating medical students and doctors about inappropriate test ordering.”

The majority of repeated tests had been ordered by nonrheumatologists (82% of cases), and Dr. Yeo said that rheumatologists ordered repeat tests in 11% of cases. However, there was little information available in this retrospective analysis as to why the tests had been repeated.

The research was picked as one of the six best clinical abstracts at the meeting, out of a total of almost 5,000 submitted abstracts.

Dr. Yeo reported having no conflicts of interest.

SOURCE: Yeo AL et al. Ann Rheum Dis. Jun 2019;78(suppl 2):76-7, Abstract OP0020. doi: 10.1136/annrheumdis-2019-eular.4517.

MADRID – Repeated antinuclear antibody testing after a negative result has limited use for the diagnosis of ANA-associated rheumatologic conditions, according to data from a multicenter, retrospective analysis that considered a 7-year period.

Sara Freeman/MDEdge News

Considering more than 7,875 repeated ANA tests in 4,887 patients, “the vast majority of results didn’t change,” Ai Li Yeo, MBBS, a PhD candidate, rheumatologist, and infectious disease fellow at Monash University, Melbourne, reported at the European Congress of Rheumatology.

ANA tests were repeated between 2 and as many as 45 times in individual patients, she reported, but the results of 79% of these tests remained unchanged – 45% of tests were persistently negative and 34% persistently positive using a cutoff titer of 1:160.

“Our study showed that there was a very low yield in repeating an ANA test for the diagnosis of ANA-associated rheumatological conditions unless there was evidence of evolving multisystem clinical features,” Dr. Yeo said.

Indeed, the positive predictive value was just 0.01. “So for a hundred patients staring off with a negative ANA results that on repeat testing became positive, the probability is that one patient will have a new ANA-associated rheumatological condition diagnosis,” Dr. Yeo said.

“ANA testing is frequently performed and is part of the classification criteria for autoimmune conditions such as lupus and scleroderma,” she observed. However, the test provides no information on the severity or activity of the disease, and the value of serial monitoring for such conditions is unclear.

“Minimizing unnecessary tests is a global health economic priority,” Dr. Yeo said. She noted that there are multiple initiatives in place to try to open a dialog about using health care resources most effectively, such as ‘Choosing Wisely’ set up by the American Board of Internal Medicine (ABIM) Foundation.

The aim of the present analysis was to calculate the cost of repeated ANA testing and to see if any change in the ANA result was associated with new diagnoses of ANA-associated rheumatological conditions.

The analysis considered more than 36,700 tests that were performed on samples from more than 28,800 patients within the Monash Health tertiary health network between 2011 and 2018. Of these, 22,657 (62%) had given a negative result and 14,058 (38%) had given a positive result.

“Not surprisingly, the age of those who tested positive was significantly higher than those who tested negative,” Dr. Yeo said (52.6 vs. 48.9 years; P less than .001). There was also a higher number of women than men tested, and women more often tested positive.

Around one-fifth of tests performed were repeat tests, of which 511 (6.5%) changed from being negative to positive over a median of 1.71 years.

“A small percentage of people alternated between results,” Dr. Yeo acknowledged, with 9.4% of people going from a positive to a negative result; 10.5% moving from a negative to a positive result, and 1.9% going from positive to negative to positive.

With repeated tests, just five new diagnoses of ANA-associated rheumatologic conditions were made: two cases of systemic lupus erythematosus (SLE), one case of scleroderma, and two cases of undifferentiated connective tissue disease. There was a range of ANA titers and patterns and evolving clinical features of a multisystem disease.

Based on the direct costs of ANA testing in her health care system, not performing repeated tests could yield significant savings, Dr. Yeo said, a 21.4% reduction, in fact, based on this analysis. The cost of an ANA test in Australia ranges from 15 to 46 euros, making the cost of all tests in this analysis 564,745 euros. Taking away the cost of all the single ANA tests performed (443,209 euros) gives a potential cost saving of more than 121,000 euros, she said.

“We now have an opportunity to prevent unnecessary ANA testing, Dr. Yeo said. “Ultimately, our aim is to change behavior at the start of the ordering cycle by educating medical students and doctors about inappropriate test ordering.”

The majority of repeated tests had been ordered by nonrheumatologists (82% of cases), and Dr. Yeo said that rheumatologists ordered repeat tests in 11% of cases. However, there was little information available in this retrospective analysis as to why the tests had been repeated.

The research was picked as one of the six best clinical abstracts at the meeting, out of a total of almost 5,000 submitted abstracts.

Dr. Yeo reported having no conflicts of interest.

SOURCE: Yeo AL et al. Ann Rheum Dis. Jun 2019;78(suppl 2):76-7, Abstract OP0020. doi: 10.1136/annrheumdis-2019-eular.4517.