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Steroids’ 75th Anniversary: Clinicians Strive to Use Less
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
Now, 75 years after the first presentations were made on the “sensational” effects of cortisone in the treatment of rheumatoid arthritis (RA), glucocorticoids (GCs) are still highly relevant and widely used in the management of RA and other immune-mediated inflammatory diseases.
“It makes me smile because this is such an old drug, and we need it still so much. It still hasn’t been replaced,” Josef S. Smolen, MD, observed at annual European Congress of Rheumatology.
At low doses, GCs are highly effective as anti-inflammatory and anti-destructive agents in RA and many other diseases, said Dr. Smolen, a rheumatologist and immunologist and professor emeritus at the Medical University of Vienna, Austria.
But even after all this time, the mechanisms that lead to efficacy vs toxicity have yet to be clarified. “Such separation may provide further insights into future treatment options,” said Dr. Smolen.
His comments, made during a special session on the 75th anniversary of GCs at EULAR 2024, underscore the endless saga to manage GCs while finding better alternatives. Opinions differ on what the research says on toxicity and dosage and whether a long-term, low-dose option is viable. Alternative therapies are being studied, but those endeavors are still in the early stages of development.
While GCs are still used chronically in many patients, clinicians should always attempt to discontinue them whenever possible, Frank Buttgereit, MD, professor of rheumatology and deputy head of the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin, Germany, told attendees at the congress. Up to 60% of patients in registries use GCs, and many patients with early or established RA enter randomized controlled trials on GCs as maintenance therapy.
The ubiquity of GC usage stems in part from overprescribing by non-rheumatologist physicians who might not have access to or aren’t aware of newer biologics or disease-modifying antirheumatic drugs (DMARDs). “We see a lot of patients on long-term glucocorticoids, chronic use for years and years, decades of glucocorticoids,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Italy, who has coauthored several studies on the use of GCs.
Societies Agree: Discontinue as Fast as Possible
GCs have been associated with a long list of adverse events, most notably Cushing syndrome, hypertension, cardiovascular disease, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency (AI), infections, mood disorders, ophthalmologic disorders such as cataracts, skin disorders, menstrual septic necrosis, and pancreatitis.
Dose matters, Dr. Smolen said, citing studies that found that cumulative GC doses of 1000 or 1100 mg increase risks. One study by German researchers found that doses above 10 mg/d significantly raised the hazard ratio for death.
Because high disease activity is also associated with an equally high mortality risk, “we have to balance this out: Active disease vs glucocorticoid use, especially in countries that have less access to modern therapies than we have in the more affluent Western regions,” Dr. Smolen said.
Rheumatology societies generally agree that clinicians should try to minimize GC use or eventually discontinue the therapy.
The American College of Rheumatology recommends not using GCs as part of the first-line treatment of RA. “And if you want to use [them], you should do that for less than 3 months, taper and discontinue as fast as possible, and use the lowest dose possible,” Dr. Adami said.
EULAR’s recommendation is more nuanced in that it allows for a lower dose but gives physicians more choice in how they want to handle GCs, Dr. Adami said. The task force added that all patients should try to taper down or discontinue as fast as possible, he said.
For GCs in the management of systemic lupus erythematosus, a EULAR task force recommended that the type and severity of organ involvement should determine dose, with a long-term goal of maintaining the dose < 5 mg/d or possibly withdrawing it.
EULAR also recommends GC bridging when initiating or changing conventional synthetic (cs) DMARDs. This effectively dismisses the use of GCs when using biologic DMARDs or targeted synthetic DMARDs. As a bridging therapy, EULAR recommends either a single parenteral dose of GC or a predefined tapering or discontinuation scheme within 3 months, when starting an oral GC.
Low-Dose Approach Gains Ground
While saying he’d be the first physician to eliminate GCs whenever possible, Dr. Buttgereit made the case before the EULAR Congress that GCs in low doses could still play a role in treatment.
Many physicians believe that very low doses between 2 and 4 mg/d are a realistic therapy option for RA, he said, adding that a mean daily usage < 5 mg could be used over a longer period with relatively low risk.
Several studies he coauthored tested the 5-mg approach. The GLORIA trial compared 5 mg/d prednisolone and placebo in 451 patients aged 65 years and older with active RA over the course of 2 years. The researchers found that patients on prednisolone had a mean Disease Activity Score in 28 joints (DAS28) that was 0.37 points lower and mean joint damage score that was 1.7 points lower than those of patients on placebo, suggesting that the GC had long-term benefits in these patients with RA.
The tradeoff was a 24% increase in the risk of having at least one adverse event of special interest, but most of these events were non-severe infections, Dr. Buttgereit said.
Another study, the SEMIRA trial, assigned 128 patients to a continued regimen of prednisone 5 mg/d for 24 weeks. Another group of 131 patients received a tapered-prednisone regimen. All patients received tocilizumab 162 mg with or without csDMARDs, maintained at stable doses.
Patients in the first cohort achieved superior disease activity control than those in the tapered regimen group. “The side effects showed that in the tapering prednisone group, there were more treatment-emergent adverse effects in this double-blind trial as compared to the continued prednisone group,” Dr. Buttgereit said.
One limitation of the SEMIRA trial was that it studied the effect of tocilizumab as a GC-sparing agent, and it didn’t consider using a tumor necrosis factor or Janus kinase (JAK) inhibitor, which might have a more potent effect on pain and GC dose reduction, Dr. Adami said. “Why do we need to use glucocorticoids if we know they might be detrimental, if we know there might be some other option in our armamentarium?”
Other studies have shown that low-dose GC protocols can be used with standard treatment, according to Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh School of Medicine.
“Examples of this are the LoVAS and PEXIVAS studies for antineutrophil cytoplasmic antibody-associated [ANCA] vasculitis. This has been highlighted in existing treatment recommendations for ANCA vasculitis and systemic lupus erythematosus nephritis,” Dr. Sattui said.
Two-year results from LoVAS showed noninferiority in remission induction rates and rates of relapse and significantly less frequent serious adverse events between a reduced-dose GC regimen at 0.5 mg/kg/d and conventional high-dose GC regimen at 1 mg/kg/d plus rituximab for ANCA vasculitis.
PEXIVAS demonstrated the noninferiority of a reduced-dose regimen of GCs vs a standard-dose regimen with respect to death or end-stage kidney disease in patients with severe disease involvement.
Debating the Toxicity Threshold
Are low GC dosages significantly associated with adverse events like mortality, cardiovascular, or diabetes risk? It depends on who you ask.
Much of the toxicity data on GCs come from inadequately powered or controlled studies and often refer to doses that currently are considered too high, Dr. Buttgereit said. His presentation highlighted a study from Hong Kong, a time-varying analysis of GC dose and incident risk for major adverse cardiovascular events (MACE) in more than 12,000 patients with RA. Researchers found that GC regimens ≥ 5 mg/d significantly increased the risk for MACE. Comparatively, doses below this threshold did not confer excessive risk, he said.
Low-dose GCs are lesser toxic than high-dose GCs, noted Joan Merrill, MD, a professor with the Arthritis and Clinical Immunology Research Program at The University of Oklahoma Health Sciences Center, Oklahoma City. “There may be less weight gain, less chance of acne, and less risk for all the slower, more organ-threatening side effects.”
Dr. Merrill, who cares for patients with lupus, said physicians can keep lupus in check for years, using constant, low-dose GCs. “The one thing we know is that steroids work.” But over many years, damage may still occur, she cautioned.
But even a low dose could present health problems to patients. The GLORIA trial of patients with RA, which showed promising results on disease control with 5 mg/d, found an association between GCs and increased risk for infection and osteoporosis. There was a higher overall risk for adverse events related to skin, infections, and bone mineral density changes. Bone mineral density loss and fractures were more common in the GC group, Adami noted.
Surprisingly, some of the trial’s authors said patients could handle such adverse events. But what is your threshold of “acceptable?” Dr. Adami asked.
Other studies have found associations between low-dose GC regimens and adverse events. Researchers of a 2023 study reported bone mineral density loss in patients with inflammatory rheumatic musculoskeletal diseases on a 2.5-mg/d regimen. Another decade-long analysis of Medicare and Optum data found a link between serious infection and low-dose GCs in patients receiving stable DMARD therapy. Investigators reported risk even at daily doses of ≤ 5 mg.
Dr. Adami acknowledged that these studies may have “confounding by indication,” a channeling bias in which people with severe RA are more likely to be treated with GCs. For this reason, it’s a challenge to disentangle the independent role of GCs from the disease activity itself, he said.
The big question is: Why don’t these observational studies show an increased risk for adverse events with biologic drugs that are given to more severe patients? “That confirms the hypothesis that confounding by indication for GCs is minimal, and most of the risk is driven by GCs,” he said.
Tapering Options Across Diseases
Rheumatologists in the field continue to navigate GC-tapering options and treatment combinations that reduce the cumulative use of GCs over time, finding their own solutions based on the conditions they treat.
In his EULAR presentation, Dr. Buttgereit suggested that current therapeutic approaches for RA may be too narrow when they don’t consider the possibility of including very low doses of GCs.
For RA, “why shouldn’t we not do a combination of something like methotrexate plus a JAK inhibitor or a biological,” plus a very low dose of GCs < 5 mg/d, he asked.
However, Dr. Adami said he generally avoids GCs if RA disease activity is not severe (based on DAS28) and if the patient has a visual analog scale pain score < 7. “Nonetheless, even in patients with more severe disease, I would avoid GCs for more than 3 months. Usually, 1 month of steroids, tapered rapidly and discontinued.”
All patients should receive an appropriate treat-to-target strategy with csDMARDs and biologics if needed, he added.
A patient coming to clinic with difficult-to-treat RA who chronically uses GCs deserves special attention. The priority is bone protection with an anti-osteoporosis medication. “I found that JAK inhibitors, in some cases, help with the discontinuation of steroids, especially in those with residual pain. Therefore, I would think of switching medication,” Dr. Adami said.
For polymyalgia rheumatica, most clinicians will likely try to taper GCs around 52 weeks, similar to ACR/EULAR guidelines, according to Robert F. Spiera, MD, director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, New York City.
“I usually challenge patients with a more rapid taper, hoping to get them off GCs in 6 or even 4 months in some patients, recognizing that many will flare, and we will have to bump up their GC dose,” Dr. Spiera said.
For patients with lupus, GCs remain the most effective treatment, Dr. Merrill said. “The toxicities are unacceptable for long-term use. So we try to get in fast when we need them and get out as soon as possible after that, tapering down as fast as the patient can tolerate it.”
Unfortunately, that’s not always as fast as the clinician or patient hopes for, she said.
“New treatments are being developed that may help us avoid the constant use of steroids. However, it would be wonderful to see how these new safer types of steroids work in lupus,” she said.
Minimizing GCs is an important goal that should be considered and aimed for in every single patient, Dr. Sattui said. “Risk of GC toxicity should be considered in all patients, assessing [them] for cardiometabolic comorbidities, bone metabolic diseases, risk of infection, among many others.” Sticking to one specific GC-tapering protocol might not be achievable for every patient, however, based on disease characteristics, response, and other factors, he added.
Monitoring for GC toxicity is important and should occur during and after every single clinical visit, he emphasized. Patient education is critical. “Different tools have been developed and employed in clinical trials, both patient- and physician-facing instruments. Implementation to clinical practice of some of these should be the next step in order to achieve a more systematic approach.”
What to Consider for AI Symptoms
Clinicians also need to address AI in patients who are coming off GCs, Dr. Sattui said. He advised that symptoms suggestive of AI, including malaise, fatigue, nausea, and muscle and/or joint pain, should guide testing.
Even in the absence of symptoms, clinicians should consider assessing patients who have been on high doses for prolonged periods or obese or older adults who might be at a high risk for AI. “Signs to consider include weight loss, hypotension, or orthostatism,” he said.
Differentiating between AI symptoms and symptoms from the underlying disease can be a challenge. This requires a physical exam and workup, including morning serum cortisol. Collaboration with endocrinology colleagues and other treating providers is important, as well as patient education of symptoms and monitoring for possible adjustments in treating AI and other acute diseases, he said.
Dr. Smolen received research grants from AbbVie, AstraZeneca, Galapagos, and Eli Lilly. Dr. Adami received speaker fees and/or was a consultant for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Buttgereit’s disclosures included AbbVie, AstraZeneca, Grünenthal, Horizon Therapeutics, Mundipharma, Pfizer, and Roche. Dr. Merrill had no relevant disclosures. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie and received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie. Dr. Sattui reported receiving research support from AstraZeneca and GlaxoSmithKline (clinical trials), receiving consulting fees from Sanofi (funds toward research support), serving on advisory boards for Sanofi and Amgen (funds toward research support), and receiving speaker fees from Fresenius Kabi (funds toward research support).
A version of this article appeared on Medscape.com.
FROM EULAR 2024
New Drugs, Treatment Strategies Aim to Lessen Rheumatic Diseases’ Reliance on Steroids
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
. Selective GC receptor agonists and modulators and GC plus hydroxysteroid dehydrogenase inhibitor combination therapy are some of the approaches under consideration.
“There is growing observational data that confirms the GC-sparing effect seen in some of these clinical trials in real-world data,” said Sebastian E. Sattui, MD, assistant professor of medicine and director of the Vasculitis Center at the University of Pittsburgh Medical Center, Pittsburgh.
GC minimization is an important goal, “and the data emerging from these trials should be reassuring for rheumatology providers,” Dr. Sattui said.
HSD-1 Inhibitors Under Study
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a tissue-specific intracellular modulator of GC action that’s been trialed for a number of rheumatic conditions. “HSD-1 deficiency or inhibition has been consistently associated with reduced GC side effects in mouse and human,” wrote the authors of a study testing the coadministration of HSD-1 inhibitor SPI-62 (clofutriben) with prednisolone in patients with polymyalgia rheumatica (PMR) to measure its impact on efficacy and toxicity.
Lead study author David Katz, PhD, chief scientific officer at Sparrow Pharmaceuticals, presented results at the at the annual European Congress of Rheumatology.
GCs are often the first-line therapy with PMR. However, it’s very difficult for patients to stop taking GCs once they start taking them. The study included patients with PMR who were taking 10 mg/d prednisolone and didn’t require a dose increase. For the study, they continued prednisolone without dose reduction for 4 weeks, receiving either SPI-62 6 mg/d or a matching placebo for 2 weeks.
During SPI-62 treatment, researchers in sequential cohorts maintained daily prednisolone doses at 10 mg, adjusted to 15 mg or adjusted to 20 mg.
A 10-mg dose of prednisolone combined with 6 mg of SPI-62 demonstrated less efficacy compared with placebo but improved upon prednisolone toxicities such as bone formation and resorption biomarkers, lipidemia, and insulin resistance. Doubling the dose to 20 mg prednisolone combined with SPI-62 achieved similar efficacy and maintained improvement of prednisolone toxicity markers.
“In patients with PMR, when we double the dose of prednisolone during coadministration with a potent HSD-1 inhibitor, we are able to have similar stability of symptoms, physical function, and systemic inflammation. At the same time, we are able to show improvements on biomarkers of bone turnover and insulin resistance,” Dr. Katz informed the EULAR 2024 audience.
An ongoing phase 2 clinical trial is testing SPI-62 in patients with endogenous Cushing syndrome. “It’s a longer-term trial, so we’re able to see at least an individual patient’s more clinical outcomes such as reversal of Cushing’s-associated myopathy and the ability of patients to discontinue all of their antidiabetic medications and yet still have good glycemic control,” he said.
Another research team from the United Kingdom explored whether AZD4017, an inhibitor of human 11ß-HSD1, could mitigate GC effects. The researchers randomly assigned 32 healthy male volunteers to AZD4017 or placebo, along with prednisolone. They reported a worsening of hepatic insulin sensitivity in the placebo group but not in the AZD4017 group, and protective effects of AZD4017 on markers of lipid metabolism and bone turnover, as well as lowered nighttime blood pressure. The results signified that coadministration of AZD4017 with prednisolone in men could be a way to reduce GC side effects.
In a Japanese phase 1/2 study, 11ß-HSD1 inhibitor S-707106 proved useful as an insulin sensitizer and antisarcopenic and anti-obesity medication in 16 patients with Cushing syndrome and autonomous cortisol secretion.
Novel Antitumor Necrosis Factor (TNF) Antibody Plus GC Receptor Modulator Conjugate
A novel antibody-drug conjugate comprising the anti-TNF monoclonal antibody adalimumab (ABBV-3373) linked to a GC receptor modulator shows promise as a GC alternative.
A notable 2022 study authored by Frank Buttgereit, MD, and other researchers assessed its safety and efficacy in a randomized, double-blind, active-controlled, proof-of-concept trial.
ABBV-3373 “was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side effects associated with glucocorticoids,” according to AbbVie, its manufacturer.
A total of 48 adults with moderate to severe rheumatoid arthritis receiving background methotrexate were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). The novel drug at 12 weeks showed a −2.65 reduction in the Disease Activity Score in 28 joints using C-reactive protein, compared with −2.13 for adalimumab. Researchers also predicted ABBV-3373 to be more effective than adalimumab based on in-trial and historical adalimumab data.
“We have great expectations for this molecule,” said Giovanni Adami, MD, PhD, a rheumatologist at the University of Verona, Verona, Italy, who has coauthored several studies on the use of GCs. Plans are underway for a phase 3 study with ABBV-3373.
C5a and Interleukin (IL)-6 Receptor Inhibitors as GC-Sparing Drugs
Investigators in a 2021 paper explored whether the C5a receptor inhibitor avacopan could effectively treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis without the need for daily GCs, following treatment with either cyclophosphamide or rituximab. They randomized 331 patients to receive avacopan or prednisone given on a tapering schedule for 20 weeks (60 mg/d tapered to discontinuation by week 21). “Avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52,” the investigators summarized.
A longer trial should test avacopan’s safety and durability in patients with ANCA-associated vasculitis, they recommended.
Sarilumab, a human monoclonal antibody that binds IL-6 receptor alpha and blocks the IL-6 pathway, yielded good results in the phase 3 SAPHYR trial as an alternative for patients with PMR who relapse while tapering prednisone therapy.
Researchers in the SAPHYR trial randomly assigned 118 patients 1:1 to receive a twice-monthly subcutaneous injection of sarilumab over 52 weeks plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. Patients in each group received a tapered GC dose initially at 15 mg/d for 2 weeks in a blinded fashion to control for disease at baseline.
Sarilumab effectively sustained remission in patients, significantly reducing the GC dose compared with placebo.
Disease flare after clinical remission took place in 57% of patients in the placebo group, vs 24% in the sarilumab group. “The placebo-treated patients had a fairly traditional 52-week GC taper. The patients treated with sarilumab had a very rapid GC taper,” said lead study author Robert Spiera, MD, director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City.
In his own practice, Dr. Spiera often treats his patients with new-onset PMR with a fairly rapid GC taper, akin to what was used in SAPHYR, recognizing that a portion of these patients can be successfully treated with a relatively brief course of GCs, although the majority will need to have “rescue” therapy for flares with that approach.
In SAPHYR, everyone had previously flared and started at 15 mg/d prednisone at study entry. “In my practice, I don’t always raise the prednisone to 15 mg for a PMR flare. I raise it to whatever dose is necessary to capture control of polymyalgia rheumatica symptoms as I add sarilumab. Often, that is less than 15 mg,” he clarified.
Patients with giant cell arteritis (GCA) also struggle to taper or stop using GCs. For these patients, the IL-6 receptor alpha inhibitor tocilizumab has demonstrated benefits in shortening the GC-tapering period.
In the GiACTA trial, researchers randomly assigned 251 patients in a 2:1:1:1 ratio with GCA to receive subcutaneous tocilizumab weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Patients in the tocilizumab arms combined with a 26-week prednisone taper had superior results with GC-free remission compared with those who underwent prednisone tapering plus placebo.
Subsequent studies have investigated the use of tocilizumab in shortening GC tapers. One pilot clinical trial assessed the use of tocilizumab monotherapy following ultrashort-term GC treatment (three pulses of 500 mg of methylprednisolone) in 18 patients with new-onset GCA. Researchers found that approximately 70% of patients were able to achieve and maintain disease remission for 52 weeks. One patient developed anterior ischemic optic neuropathy.
Another pilot study of 30 patients with GCA (50% new-onset disease, 50% relapsing disease) concluded that a year of tocilizumab combined with 8 weeks of prednisone could lead to remission. The majority of patients (77% of 30) maintained prednisone-free remission at 52 weeks, and no cases of anterior ischemic optic neuropathy were observed.
“The results of the studies mentioned above are encouraging and suggest that in the setting of IL-6 blockade treatment with tocilizumab, GC tapers shorter than 6 months may be possible. However, in order to be able to recommend short prednisone tapers in GCA, clinical trials comparing the efficacy and safety of different prednisone tapers [such as 8 vs 26 weeks] are required,” said Sebastian H. Unizony, MD, the study’s lead author and an assistant professor at Harvard Medical School and codirector of the Massachusetts General Hospital Rheumatology Vasculitis Program, Boston.
“The last several years have been a breakthrough period in GCA, which started with addition of tocilizumab to the therapeutic armamentarium against this disease and continued with several other agents showing promising results in phase 2 trials [of abatacept, mavrilimumab, and secukinumab] and a recently successful phase 3 trial with upadacitinib,” Dr. Unizony said.
Dr. Katz is a corporate officer and stockholder of Sparrow Pharmaceuticals. Dr. Adami has received speaker fees and/or has consulted for Galapagos, Theramex, Amgen, Eli Lilly, UCB, Fresenius Kabi, Bristol Myers Squibb, Abiogen, and Pfizer. Dr. Spiera has been a consultant for Roche-Genentech, GlaxoSmithKline, Sanofi, ChemoCentryx, Novartis, Galderma, Cytori, AstraZeneca, Amgen, and AbbVie, and has received research grant support from GlaxoSmithKline, Roche-Genentech, AstraZeneca, Bristol Myers Squibb, Kadmon, Boehringer Ingelheim, Cytori, ChemoCentryx, Corbus, Novartis, Amgen, and AbbVie.
A version of this article appeared on Medscape.com.
Mysteries Persist About Tissue Resident Memory T Cells in Psoriasis
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
SEATTLE — In fact, flare-ups often recur at the same site, a phenomenon that might be driven by these resident memory cells, according to Liv Eidsmo, MD, PhD.
This has led to their use as biomarkers in clinical trials for new therapies, but TRM T cells have a complex biology that is far from fully understood, Dr. Eidsmo said at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “With time, we’re understanding that the regulation of the functionality is more complicated than we thought, so following these cells as a positive outcome of a clinical trial is a little bit premature,” said Dr. Eidsmo, who is a consultant dermatologist at the University of Copenhagen, Copenhagen, Denmark.
Treatment strategies focus on inhibition of interleukin (IL)-23, which is an activator of TRM T cells and probably keeps them alive, according to Dr. Eidsmo. “The hope is that these cells can be silenced by IL-23 inhibition, which is a great idea, and it probably works. It’s just a matter of what is the readout of long-term remission, because the big challenge in the clinical world is when do we stop these expensive biological treatments? When can we feel secure that patients are in deep remission?” she asked.
TRM cells are also far from the only immune cells involved in psoriasis. Others include keratinocytes, Langerhans cells, and fibroblasts. Dr. Eidsmo referenced a recent spatial analysis that used single-cell and spatial RNA sequencing to identify the localization of specific cell populations and inflammatory pathways within psoriasis lesions and epidermal compartments as well as also suggested crosstalk links between cell types. Epigenetic changes in stem cells may also maintain a lower threshold for tissue inflammation.
Dr. Eidsmo advised caution in eliminating TRM T cells, which play a key role in protecting against melanoma and other cancers, especially later in life. “We don’t want to get rid of them. We want to have the right balance.”
She noted a study in her own lab that mapped TRM T cells in healthy epidermis and found that they could be renewed from both circulating precursors and cells within the epidermis. “So getting rid of the mature TRM T cells will most likely just lead to a new generation of the same subset.”
Other data show that there are a wide range of subsets of TRM T cells, and she recommended focusing on the functionality of TRM T cells rather than sheer numbers. “This is something we’re working on now: Can we change the functionality [of TRM T cells], rather than eradicate them and hope for the best in the next generation? Can we change the functionality of the T cells we already have in the skin?”
There is also epigenetic data in TRM T cells, keratinocytes, stem cells, and other cells thus suggesting complexity and plasticity in the system that remains poorly understood.
Taken together, the research is at too early of a stage to be clinically useful, said Dr. Eidsmo. “We need to go back to the drawing board and just realize what we need to measure, and with the new techniques coming out, maybe spatial [measurement] at a high resolution, we can find biomarkers that better dictate the future of this. Be a little bit wary when you read the outcomes from the clinical trials that are ongoing, because right now, it’s a bit of a race between different biologics. These cells are used as a readout of efficacy of the treatments, and we’re not quite there yet.”
During the Q&A session after the presentation, one audience member asked about the heterogeneity of cells found within the skin of patients with psoriasis and pointed out that many proinflammatory cells likely play a role in tumor control. Dr. Eidsmo responded that her group’s analysis of a large database of patients with metastatic melanoma found that a factor that is important to the development of TRM T cells was strongly correlated to survival in patients with metastatic melanoma receiving immune checkpoint blockade. “So we really don’t want to eradicate them,” she said.
Also during the Q&A, Iain McInnes, MD, PhD, commented about the need to understand the previous events that drove the creation of memory T cells. “For me, the question is about the hierarchy, the primacy of what really drives the memory. In the infectious world, we’re trained to think [that memory responses] are T cell driven memory, but I wonder whether you have an idea of whether the T cell is responding to other memories, particularly in the stroma. Because certainly in the arthropathies, we have really good evidence now of epigenetic change in the synovial stroma and subsets,” said Dr. McInnes, who is director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Glasgow, Scotland.
Dr. Eidsmo responded that she believes responses are different among different individuals. “We know too little about how these two systems interact with one another. I think the TRM T cells are very good at amplifying the stroma to recruit cells in. I think we need to think of two-step therapies. You need to normalize this [stromal] environment. How you can do that, I don’t know.”
Dr. McInnes agreed. “As a myeloid doctor, I strongly believe that perpetuators are innate and the adaptive is following on. But how do we test that? That’s really hard,” he said.
Dr. Eidsmo did not list any disclosures. Dr. McInnes has financial relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer, Compugen, Cabaletta, Causeway, Dextera, Eli Lilly, Celgene, MoonLake, Pfizer, Novartis, Janssen, Roche, Versus Arthritis, MRC, and UCB.
FROM GRAPPA 2024
Financial Hardship Common With Rheumatologic Disease: How Can Doctors Help?
Many patients struggle with healthcare costs and basic expenses, according to new research.
People with rheumatologic diseases often experience a hidden symptom: financial toxicity or significant economic strain from out-of-pocket costs. A new study of 41,502 patients published in JCR: Journal of Clinical Rheumatology showed that 20% of those with rheumatologic diseases faced financial hardship from medical expenses, with 55% of those unable to pay their bills.
Compared with patients who do not have rheumatologic diseases, and after clinical and sociodemographic factors were controlled for, patients with rheumatologic diseases were:
- 29% more likely to have high levels of financial hardship — difficulty paying; needing to pay over time; or inability to pay bills for doctors, dentists, hospitals, therapists, medication, equipment, nursing homes, or home care.
- 53% more likely to have high levels of financial distress — significant worry about having enough money for retirement, paying medical costs in the event of a serious illness or accident, maintaining their standard of living, paying their usual healthcare costs, and affording their normal monthly bills and housing costs.
- 29% more likely to experience food insecurity, defined as limited or uncertain access to adequate food.
- 58% more likely to report cost-related medication nonadherence — skipping doses, taking less medication, or delaying filling a prescription to save money.
People who were younger than 64 years, male, Black, or uninsured had higher odds of experiencing financial hardship, financial distress, food insecurity, and cost-related medication nonadherence.
This study highlights “just how costly everyday rheumatologic conditions can be for your average American,” said lead study author Troy Amen, MD, MBA, an orthopedic surgery resident at the Hospital for Special Surgery in New York City. These diseases can be disabling, limiting a patient’s ability to work at the very time when expensive medications are needed.
“It’s critical for clinicians to recognize how common the financial burden from healthcare costs can be, and only then can they take steps to better support patients,” said G. Caleb Alexander, MD, MS, professor of epidemiology at Johns Hopkins University in Baltimore, who was not involved in the study.
Here’s how healthcare providers can help.
Consider skipped medication a red flag. It’s often the first sign of a financial concern. “Sometimes with these problems, it looks like simple medication noncompliance, but it’s really a more complex form of nonadherence,” said Susan M. Goodman, MD, professor of clinical medicine at Weill Cornell Medicine in New York City and a coauthor of the study. “And I think if someone’s not taking the medication that had been very helpful, it does behoove the physician to try and figure out why that is.”
Normalize the issue to help patients open up. “I will often say, ‘You know, many, many patients don’t take their medicines exactly as prescribed. About how many days a week do you take this medicine?’” said Dr. Alexander. “If you ask in a nonconfrontational, supportive manner, I’ve found that patients are quite candid.”
Don’t assume insurance has it covered. If patients are uninsured, help them enroll in (or renew) insurance coverage. But don’t assume insurance will solve the whole problem. “There are many people who, although they do have coverage, still can’t afford their medications,” said Dr. Goodman.
For products on high formulary tiers, the patient’s monthly cost can be hundreds to thousands of dollars. “Over the past 10-20 years, we’ve seen remarkable technological innovation in the types of medicines being brought to market, and here, I’m referring primarily to biologics and medicines made from living cells,” said Dr. Alexander, “but many of these have a price tag that is simply astronomical, and insurers aren’t going to bear the brunt of these costs alone.”
Biosimilars can be a bit more affordable, but “the dirty little secret of biosimilars is that they’re not really very much less expensive,” said Dr. Goodman. “If your patient is doing well on a drug that gets dropped from their insurance plan’s formulary, or if they switch to a plan that doesn’t cover it, try calling and advocating for an exception. It’s an uphill battle, but it sometimes works,” she said.
If not? Help your patients apply for a patient assistance program. Many drug manufacturers offer copay assistance through their websites, and nonprofit patient assistance organizations such as the PAN Foundation, the Patient Advocate Foundation’s Co-Pay Relief Program, or The Assistance Fund can also help fill the gaps. One study published in the Journal of Managed Care and Specialty Pharmacy showed that in patients with rheumatoid arthritis, copay assistance was associated with 79% lower odds of prescription abandonment (failure to fill within 30 days of health plan approval).
Beware of “shiny penny syndrome.” It’s easy to get excited about new, innovative medications, especially when sales reps provide plenty of free samples. “There is a tendency to treat every new medicine as if it’s a bright shiny object in the streambed, and you know that’s not always the case,” said Dr. Alexander. “So, I think we have to be careful, especially in settings when we’re talking about ultra–high-cost medicines, that we’re aware of the burden these medicines may place on patients and that we’re navigating that with patients together, and not simply leaving that as a conversation that never happens in the exam room.”
Maybe there’s an older, time-tested drug that works just as well as the newer, more expensive one. Perhaps there is a slightly less effective medicine that costs a lot less. “These are cost–quality trade-offs that clinicians and patients should be navigating together,” said Dr. Alexander. For example, in a patient with rheumatoid arthritis, a tumor necrosis factor alpha inhibitor might work similarly to or almost as well as an interleukin inhibitor, the newer and typically more expensive choice.
“Some clinicians may find it quite unpalatable to be potentially compromising on safety or efficacy in the interest of reducing the cost of therapies, but as former Surgeon General C. Everett Koop said, ‘Drugs don’t work in patients who don’t take them,’ ” said Dr. Alexander. “So, if the choice is for someone not to be taking a treatment, or to be taking one that may be a little bit less good, I’ll take the latter.”
Consider the patient’s broader care team. Encourage patients to discuss costs with their other healthcare providers. For patients taking multiple medications, a few adjustments could make a big impact on their wallets. Primary care providers or other specialists might recommend some older and less expensive, but still effective, drugs, such as thiazides for hypertension or metformin for type 2 diabetes. Another option might be to simplify the patient’s regimen or include some fixed-dose combination pills in place of two others.
And if no one has referred the patient to a medical social worker, make the connection. A social worker can put patients in touch with local agencies that can help them with food, housing, and other nonmedical costs.
Talk about this problem with anyone who will listen. One of the best ways to help patients with rheumatologic diseases is to ensure that decision-makers don’t overlook them. Professional societies such as the American College of Rheumatology can be great resources for advocacy in Washington, DC. Political movements can make drugs more affordable — for example, insulin prices have dropped in recent years because of political pressure, said Dr. Goodman.
“A lot of our national policy now focuses on aiding patients with single high-cost events, but we hope studies like these can really get policymakers to think through how to better support patients with chronic conditions that may have been historically ignored, such as patients with rheumatologic disease,” said Dr. Amen.
The first step is raising awareness and telling your story. “As providers, we are often [at the] forefront in witnessing how chronic conditions and their associated costs can negatively affect patients’ lives and even alter clinical outcomes,” Dr. Amen added. “By publishing data and sharing meaningful patient stories and clinical vignettes, we can begin to advocate and humanize these patients to policymakers.”
Information on study funding was not available. All authors reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
Many patients struggle with healthcare costs and basic expenses, according to new research.
People with rheumatologic diseases often experience a hidden symptom: financial toxicity or significant economic strain from out-of-pocket costs. A new study of 41,502 patients published in JCR: Journal of Clinical Rheumatology showed that 20% of those with rheumatologic diseases faced financial hardship from medical expenses, with 55% of those unable to pay their bills.
Compared with patients who do not have rheumatologic diseases, and after clinical and sociodemographic factors were controlled for, patients with rheumatologic diseases were:
- 29% more likely to have high levels of financial hardship — difficulty paying; needing to pay over time; or inability to pay bills for doctors, dentists, hospitals, therapists, medication, equipment, nursing homes, or home care.
- 53% more likely to have high levels of financial distress — significant worry about having enough money for retirement, paying medical costs in the event of a serious illness or accident, maintaining their standard of living, paying their usual healthcare costs, and affording their normal monthly bills and housing costs.
- 29% more likely to experience food insecurity, defined as limited or uncertain access to adequate food.
- 58% more likely to report cost-related medication nonadherence — skipping doses, taking less medication, or delaying filling a prescription to save money.
People who were younger than 64 years, male, Black, or uninsured had higher odds of experiencing financial hardship, financial distress, food insecurity, and cost-related medication nonadherence.
This study highlights “just how costly everyday rheumatologic conditions can be for your average American,” said lead study author Troy Amen, MD, MBA, an orthopedic surgery resident at the Hospital for Special Surgery in New York City. These diseases can be disabling, limiting a patient’s ability to work at the very time when expensive medications are needed.
“It’s critical for clinicians to recognize how common the financial burden from healthcare costs can be, and only then can they take steps to better support patients,” said G. Caleb Alexander, MD, MS, professor of epidemiology at Johns Hopkins University in Baltimore, who was not involved in the study.
Here’s how healthcare providers can help.
Consider skipped medication a red flag. It’s often the first sign of a financial concern. “Sometimes with these problems, it looks like simple medication noncompliance, but it’s really a more complex form of nonadherence,” said Susan M. Goodman, MD, professor of clinical medicine at Weill Cornell Medicine in New York City and a coauthor of the study. “And I think if someone’s not taking the medication that had been very helpful, it does behoove the physician to try and figure out why that is.”
Normalize the issue to help patients open up. “I will often say, ‘You know, many, many patients don’t take their medicines exactly as prescribed. About how many days a week do you take this medicine?’” said Dr. Alexander. “If you ask in a nonconfrontational, supportive manner, I’ve found that patients are quite candid.”
Don’t assume insurance has it covered. If patients are uninsured, help them enroll in (or renew) insurance coverage. But don’t assume insurance will solve the whole problem. “There are many people who, although they do have coverage, still can’t afford their medications,” said Dr. Goodman.
For products on high formulary tiers, the patient’s monthly cost can be hundreds to thousands of dollars. “Over the past 10-20 years, we’ve seen remarkable technological innovation in the types of medicines being brought to market, and here, I’m referring primarily to biologics and medicines made from living cells,” said Dr. Alexander, “but many of these have a price tag that is simply astronomical, and insurers aren’t going to bear the brunt of these costs alone.”
Biosimilars can be a bit more affordable, but “the dirty little secret of biosimilars is that they’re not really very much less expensive,” said Dr. Goodman. “If your patient is doing well on a drug that gets dropped from their insurance plan’s formulary, or if they switch to a plan that doesn’t cover it, try calling and advocating for an exception. It’s an uphill battle, but it sometimes works,” she said.
If not? Help your patients apply for a patient assistance program. Many drug manufacturers offer copay assistance through their websites, and nonprofit patient assistance organizations such as the PAN Foundation, the Patient Advocate Foundation’s Co-Pay Relief Program, or The Assistance Fund can also help fill the gaps. One study published in the Journal of Managed Care and Specialty Pharmacy showed that in patients with rheumatoid arthritis, copay assistance was associated with 79% lower odds of prescription abandonment (failure to fill within 30 days of health plan approval).
Beware of “shiny penny syndrome.” It’s easy to get excited about new, innovative medications, especially when sales reps provide plenty of free samples. “There is a tendency to treat every new medicine as if it’s a bright shiny object in the streambed, and you know that’s not always the case,” said Dr. Alexander. “So, I think we have to be careful, especially in settings when we’re talking about ultra–high-cost medicines, that we’re aware of the burden these medicines may place on patients and that we’re navigating that with patients together, and not simply leaving that as a conversation that never happens in the exam room.”
Maybe there’s an older, time-tested drug that works just as well as the newer, more expensive one. Perhaps there is a slightly less effective medicine that costs a lot less. “These are cost–quality trade-offs that clinicians and patients should be navigating together,” said Dr. Alexander. For example, in a patient with rheumatoid arthritis, a tumor necrosis factor alpha inhibitor might work similarly to or almost as well as an interleukin inhibitor, the newer and typically more expensive choice.
“Some clinicians may find it quite unpalatable to be potentially compromising on safety or efficacy in the interest of reducing the cost of therapies, but as former Surgeon General C. Everett Koop said, ‘Drugs don’t work in patients who don’t take them,’ ” said Dr. Alexander. “So, if the choice is for someone not to be taking a treatment, or to be taking one that may be a little bit less good, I’ll take the latter.”
Consider the patient’s broader care team. Encourage patients to discuss costs with their other healthcare providers. For patients taking multiple medications, a few adjustments could make a big impact on their wallets. Primary care providers or other specialists might recommend some older and less expensive, but still effective, drugs, such as thiazides for hypertension or metformin for type 2 diabetes. Another option might be to simplify the patient’s regimen or include some fixed-dose combination pills in place of two others.
And if no one has referred the patient to a medical social worker, make the connection. A social worker can put patients in touch with local agencies that can help them with food, housing, and other nonmedical costs.
Talk about this problem with anyone who will listen. One of the best ways to help patients with rheumatologic diseases is to ensure that decision-makers don’t overlook them. Professional societies such as the American College of Rheumatology can be great resources for advocacy in Washington, DC. Political movements can make drugs more affordable — for example, insulin prices have dropped in recent years because of political pressure, said Dr. Goodman.
“A lot of our national policy now focuses on aiding patients with single high-cost events, but we hope studies like these can really get policymakers to think through how to better support patients with chronic conditions that may have been historically ignored, such as patients with rheumatologic disease,” said Dr. Amen.
The first step is raising awareness and telling your story. “As providers, we are often [at the] forefront in witnessing how chronic conditions and their associated costs can negatively affect patients’ lives and even alter clinical outcomes,” Dr. Amen added. “By publishing data and sharing meaningful patient stories and clinical vignettes, we can begin to advocate and humanize these patients to policymakers.”
Information on study funding was not available. All authors reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
Many patients struggle with healthcare costs and basic expenses, according to new research.
People with rheumatologic diseases often experience a hidden symptom: financial toxicity or significant economic strain from out-of-pocket costs. A new study of 41,502 patients published in JCR: Journal of Clinical Rheumatology showed that 20% of those with rheumatologic diseases faced financial hardship from medical expenses, with 55% of those unable to pay their bills.
Compared with patients who do not have rheumatologic diseases, and after clinical and sociodemographic factors were controlled for, patients with rheumatologic diseases were:
- 29% more likely to have high levels of financial hardship — difficulty paying; needing to pay over time; or inability to pay bills for doctors, dentists, hospitals, therapists, medication, equipment, nursing homes, or home care.
- 53% more likely to have high levels of financial distress — significant worry about having enough money for retirement, paying medical costs in the event of a serious illness or accident, maintaining their standard of living, paying their usual healthcare costs, and affording their normal monthly bills and housing costs.
- 29% more likely to experience food insecurity, defined as limited or uncertain access to adequate food.
- 58% more likely to report cost-related medication nonadherence — skipping doses, taking less medication, or delaying filling a prescription to save money.
People who were younger than 64 years, male, Black, or uninsured had higher odds of experiencing financial hardship, financial distress, food insecurity, and cost-related medication nonadherence.
This study highlights “just how costly everyday rheumatologic conditions can be for your average American,” said lead study author Troy Amen, MD, MBA, an orthopedic surgery resident at the Hospital for Special Surgery in New York City. These diseases can be disabling, limiting a patient’s ability to work at the very time when expensive medications are needed.
“It’s critical for clinicians to recognize how common the financial burden from healthcare costs can be, and only then can they take steps to better support patients,” said G. Caleb Alexander, MD, MS, professor of epidemiology at Johns Hopkins University in Baltimore, who was not involved in the study.
Here’s how healthcare providers can help.
Consider skipped medication a red flag. It’s often the first sign of a financial concern. “Sometimes with these problems, it looks like simple medication noncompliance, but it’s really a more complex form of nonadherence,” said Susan M. Goodman, MD, professor of clinical medicine at Weill Cornell Medicine in New York City and a coauthor of the study. “And I think if someone’s not taking the medication that had been very helpful, it does behoove the physician to try and figure out why that is.”
Normalize the issue to help patients open up. “I will often say, ‘You know, many, many patients don’t take their medicines exactly as prescribed. About how many days a week do you take this medicine?’” said Dr. Alexander. “If you ask in a nonconfrontational, supportive manner, I’ve found that patients are quite candid.”
Don’t assume insurance has it covered. If patients are uninsured, help them enroll in (or renew) insurance coverage. But don’t assume insurance will solve the whole problem. “There are many people who, although they do have coverage, still can’t afford their medications,” said Dr. Goodman.
For products on high formulary tiers, the patient’s monthly cost can be hundreds to thousands of dollars. “Over the past 10-20 years, we’ve seen remarkable technological innovation in the types of medicines being brought to market, and here, I’m referring primarily to biologics and medicines made from living cells,” said Dr. Alexander, “but many of these have a price tag that is simply astronomical, and insurers aren’t going to bear the brunt of these costs alone.”
Biosimilars can be a bit more affordable, but “the dirty little secret of biosimilars is that they’re not really very much less expensive,” said Dr. Goodman. “If your patient is doing well on a drug that gets dropped from their insurance plan’s formulary, or if they switch to a plan that doesn’t cover it, try calling and advocating for an exception. It’s an uphill battle, but it sometimes works,” she said.
If not? Help your patients apply for a patient assistance program. Many drug manufacturers offer copay assistance through their websites, and nonprofit patient assistance organizations such as the PAN Foundation, the Patient Advocate Foundation’s Co-Pay Relief Program, or The Assistance Fund can also help fill the gaps. One study published in the Journal of Managed Care and Specialty Pharmacy showed that in patients with rheumatoid arthritis, copay assistance was associated with 79% lower odds of prescription abandonment (failure to fill within 30 days of health plan approval).
Beware of “shiny penny syndrome.” It’s easy to get excited about new, innovative medications, especially when sales reps provide plenty of free samples. “There is a tendency to treat every new medicine as if it’s a bright shiny object in the streambed, and you know that’s not always the case,” said Dr. Alexander. “So, I think we have to be careful, especially in settings when we’re talking about ultra–high-cost medicines, that we’re aware of the burden these medicines may place on patients and that we’re navigating that with patients together, and not simply leaving that as a conversation that never happens in the exam room.”
Maybe there’s an older, time-tested drug that works just as well as the newer, more expensive one. Perhaps there is a slightly less effective medicine that costs a lot less. “These are cost–quality trade-offs that clinicians and patients should be navigating together,” said Dr. Alexander. For example, in a patient with rheumatoid arthritis, a tumor necrosis factor alpha inhibitor might work similarly to or almost as well as an interleukin inhibitor, the newer and typically more expensive choice.
“Some clinicians may find it quite unpalatable to be potentially compromising on safety or efficacy in the interest of reducing the cost of therapies, but as former Surgeon General C. Everett Koop said, ‘Drugs don’t work in patients who don’t take them,’ ” said Dr. Alexander. “So, if the choice is for someone not to be taking a treatment, or to be taking one that may be a little bit less good, I’ll take the latter.”
Consider the patient’s broader care team. Encourage patients to discuss costs with their other healthcare providers. For patients taking multiple medications, a few adjustments could make a big impact on their wallets. Primary care providers or other specialists might recommend some older and less expensive, but still effective, drugs, such as thiazides for hypertension or metformin for type 2 diabetes. Another option might be to simplify the patient’s regimen or include some fixed-dose combination pills in place of two others.
And if no one has referred the patient to a medical social worker, make the connection. A social worker can put patients in touch with local agencies that can help them with food, housing, and other nonmedical costs.
Talk about this problem with anyone who will listen. One of the best ways to help patients with rheumatologic diseases is to ensure that decision-makers don’t overlook them. Professional societies such as the American College of Rheumatology can be great resources for advocacy in Washington, DC. Political movements can make drugs more affordable — for example, insulin prices have dropped in recent years because of political pressure, said Dr. Goodman.
“A lot of our national policy now focuses on aiding patients with single high-cost events, but we hope studies like these can really get policymakers to think through how to better support patients with chronic conditions that may have been historically ignored, such as patients with rheumatologic disease,” said Dr. Amen.
The first step is raising awareness and telling your story. “As providers, we are often [at the] forefront in witnessing how chronic conditions and their associated costs can negatively affect patients’ lives and even alter clinical outcomes,” Dr. Amen added. “By publishing data and sharing meaningful patient stories and clinical vignettes, we can begin to advocate and humanize these patients to policymakers.”
Information on study funding was not available. All authors reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
Early RA Diagnosis and Treatment Lowers Treatment Costs
TOPLINE:
Early detection and treatment of rheumatoid arthritis (RA; within 12 weeks of symptom onset) results in lower treatment-related costs over 5 years compared with later diagnosis.
METHODOLOGY:
- The study enrolled 431 patients in the Leiden Early Arthritis Clinic at Leiden University Medical Center, Leiden, the Netherlands.
- Symptom duration was defined as time between symptom onset and first clinic visit.
- Early treatment was defined as a symptom duration of under 12 weeks, and later treatment defined as symptom duration over 12 weeks.
- Prescription data from patient records and 2022 disease-modifying antirheumatic drug prices (including biologics) was used to determine overall costs over 5 years.
- Autoantibody-negative and autoantibody-positive RA were studied separately because of possible differences in disease severity.
TAKEAWAY:
- For the 165 patients with autoantibody-negative RA, late treatment was associated with 316% higher costs over 5 years than early treatment (€4856/$5292 vs €1159/$1263)
- For antibody-positive RA, costs were 19% higher in the late-treatment group.
- In the 43 patients with antibody-positive RA only prescribed biologics, costs were 46% higher for those with delayed treatment.
IN PRACTICE:
“This is the first study showing the effect of early diagnosis and treatment on treatment-related costs,” wrote the authors. “When RA is detected within 12 weeks after symptom onset, treatment-related costs seem to be lower.”
SOURCE:
The study was led by Elise van Mulligen, PhD, Department of Rheumatology, Leiden University Medical Center. It was published online in Annals of the Rheumatic Diseases.
LIMITATIONS:
The division of symptom duration by 12 weeks was “arbitrary.” Baseline characteristics, though similar, showed differences for inflammatory markers in autoantibody-positive and autoantibody-negative RA. Thirty seven patients were lost to follow-up, which could induce attrition bias, though the percentage of these patients in the early- and late-treatment groups was similar.
DISCLOSURES:
This study was funded by ZonMw, a Dutch organization for healthcare research. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Early detection and treatment of rheumatoid arthritis (RA; within 12 weeks of symptom onset) results in lower treatment-related costs over 5 years compared with later diagnosis.
METHODOLOGY:
- The study enrolled 431 patients in the Leiden Early Arthritis Clinic at Leiden University Medical Center, Leiden, the Netherlands.
- Symptom duration was defined as time between symptom onset and first clinic visit.
- Early treatment was defined as a symptom duration of under 12 weeks, and later treatment defined as symptom duration over 12 weeks.
- Prescription data from patient records and 2022 disease-modifying antirheumatic drug prices (including biologics) was used to determine overall costs over 5 years.
- Autoantibody-negative and autoantibody-positive RA were studied separately because of possible differences in disease severity.
TAKEAWAY:
- For the 165 patients with autoantibody-negative RA, late treatment was associated with 316% higher costs over 5 years than early treatment (€4856/$5292 vs €1159/$1263)
- For antibody-positive RA, costs were 19% higher in the late-treatment group.
- In the 43 patients with antibody-positive RA only prescribed biologics, costs were 46% higher for those with delayed treatment.
IN PRACTICE:
“This is the first study showing the effect of early diagnosis and treatment on treatment-related costs,” wrote the authors. “When RA is detected within 12 weeks after symptom onset, treatment-related costs seem to be lower.”
SOURCE:
The study was led by Elise van Mulligen, PhD, Department of Rheumatology, Leiden University Medical Center. It was published online in Annals of the Rheumatic Diseases.
LIMITATIONS:
The division of symptom duration by 12 weeks was “arbitrary.” Baseline characteristics, though similar, showed differences for inflammatory markers in autoantibody-positive and autoantibody-negative RA. Thirty seven patients were lost to follow-up, which could induce attrition bias, though the percentage of these patients in the early- and late-treatment groups was similar.
DISCLOSURES:
This study was funded by ZonMw, a Dutch organization for healthcare research. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
TOPLINE:
Early detection and treatment of rheumatoid arthritis (RA; within 12 weeks of symptom onset) results in lower treatment-related costs over 5 years compared with later diagnosis.
METHODOLOGY:
- The study enrolled 431 patients in the Leiden Early Arthritis Clinic at Leiden University Medical Center, Leiden, the Netherlands.
- Symptom duration was defined as time between symptom onset and first clinic visit.
- Early treatment was defined as a symptom duration of under 12 weeks, and later treatment defined as symptom duration over 12 weeks.
- Prescription data from patient records and 2022 disease-modifying antirheumatic drug prices (including biologics) was used to determine overall costs over 5 years.
- Autoantibody-negative and autoantibody-positive RA were studied separately because of possible differences in disease severity.
TAKEAWAY:
- For the 165 patients with autoantibody-negative RA, late treatment was associated with 316% higher costs over 5 years than early treatment (€4856/$5292 vs €1159/$1263)
- For antibody-positive RA, costs were 19% higher in the late-treatment group.
- In the 43 patients with antibody-positive RA only prescribed biologics, costs were 46% higher for those with delayed treatment.
IN PRACTICE:
“This is the first study showing the effect of early diagnosis and treatment on treatment-related costs,” wrote the authors. “When RA is detected within 12 weeks after symptom onset, treatment-related costs seem to be lower.”
SOURCE:
The study was led by Elise van Mulligen, PhD, Department of Rheumatology, Leiden University Medical Center. It was published online in Annals of the Rheumatic Diseases.
LIMITATIONS:
The division of symptom duration by 12 weeks was “arbitrary.” Baseline characteristics, though similar, showed differences for inflammatory markers in autoantibody-positive and autoantibody-negative RA. Thirty seven patients were lost to follow-up, which could induce attrition bias, though the percentage of these patients in the early- and late-treatment groups was similar.
DISCLOSURES:
This study was funded by ZonMw, a Dutch organization for healthcare research. The authors declared no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
Debate: Should Dermatologists or Rheumatologists Manage Musculoskeletal Symptoms in Patients With Psoriasis?
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
SEATTLE — That was the subject of a debate between a dermatologist and a rheumatologist at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Fabian Proft, MD, the rheumatologist, spoke first and emphasized the potential that MSK symptoms are a sign of psoriatic arthritis (PsA) and therefore should be managed by a rheumatologist.
“Obviously, the rheumatologist perspective [is that] I should be in the driver’s seat when taking care of patient with psoriasis and MSK symptoms, but I will still need to have a copilot there: [The dermatologist] will have a slot,” said Dr. Proft, who is a rheumatologist at Charité — Universitätsmedizin Berlin.
“It’s so important that we make the correct and early diagnosis of [psoriatic arthritis and psoriasis] symptoms,” said Dr. Proft. He specifically called out cases where patients have symptoms that are difficult to determine, whether the cause is inflammatory, and when experience with imaging can be a key factor in the diagnosis.
It’s important not to overdiagnose or overtreat patients, he said, providing an example of a patient with psoriasis who had been training for a marathon. The MRI image suggested that his Achilles tendonitis pain was related to his athletic training, not PsA-associated inflammation. “So I think this is very important that you have the knowledge to read MRIs, and especially also carefully assessing them so as not to overdiagnose patients,” said Dr. Proft.
Dermatologist Rebuttal
In her rebuttal, Laura Savage, MD, PhD, emphasized the need for more of a coequal partnership between the two specialties because of the ability of dermatologists to intervene early in the treatment and prevention of PsA.
“Traditionally, I agree rheumatologists would solely be responsible for the assessment and the management of psoriatic arthritis, but I think that paradigm has shifted in part due to the increased recognition of the need for earlier intervention to limit disease progression and to reduce or even prevent functional limitation,” said Dr. Savage, who is a consultant dermatologist at Leeds Teaching Hospitals NHS Trust and a senior lecturer at the University of Leeds, Leeds, England.
Ideally, molecular biomarkers would be available to predict the development of PsA, but there aren’t any. Still, “we have a huge biomarker in the form of the skin, and it’s recognized that the majority of patients who will develop psoriatic arthritis will have antecedent psoriasis in about 70% of cases,” Dr. Savage said. “There’s a typical time delay of around 7-12 years between the onset of the skin [disease] and the patients developing psoriatic arthritis, and so many of them are going to be into the care of other healthcare practitioners, and particularly the care of dermatologists.”
Dermatologists may also be able to play a role in the prevention of PsA, according to Dr. Savage. In one retrospective study, treatment of skin lesions with biologics was associated with a reduced frequency of progression to PsA (11.1% vs 16.4%) over 10 years (P = .0006). Studies with tumor necrosis factor inhibitors and other interventions have shown similar results.
Such findings have led to the treat intercept strategy, which targets patients with psoriasis who have risk factors for transition to PsA — such as nail pitting, gluteal cleft disease, scalp disease, type 2 diabetes, obesity, and a first-degree relative with PsA — as well as symptoms of prodromal PSA, such as arthralgia and fatigue.
“I think dermatologists are aware of the need to not leave our patients languishing on these therapies and actually escalating them onto effective treatments that may also be able to treat early psoriatic arthritis. We could be more mindful about our choice of treatments for these patients, going on to thinking about their increased risk of PSA and trying to intercept,” Dr. Savage said. “What we don’t want is our patients to be developing these musculoskeletal symptoms of pain and stiffness and functional limitation and disability. We want to be treating the patients with musculoskeletal symptoms of that earlier prodromal phase when they’re developing arthralgia and fatigue.”
She conceded that more complicated patients are good candidates for care by the rheumatologist. “You can do your fancy imaging, and we’ll leave that to you, and the difficult-to-treat patients to [the rheumatologist], but actually we need to just get on and treat them,” she said. “One could argue as well that as a dermatologist, I’m likely to broaden my horizons in terms of choice of therapy and treat all of the domains of the patient. So I would argue that actually it should be the dermatologist who is in that driving seat, particularly when it comes to the management of early psoriatic arthritis, and actually what we should be doing is driving our patients and steering them to earlier intervention and better control for all domains of disease.”
Collaborative Care
During the follow-up discussion, both Dr. Proft and Dr. Savage agreed that dermatologists and rheumatologists should be working together in managing patients. “What we need to do is steer our patients toward collaborative care with our rheumatologists by trying to minimize delays to treatment, by working together in parallel clinics, combined clinics, and on virtual [multidisciplinary teams],” said Dr. Savage.
Dr. Proft agreed. “We should join forces and make decisions together.”
Dr. Savage and Dr. Proft did not provide any financial disclosures.
A version of this article appeared on Medscape.com.
FROM GRAPPA 2024
Treating Psoriatic Arthritis in Primary Care
Since the European Alliance of Associations for Rheumatology (EULAR) published its 2019 recommendations, the range of therapeutic options in the management of psoriatic arthritis (PsA) has expanded significantly. Univadis France spoke to Laure Gossec, MD, PhD, a rheumatologist at Pitié-Salpêtrière Hospital and Sorbonne University in Paris, about the updates to these recommendations.
What is the role of nonsteroidal anti-inflammatory drugs (NSAIDs) today?
NSAIDs remain the first-line treatment, but their place as monotherapy without background treatment has been mainly limited to patients with mild peripheral disease. For them, NSAIDs are recommended as monotherapy for a short duration, 2-4 weeks, while the clinician assesses and promptly introduces background treatment. We have a window of opportunity. Inflammation must be targeted quickly, especially if the patient has a form of disease associated with poor prognosis. Such patients include those with polyarticular forms or high C-reactive protein (CRP).
The two criteria of at least four swollen joints and/or a CRP greater than 5 mg/L should prompt the physician to introduce background treatment.
When prescribing NSAIDs, clinicians must rigorously evaluate the benefit-risk ratio because patients with PsA often have comorbidities. In France, one third of them have obesity, 20% have hypertension, and 20% have diabetes.
What is the recommended hierarchy for other treatments?
In the second phase of treatment, synthetic conventional treatments (like methotrexate, leflunomide, or sulfasalazine) are recommended. Methotrexate is by far the most used. This choice is based on efficacy, the efficacy-safety ratio, and cost.
A biologic therapy has no place as a first-line treatment because most PsA cases are moderate. In this regard, our European recommendations differ from American recommendations, which leave the choice between conventional or targeted therapies as a first-line treatment.
We have opted for a step-up approach. Although there is no study comparing a biologic therapy vs methotrexate as a first-line treatment, we have many data showing that more than half of patients will never need a biologic therapy.
We have a lot of experience with molecules like methotrexate. The benefit-risk ratio of this treatment as a first-line option is favorable, with efficacy for the skin. However, in axial forms, methotrexate is ineffective and calls for the use of biologic therapy.
Are there selection criteria for second-line biologic therapies?
Five classes of molecules are authorized and reimbursed in France: anti-TNF (tumor necrosis factor), anti–IL (interleukin)-17A, anti–IL-17A, -F, and -AF (bimekizumab), anti–IL-12/23 (ustekinumab), and anti–IL-23. All these treatments are effective in about two thirds of patients.
Unfortunately, we are not yet practicing personalized medicine to choose the most appropriate treatment for each patient, because we cannot predict this response. However, there are specific cases. Anti–IL-17 and anti–IL-23 can be favored in patients with bothersome skin involvement, either because it is extensive or located on the face or genital area. If a patient also has chronic inflammatory bowel disease, anti-TNF, anti–IL-23, or Janus kinase (JAK) inhibitors should be prioritized. In axial forms, anti-TNF or anti–IL-17 is recommended. But these cases concern only a minority of our patients.
We have kept a place for JAK inhibitors in patients for whom biologic therapies are not suitable or effective. It is important to follow the recommendations of the European Medicines Agency, avoiding the use of JAK inhibitors after age 60 years, in smokers, or in those with cardiovascular risk. Oncologic monitoring is also important for patients treated with this therapeutic class.
Let’s also remember the role of apremilast, which is an alternative to biologic therapies in patients with moderate forms of the disease.
In the next 2 or 3 years, new modes of action or new molecules should be available, such as tyrosine kinase 2 (TYK2) inhibitors; izokibep, an oral nanomolecule targeting IL-17; or a new injectable anti–IL-17 with an affinity with interleukin that is incomparable to that of previous antibodies.
What message should be conveyed to the general practitioner?
PsA treatments are prescribed initially in hospitals, but rheumatologists will be able to prescribe them in the coming months. The general practitioner cannot initiate targeted treatment but has the role of starting methotrexate and referring the patient to specialized follow-up.
The most important thing to know is that in France, about half of patients will be on targeted treatment. The median maintenance of such therapy is only 3 years, which means that half of the patients will have replaced it with another therapy after 3 years. This switch could indicate a loss of efficacy or escape. It is therefore important for a specialist to follow the patient and to continue biologic monitoring every 2-6 months, as well as imaging every 2-5 years to check radiographic progression.
In cases of prolonged remission of more than 6 months, a gradual and cautious decrease in background treatments can be considered in a shared medical decision. However, treatment discontinuation leads to a systemic relapse in the short or long term, and a gradual decrease results in relapse in about half of the patients.
And in terms of monitoring?
The management of comorbidities is crucial. It is essential to keep vaccinations up to date, especially because of the increased risk for potential infections with targeted treatments. Regular screening for infections, including dental follow-up, is also recommended.
Preventive medicine is also important, especially regarding breast and colon cancer screening. General population recommendations apply.
Cardiovascular risk, which is doubled in patients with PsA compared with the general population due to chronic inflammation, should prompt monitoring of blood pressure and metabolic diseases. It should be noted that there is an 11% higher mortality rate after 8 years of follow-up, mainly due to cardiovascular and neoplastic risks.
Dr. Gossec reported receiving research grants from AbbVie, Biogen, Lilly, Novartis, and UCB and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Stada, and UCB.
This story was translated from Univadis France, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Since the European Alliance of Associations for Rheumatology (EULAR) published its 2019 recommendations, the range of therapeutic options in the management of psoriatic arthritis (PsA) has expanded significantly. Univadis France spoke to Laure Gossec, MD, PhD, a rheumatologist at Pitié-Salpêtrière Hospital and Sorbonne University in Paris, about the updates to these recommendations.
What is the role of nonsteroidal anti-inflammatory drugs (NSAIDs) today?
NSAIDs remain the first-line treatment, but their place as monotherapy without background treatment has been mainly limited to patients with mild peripheral disease. For them, NSAIDs are recommended as monotherapy for a short duration, 2-4 weeks, while the clinician assesses and promptly introduces background treatment. We have a window of opportunity. Inflammation must be targeted quickly, especially if the patient has a form of disease associated with poor prognosis. Such patients include those with polyarticular forms or high C-reactive protein (CRP).
The two criteria of at least four swollen joints and/or a CRP greater than 5 mg/L should prompt the physician to introduce background treatment.
When prescribing NSAIDs, clinicians must rigorously evaluate the benefit-risk ratio because patients with PsA often have comorbidities. In France, one third of them have obesity, 20% have hypertension, and 20% have diabetes.
What is the recommended hierarchy for other treatments?
In the second phase of treatment, synthetic conventional treatments (like methotrexate, leflunomide, or sulfasalazine) are recommended. Methotrexate is by far the most used. This choice is based on efficacy, the efficacy-safety ratio, and cost.
A biologic therapy has no place as a first-line treatment because most PsA cases are moderate. In this regard, our European recommendations differ from American recommendations, which leave the choice between conventional or targeted therapies as a first-line treatment.
We have opted for a step-up approach. Although there is no study comparing a biologic therapy vs methotrexate as a first-line treatment, we have many data showing that more than half of patients will never need a biologic therapy.
We have a lot of experience with molecules like methotrexate. The benefit-risk ratio of this treatment as a first-line option is favorable, with efficacy for the skin. However, in axial forms, methotrexate is ineffective and calls for the use of biologic therapy.
Are there selection criteria for second-line biologic therapies?
Five classes of molecules are authorized and reimbursed in France: anti-TNF (tumor necrosis factor), anti–IL (interleukin)-17A, anti–IL-17A, -F, and -AF (bimekizumab), anti–IL-12/23 (ustekinumab), and anti–IL-23. All these treatments are effective in about two thirds of patients.
Unfortunately, we are not yet practicing personalized medicine to choose the most appropriate treatment for each patient, because we cannot predict this response. However, there are specific cases. Anti–IL-17 and anti–IL-23 can be favored in patients with bothersome skin involvement, either because it is extensive or located on the face or genital area. If a patient also has chronic inflammatory bowel disease, anti-TNF, anti–IL-23, or Janus kinase (JAK) inhibitors should be prioritized. In axial forms, anti-TNF or anti–IL-17 is recommended. But these cases concern only a minority of our patients.
We have kept a place for JAK inhibitors in patients for whom biologic therapies are not suitable or effective. It is important to follow the recommendations of the European Medicines Agency, avoiding the use of JAK inhibitors after age 60 years, in smokers, or in those with cardiovascular risk. Oncologic monitoring is also important for patients treated with this therapeutic class.
Let’s also remember the role of apremilast, which is an alternative to biologic therapies in patients with moderate forms of the disease.
In the next 2 or 3 years, new modes of action or new molecules should be available, such as tyrosine kinase 2 (TYK2) inhibitors; izokibep, an oral nanomolecule targeting IL-17; or a new injectable anti–IL-17 with an affinity with interleukin that is incomparable to that of previous antibodies.
What message should be conveyed to the general practitioner?
PsA treatments are prescribed initially in hospitals, but rheumatologists will be able to prescribe them in the coming months. The general practitioner cannot initiate targeted treatment but has the role of starting methotrexate and referring the patient to specialized follow-up.
The most important thing to know is that in France, about half of patients will be on targeted treatment. The median maintenance of such therapy is only 3 years, which means that half of the patients will have replaced it with another therapy after 3 years. This switch could indicate a loss of efficacy or escape. It is therefore important for a specialist to follow the patient and to continue biologic monitoring every 2-6 months, as well as imaging every 2-5 years to check radiographic progression.
In cases of prolonged remission of more than 6 months, a gradual and cautious decrease in background treatments can be considered in a shared medical decision. However, treatment discontinuation leads to a systemic relapse in the short or long term, and a gradual decrease results in relapse in about half of the patients.
And in terms of monitoring?
The management of comorbidities is crucial. It is essential to keep vaccinations up to date, especially because of the increased risk for potential infections with targeted treatments. Regular screening for infections, including dental follow-up, is also recommended.
Preventive medicine is also important, especially regarding breast and colon cancer screening. General population recommendations apply.
Cardiovascular risk, which is doubled in patients with PsA compared with the general population due to chronic inflammation, should prompt monitoring of blood pressure and metabolic diseases. It should be noted that there is an 11% higher mortality rate after 8 years of follow-up, mainly due to cardiovascular and neoplastic risks.
Dr. Gossec reported receiving research grants from AbbVie, Biogen, Lilly, Novartis, and UCB and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Stada, and UCB.
This story was translated from Univadis France, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Since the European Alliance of Associations for Rheumatology (EULAR) published its 2019 recommendations, the range of therapeutic options in the management of psoriatic arthritis (PsA) has expanded significantly. Univadis France spoke to Laure Gossec, MD, PhD, a rheumatologist at Pitié-Salpêtrière Hospital and Sorbonne University in Paris, about the updates to these recommendations.
What is the role of nonsteroidal anti-inflammatory drugs (NSAIDs) today?
NSAIDs remain the first-line treatment, but their place as monotherapy without background treatment has been mainly limited to patients with mild peripheral disease. For them, NSAIDs are recommended as monotherapy for a short duration, 2-4 weeks, while the clinician assesses and promptly introduces background treatment. We have a window of opportunity. Inflammation must be targeted quickly, especially if the patient has a form of disease associated with poor prognosis. Such patients include those with polyarticular forms or high C-reactive protein (CRP).
The two criteria of at least four swollen joints and/or a CRP greater than 5 mg/L should prompt the physician to introduce background treatment.
When prescribing NSAIDs, clinicians must rigorously evaluate the benefit-risk ratio because patients with PsA often have comorbidities. In France, one third of them have obesity, 20% have hypertension, and 20% have diabetes.
What is the recommended hierarchy for other treatments?
In the second phase of treatment, synthetic conventional treatments (like methotrexate, leflunomide, or sulfasalazine) are recommended. Methotrexate is by far the most used. This choice is based on efficacy, the efficacy-safety ratio, and cost.
A biologic therapy has no place as a first-line treatment because most PsA cases are moderate. In this regard, our European recommendations differ from American recommendations, which leave the choice between conventional or targeted therapies as a first-line treatment.
We have opted for a step-up approach. Although there is no study comparing a biologic therapy vs methotrexate as a first-line treatment, we have many data showing that more than half of patients will never need a biologic therapy.
We have a lot of experience with molecules like methotrexate. The benefit-risk ratio of this treatment as a first-line option is favorable, with efficacy for the skin. However, in axial forms, methotrexate is ineffective and calls for the use of biologic therapy.
Are there selection criteria for second-line biologic therapies?
Five classes of molecules are authorized and reimbursed in France: anti-TNF (tumor necrosis factor), anti–IL (interleukin)-17A, anti–IL-17A, -F, and -AF (bimekizumab), anti–IL-12/23 (ustekinumab), and anti–IL-23. All these treatments are effective in about two thirds of patients.
Unfortunately, we are not yet practicing personalized medicine to choose the most appropriate treatment for each patient, because we cannot predict this response. However, there are specific cases. Anti–IL-17 and anti–IL-23 can be favored in patients with bothersome skin involvement, either because it is extensive or located on the face or genital area. If a patient also has chronic inflammatory bowel disease, anti-TNF, anti–IL-23, or Janus kinase (JAK) inhibitors should be prioritized. In axial forms, anti-TNF or anti–IL-17 is recommended. But these cases concern only a minority of our patients.
We have kept a place for JAK inhibitors in patients for whom biologic therapies are not suitable or effective. It is important to follow the recommendations of the European Medicines Agency, avoiding the use of JAK inhibitors after age 60 years, in smokers, or in those with cardiovascular risk. Oncologic monitoring is also important for patients treated with this therapeutic class.
Let’s also remember the role of apremilast, which is an alternative to biologic therapies in patients with moderate forms of the disease.
In the next 2 or 3 years, new modes of action or new molecules should be available, such as tyrosine kinase 2 (TYK2) inhibitors; izokibep, an oral nanomolecule targeting IL-17; or a new injectable anti–IL-17 with an affinity with interleukin that is incomparable to that of previous antibodies.
What message should be conveyed to the general practitioner?
PsA treatments are prescribed initially in hospitals, but rheumatologists will be able to prescribe them in the coming months. The general practitioner cannot initiate targeted treatment but has the role of starting methotrexate and referring the patient to specialized follow-up.
The most important thing to know is that in France, about half of patients will be on targeted treatment. The median maintenance of such therapy is only 3 years, which means that half of the patients will have replaced it with another therapy after 3 years. This switch could indicate a loss of efficacy or escape. It is therefore important for a specialist to follow the patient and to continue biologic monitoring every 2-6 months, as well as imaging every 2-5 years to check radiographic progression.
In cases of prolonged remission of more than 6 months, a gradual and cautious decrease in background treatments can be considered in a shared medical decision. However, treatment discontinuation leads to a systemic relapse in the short or long term, and a gradual decrease results in relapse in about half of the patients.
And in terms of monitoring?
The management of comorbidities is crucial. It is essential to keep vaccinations up to date, especially because of the increased risk for potential infections with targeted treatments. Regular screening for infections, including dental follow-up, is also recommended.
Preventive medicine is also important, especially regarding breast and colon cancer screening. General population recommendations apply.
Cardiovascular risk, which is doubled in patients with PsA compared with the general population due to chronic inflammation, should prompt monitoring of blood pressure and metabolic diseases. It should be noted that there is an 11% higher mortality rate after 8 years of follow-up, mainly due to cardiovascular and neoplastic risks.
Dr. Gossec reported receiving research grants from AbbVie, Biogen, Lilly, Novartis, and UCB and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Stada, and UCB.
This story was translated from Univadis France, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Meet the Pregnancy Challenges of Women With Chronic Conditions
Preconception and prenatal care are more complicated in women with chronic health conditions but attention to disease management and promoting the adoption of a healthier lifestyle can improve outcomes for mothers and infants, according to a growing body of research.
The latest version of the International Federation of Gynecology and Obstetrics Preconception Checklist, published in the International Journal of Gynecology & Obstetrics, highlights preexisting chronic medical conditions such as diabetes, lupus, and obesity as key factors to address in preconception care through disease management. A growing number of studies support the impact of these strategies on short- and long-term outcomes for mothers and babies, according to the authors.
Meet Glycemic Control Goals Prior to Pregnancy
“Women with diabetes can have healthy pregnancies but need to prepare for pregnancy in advance,” Ellen W. Seely, MD, professor of medicine at Harvard Medical School and director of clinical research in the endocrinology, diabetes, and hypertension division of Brigham and Women’s Hospital, Boston, said in an interview.
“If glucose levels are running high in the first trimester, this is associated with an increased risk of birth defects, some of which are very serious,” said Dr. Seely. Getting glucose levels under control reduces the risk of birth defects in women with diabetes close to that of the general population, she said.
The American Diabetes Association has set a goal for women to attain an HbA1c of less than 6.5% before conception, Dr. Seely said. “In addition, some women with diabetes may be on medications that should be changed to another class prior to pregnancy,” she noted. Women with type 1 or type 2 diabetes often have hypertension as well, but ACE inhibitors are associated with an increased risk of fetal renal damage that can result in neonatal death; therefore, these medications should be stopped prior to pregnancy, Dr. Seely emphasized.
“If a woman with type 2 diabetes is on medications other than insulin, recommendations from the ADA are to change to insulin prior to pregnancy, since we have the most data on the safety profile of insulin use in pregnancy,” she said.
To help women with diabetes improve glycemic control prior to pregnancy, Dr. Seely recommends home glucose monitoring, with checks of glucose four times a day, fasting, and 2 hours after each meal, and adjustment of insulin accordingly.
A healthy diet and physical activity remain important components of glycemic control as well. A barrier to proper preconception and prenatal care for women with diabetes is not knowing that a pregnancy should be planned, Dr. Seely said. Discussions about pregnancy should start at puberty for women with diabetes, according to the ADA, and the topic should be raised yearly so women can optimize their health and adjust medications prior to conception.
Although studies of drugs have been done to inform preconception care for women with diabetes, research is lacking in several areas, notably the safety of GLP-1 agonists in pregnancy, said Dr. Seely. “This class of drug is commonly used in type 2 diabetes and the current recommendation is to stop these agents 2 months prior to conception,” she said.
Conceive in Times of Lupus Remission
Advance planning also is important for a healthy pregnancy in women with systemic lupus erythematosus (SLE), Sayna Norouzi, MD, director of the glomerular disease clinic and polycystic kidney disease clinic of Loma Linda University Medical Center, California, said in an interview.
“Lupus mostly affects women of childbearing age and can create many challenges during pregnancy,” said Dr. Norouzi, the corresponding author of a recent review on managing lupus nephritis during pregnancy.
“Women with lupus face an increased risk of pregnancy complications such as preeclampsia, problems with fetal growth, stillbirth, and premature birth, and these risks increase based on factors such as disease activity, certain antibodies in the body, and other baseline existing conditions such as high blood pressure,” she said.
“It can be difficult to distinguish between a lupus flare and pregnancy-related issues, so proper management is important,” she noted. The Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (PROMISSE) study findings indicated a lupus nephritis relapse rate of 7.8% of patients in complete remission and 21% of those in partial remission during pregnancy, said Dr. Norouzi. “Current evidence has shown that SLE patients without lupus nephritis flare in the preconception period have a small risk of relapse during pregnancy,” she said.
Before and during pregnancy, women with lupus should work with their treating physicians to adjust medications for safety, watch for signs of flare, and aim to conceive during a period of lupus remission.
Preconception care for women with lupus nephritis involves a careful review of the medications used to control the disease and protect the kidneys and other organs, said Dr. Norouzi.
“Adjustments,” she said, “should be personalized, taking into account the mother’s health and the safety of the baby. Managing the disease actively during pregnancy may require changes to the treatment plan while minimizing risks,” she noted. However, changing medications can cause challenges for patients, as medications that are safer for pregnancy may lead to new symptoms and side effects, and patients will need to work closely with their healthcare providers to overcome new issues that arise, she added.
Preconception lifestyle changes such as increasing exercise and adopting a healthier diet can help with blood pressure control for kidney disease patients, said Dr. Norouzi.
In the review article, Dr. Norouzi and colleagues noted that preconception counseling for patients with lupus should address common comorbidities such as hypertension, diabetes, obesity, and dyslipidemia, and the risk for immediate and long-term cardiovascular complications.
Benefits of Preconception Obesity Care Extend to Infants
Current guidelines from the American College of Obstetricians and Gynecologists and the Institute of Medicine advise lifestyle interventions to reduce excessive weight gain during pregnancy and reduce the risk of inflammation, oxidative stress, insulin resistance, and lipotoxicity that can promote complications in the mother and fetus during pregnancy.
In addition, a growing number of studies suggest that women with obesity who make healthy lifestyle changes prior to conception can reduce obesity-associated risks to their infants.
Adults born to women with obesity are at increased risk of cardiovascular disease and early signs of heart remodeling are identifiable in newborns, Samuel J. Burden, PhD, a research associate in the department of women and children’s health, Kings’ College, London, said in an interview. “It is therefore important to investigate whether intervening either before or during pregnancy by promoting a healthy lifestyle can reduce this adverse impact on the heart and blood vessels,” he said.
In a recent study published in the International Journal of Obesity, Dr. Burden and colleagues examined data from eight studies based on data from five randomized, controlled trials including children of mothers with obesity who engaged in healthy lifestyle interventions of improved diet and increased physical activity prior to and during pregnancy. The study population included children ranging in age from less than 2 months to 3-7 years.
Lifestyle interventions for mothers both before conception and during pregnancy were associated with significant changes in cardiac remodeling in the children, notably reduced interventricular septal wall thickness. Additionally, five studies of cardiac systolic function and three studies of diastolic function showed improvement in blood pressure in children of mothers who took part in the interventions.
Dr. Burden acknowledged that lifestyle changes in women with obesity before conception and during pregnancy can be challenging, but should be encouraged. “During pregnancy, it may also seem unnatural to increase daily physical activity or change the way you are eating.” He emphasized that patients should consult their physicians and follow an established program. More randomized, controlled trials are needed from the preconception period to examine whether the health benefits are greater if the intervention begins prior to pregnancy, said Dr. Burden. However, “the current findings indeed indicate that women with obesity who lead a healthy lifestyle before and during their pregnancy can reduce the degree of unhealthy heart remodeling in their children,” he said.
Dr. Seely, Dr. Norouzi, and Dr. Burden had no financial conflicts to disclose.
Preconception and prenatal care are more complicated in women with chronic health conditions but attention to disease management and promoting the adoption of a healthier lifestyle can improve outcomes for mothers and infants, according to a growing body of research.
The latest version of the International Federation of Gynecology and Obstetrics Preconception Checklist, published in the International Journal of Gynecology & Obstetrics, highlights preexisting chronic medical conditions such as diabetes, lupus, and obesity as key factors to address in preconception care through disease management. A growing number of studies support the impact of these strategies on short- and long-term outcomes for mothers and babies, according to the authors.
Meet Glycemic Control Goals Prior to Pregnancy
“Women with diabetes can have healthy pregnancies but need to prepare for pregnancy in advance,” Ellen W. Seely, MD, professor of medicine at Harvard Medical School and director of clinical research in the endocrinology, diabetes, and hypertension division of Brigham and Women’s Hospital, Boston, said in an interview.
“If glucose levels are running high in the first trimester, this is associated with an increased risk of birth defects, some of which are very serious,” said Dr. Seely. Getting glucose levels under control reduces the risk of birth defects in women with diabetes close to that of the general population, she said.
The American Diabetes Association has set a goal for women to attain an HbA1c of less than 6.5% before conception, Dr. Seely said. “In addition, some women with diabetes may be on medications that should be changed to another class prior to pregnancy,” she noted. Women with type 1 or type 2 diabetes often have hypertension as well, but ACE inhibitors are associated with an increased risk of fetal renal damage that can result in neonatal death; therefore, these medications should be stopped prior to pregnancy, Dr. Seely emphasized.
“If a woman with type 2 diabetes is on medications other than insulin, recommendations from the ADA are to change to insulin prior to pregnancy, since we have the most data on the safety profile of insulin use in pregnancy,” she said.
To help women with diabetes improve glycemic control prior to pregnancy, Dr. Seely recommends home glucose monitoring, with checks of glucose four times a day, fasting, and 2 hours after each meal, and adjustment of insulin accordingly.
A healthy diet and physical activity remain important components of glycemic control as well. A barrier to proper preconception and prenatal care for women with diabetes is not knowing that a pregnancy should be planned, Dr. Seely said. Discussions about pregnancy should start at puberty for women with diabetes, according to the ADA, and the topic should be raised yearly so women can optimize their health and adjust medications prior to conception.
Although studies of drugs have been done to inform preconception care for women with diabetes, research is lacking in several areas, notably the safety of GLP-1 agonists in pregnancy, said Dr. Seely. “This class of drug is commonly used in type 2 diabetes and the current recommendation is to stop these agents 2 months prior to conception,” she said.
Conceive in Times of Lupus Remission
Advance planning also is important for a healthy pregnancy in women with systemic lupus erythematosus (SLE), Sayna Norouzi, MD, director of the glomerular disease clinic and polycystic kidney disease clinic of Loma Linda University Medical Center, California, said in an interview.
“Lupus mostly affects women of childbearing age and can create many challenges during pregnancy,” said Dr. Norouzi, the corresponding author of a recent review on managing lupus nephritis during pregnancy.
“Women with lupus face an increased risk of pregnancy complications such as preeclampsia, problems with fetal growth, stillbirth, and premature birth, and these risks increase based on factors such as disease activity, certain antibodies in the body, and other baseline existing conditions such as high blood pressure,” she said.
“It can be difficult to distinguish between a lupus flare and pregnancy-related issues, so proper management is important,” she noted. The Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (PROMISSE) study findings indicated a lupus nephritis relapse rate of 7.8% of patients in complete remission and 21% of those in partial remission during pregnancy, said Dr. Norouzi. “Current evidence has shown that SLE patients without lupus nephritis flare in the preconception period have a small risk of relapse during pregnancy,” she said.
Before and during pregnancy, women with lupus should work with their treating physicians to adjust medications for safety, watch for signs of flare, and aim to conceive during a period of lupus remission.
Preconception care for women with lupus nephritis involves a careful review of the medications used to control the disease and protect the kidneys and other organs, said Dr. Norouzi.
“Adjustments,” she said, “should be personalized, taking into account the mother’s health and the safety of the baby. Managing the disease actively during pregnancy may require changes to the treatment plan while minimizing risks,” she noted. However, changing medications can cause challenges for patients, as medications that are safer for pregnancy may lead to new symptoms and side effects, and patients will need to work closely with their healthcare providers to overcome new issues that arise, she added.
Preconception lifestyle changes such as increasing exercise and adopting a healthier diet can help with blood pressure control for kidney disease patients, said Dr. Norouzi.
In the review article, Dr. Norouzi and colleagues noted that preconception counseling for patients with lupus should address common comorbidities such as hypertension, diabetes, obesity, and dyslipidemia, and the risk for immediate and long-term cardiovascular complications.
Benefits of Preconception Obesity Care Extend to Infants
Current guidelines from the American College of Obstetricians and Gynecologists and the Institute of Medicine advise lifestyle interventions to reduce excessive weight gain during pregnancy and reduce the risk of inflammation, oxidative stress, insulin resistance, and lipotoxicity that can promote complications in the mother and fetus during pregnancy.
In addition, a growing number of studies suggest that women with obesity who make healthy lifestyle changes prior to conception can reduce obesity-associated risks to their infants.
Adults born to women with obesity are at increased risk of cardiovascular disease and early signs of heart remodeling are identifiable in newborns, Samuel J. Burden, PhD, a research associate in the department of women and children’s health, Kings’ College, London, said in an interview. “It is therefore important to investigate whether intervening either before or during pregnancy by promoting a healthy lifestyle can reduce this adverse impact on the heart and blood vessels,” he said.
In a recent study published in the International Journal of Obesity, Dr. Burden and colleagues examined data from eight studies based on data from five randomized, controlled trials including children of mothers with obesity who engaged in healthy lifestyle interventions of improved diet and increased physical activity prior to and during pregnancy. The study population included children ranging in age from less than 2 months to 3-7 years.
Lifestyle interventions for mothers both before conception and during pregnancy were associated with significant changes in cardiac remodeling in the children, notably reduced interventricular septal wall thickness. Additionally, five studies of cardiac systolic function and three studies of diastolic function showed improvement in blood pressure in children of mothers who took part in the interventions.
Dr. Burden acknowledged that lifestyle changes in women with obesity before conception and during pregnancy can be challenging, but should be encouraged. “During pregnancy, it may also seem unnatural to increase daily physical activity or change the way you are eating.” He emphasized that patients should consult their physicians and follow an established program. More randomized, controlled trials are needed from the preconception period to examine whether the health benefits are greater if the intervention begins prior to pregnancy, said Dr. Burden. However, “the current findings indeed indicate that women with obesity who lead a healthy lifestyle before and during their pregnancy can reduce the degree of unhealthy heart remodeling in their children,” he said.
Dr. Seely, Dr. Norouzi, and Dr. Burden had no financial conflicts to disclose.
Preconception and prenatal care are more complicated in women with chronic health conditions but attention to disease management and promoting the adoption of a healthier lifestyle can improve outcomes for mothers and infants, according to a growing body of research.
The latest version of the International Federation of Gynecology and Obstetrics Preconception Checklist, published in the International Journal of Gynecology & Obstetrics, highlights preexisting chronic medical conditions such as diabetes, lupus, and obesity as key factors to address in preconception care through disease management. A growing number of studies support the impact of these strategies on short- and long-term outcomes for mothers and babies, according to the authors.
Meet Glycemic Control Goals Prior to Pregnancy
“Women with diabetes can have healthy pregnancies but need to prepare for pregnancy in advance,” Ellen W. Seely, MD, professor of medicine at Harvard Medical School and director of clinical research in the endocrinology, diabetes, and hypertension division of Brigham and Women’s Hospital, Boston, said in an interview.
“If glucose levels are running high in the first trimester, this is associated with an increased risk of birth defects, some of which are very serious,” said Dr. Seely. Getting glucose levels under control reduces the risk of birth defects in women with diabetes close to that of the general population, she said.
The American Diabetes Association has set a goal for women to attain an HbA1c of less than 6.5% before conception, Dr. Seely said. “In addition, some women with diabetes may be on medications that should be changed to another class prior to pregnancy,” she noted. Women with type 1 or type 2 diabetes often have hypertension as well, but ACE inhibitors are associated with an increased risk of fetal renal damage that can result in neonatal death; therefore, these medications should be stopped prior to pregnancy, Dr. Seely emphasized.
“If a woman with type 2 diabetes is on medications other than insulin, recommendations from the ADA are to change to insulin prior to pregnancy, since we have the most data on the safety profile of insulin use in pregnancy,” she said.
To help women with diabetes improve glycemic control prior to pregnancy, Dr. Seely recommends home glucose monitoring, with checks of glucose four times a day, fasting, and 2 hours after each meal, and adjustment of insulin accordingly.
A healthy diet and physical activity remain important components of glycemic control as well. A barrier to proper preconception and prenatal care for women with diabetes is not knowing that a pregnancy should be planned, Dr. Seely said. Discussions about pregnancy should start at puberty for women with diabetes, according to the ADA, and the topic should be raised yearly so women can optimize their health and adjust medications prior to conception.
Although studies of drugs have been done to inform preconception care for women with diabetes, research is lacking in several areas, notably the safety of GLP-1 agonists in pregnancy, said Dr. Seely. “This class of drug is commonly used in type 2 diabetes and the current recommendation is to stop these agents 2 months prior to conception,” she said.
Conceive in Times of Lupus Remission
Advance planning also is important for a healthy pregnancy in women with systemic lupus erythematosus (SLE), Sayna Norouzi, MD, director of the glomerular disease clinic and polycystic kidney disease clinic of Loma Linda University Medical Center, California, said in an interview.
“Lupus mostly affects women of childbearing age and can create many challenges during pregnancy,” said Dr. Norouzi, the corresponding author of a recent review on managing lupus nephritis during pregnancy.
“Women with lupus face an increased risk of pregnancy complications such as preeclampsia, problems with fetal growth, stillbirth, and premature birth, and these risks increase based on factors such as disease activity, certain antibodies in the body, and other baseline existing conditions such as high blood pressure,” she said.
“It can be difficult to distinguish between a lupus flare and pregnancy-related issues, so proper management is important,” she noted. The Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (PROMISSE) study findings indicated a lupus nephritis relapse rate of 7.8% of patients in complete remission and 21% of those in partial remission during pregnancy, said Dr. Norouzi. “Current evidence has shown that SLE patients without lupus nephritis flare in the preconception period have a small risk of relapse during pregnancy,” she said.
Before and during pregnancy, women with lupus should work with their treating physicians to adjust medications for safety, watch for signs of flare, and aim to conceive during a period of lupus remission.
Preconception care for women with lupus nephritis involves a careful review of the medications used to control the disease and protect the kidneys and other organs, said Dr. Norouzi.
“Adjustments,” she said, “should be personalized, taking into account the mother’s health and the safety of the baby. Managing the disease actively during pregnancy may require changes to the treatment plan while minimizing risks,” she noted. However, changing medications can cause challenges for patients, as medications that are safer for pregnancy may lead to new symptoms and side effects, and patients will need to work closely with their healthcare providers to overcome new issues that arise, she added.
Preconception lifestyle changes such as increasing exercise and adopting a healthier diet can help with blood pressure control for kidney disease patients, said Dr. Norouzi.
In the review article, Dr. Norouzi and colleagues noted that preconception counseling for patients with lupus should address common comorbidities such as hypertension, diabetes, obesity, and dyslipidemia, and the risk for immediate and long-term cardiovascular complications.
Benefits of Preconception Obesity Care Extend to Infants
Current guidelines from the American College of Obstetricians and Gynecologists and the Institute of Medicine advise lifestyle interventions to reduce excessive weight gain during pregnancy and reduce the risk of inflammation, oxidative stress, insulin resistance, and lipotoxicity that can promote complications in the mother and fetus during pregnancy.
In addition, a growing number of studies suggest that women with obesity who make healthy lifestyle changes prior to conception can reduce obesity-associated risks to their infants.
Adults born to women with obesity are at increased risk of cardiovascular disease and early signs of heart remodeling are identifiable in newborns, Samuel J. Burden, PhD, a research associate in the department of women and children’s health, Kings’ College, London, said in an interview. “It is therefore important to investigate whether intervening either before or during pregnancy by promoting a healthy lifestyle can reduce this adverse impact on the heart and blood vessels,” he said.
In a recent study published in the International Journal of Obesity, Dr. Burden and colleagues examined data from eight studies based on data from five randomized, controlled trials including children of mothers with obesity who engaged in healthy lifestyle interventions of improved diet and increased physical activity prior to and during pregnancy. The study population included children ranging in age from less than 2 months to 3-7 years.
Lifestyle interventions for mothers both before conception and during pregnancy were associated with significant changes in cardiac remodeling in the children, notably reduced interventricular septal wall thickness. Additionally, five studies of cardiac systolic function and three studies of diastolic function showed improvement in blood pressure in children of mothers who took part in the interventions.
Dr. Burden acknowledged that lifestyle changes in women with obesity before conception and during pregnancy can be challenging, but should be encouraged. “During pregnancy, it may also seem unnatural to increase daily physical activity or change the way you are eating.” He emphasized that patients should consult their physicians and follow an established program. More randomized, controlled trials are needed from the preconception period to examine whether the health benefits are greater if the intervention begins prior to pregnancy, said Dr. Burden. However, “the current findings indeed indicate that women with obesity who lead a healthy lifestyle before and during their pregnancy can reduce the degree of unhealthy heart remodeling in their children,” he said.
Dr. Seely, Dr. Norouzi, and Dr. Burden had no financial conflicts to disclose.
Women’s Risk for Lupus Rises With Greater Intake of Ultraprocessed Foods
TOPLINE:
A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.
METHODOLOGY:
- Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
- Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
- Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.
TAKEAWAY:
- A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
- The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
- Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
- No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.
IN PRACTICE:
This study is too preliminary to have practical application.
SOURCE:
The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.
LIMITATIONS:
The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.
DISCLOSURES:
The study was supported by the National Institutes of Health. The authors did not declare any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.
METHODOLOGY:
- Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
- Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
- Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.
TAKEAWAY:
- A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
- The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
- Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
- No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.
IN PRACTICE:
This study is too preliminary to have practical application.
SOURCE:
The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.
LIMITATIONS:
The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.
DISCLOSURES:
The study was supported by the National Institutes of Health. The authors did not declare any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
A higher intake of ultraprocessed foods increases the risk for systemic lupus erythematosus (SLE) by over 50% in women. The risk doubled in those with anti–double-stranded DNA antibodies.
METHODOLOGY:
- Researchers assessed 204,175 women from two Nurses’ Health Study cohorts from 1984 to 2016.
- Participants completed semiquantitative food frequency questionnaires every 4 years for the assessment of dietary intake.
- Incident SLE cases were self-reported and confirmed using medical records, with 212 cases identified.
TAKEAWAY:
- A higher cumulative average daily intake of ultraprocessed foods was associated with a 56% increased risk for SLE (95% confidence interval [CI], 1.04-2.32).
- The risk for anti–double-stranded DNA antibody-positive SLE was more than doubled (hazard ratio, 2.05; 95% CI, 1.15-3.65).
- Sugar or artificially sweetened beverages were associated with a 45% increased risk for SLE (95% CI, 1.01-2.09).
- No significant interactions with body mass index were observed in the association between ultraprocessed food intake and SLE.
IN PRACTICE:
This study is too preliminary to have practical application.
SOURCE:
The study was led by Sinara Rossato, PhD, Harvard T.H. Chan School of Public Health, Boston. It was published online in Arthritis Care & Research.
LIMITATIONS:
The study’s generalizability is limited due to the predominantly White female population of registered nurses. The relatively high baseline age of participants may not fully capture the peak incidence age range for SLE. The observational nature of the study cannot establish causality between ultraprocessed food intake and SLE risk.
DISCLOSURES:
The study was supported by the National Institutes of Health. The authors did not declare any competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
Gout Drugs in Late-Phase Trials Might Increase Patients at Target Urate Level
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
VIENNA — Safe and effective options for lowering serum uric acid (sUA) in patients with gout who are refractory to conventional therapies appear to be near, judging from phase 2 and 3 trials that produced positive results at the annual European Congress of Rheumatology.
Reports from the meeting included two phase 2 studies with novel urate anion transporter 1 (URAT1) inhibitors for patients with refractory gout, in addition to extension data from the phase 3 trial program for SEL-212. In all cases, efficacy appeared to be on the same order of currently available drugs with potentially better tolerability, an important unmet need for patients with gout refractory to traditional therapies.
12-Month Outcomes With SEL-212
The extension data with SEL-212 follow the 6-month results presented from the DISSOLVE I and II trials at EULAR 2023. Now at 12 months, the benefits have proven to be generally sustained with no new safety signals, according to Herbert S.B. Baraf, MD, The Center for Rheumatology and Bone Research, Wheaton, Maryland.
SEL-212 is a drug platform involving two components delivered by intravenous infusion once monthly in sequence. The first, SEL-110, consists of tolerogenic nanoparticles containing sirolimus. The second, SEL-037, is the pegylated uricase pegadricase.
On the 1-month dosing schedule, most patients who had responded at 6 months were still responding at 12 months, and both of the two study doses of SEL-212 in the DISSOLVE trials were well tolerated over the extension, Dr. Baraf reported.
On the basis of the data so far, “this will be an effective and well tolerated therapy for refractory gout over a period of at least 12 months,” Dr. Baraf said.
The DISSOLVE I and II trials were identically designed. Patients with refractory gout, defined as failure to normalize sUA or control symptoms with a xanthine oxidase inhibitor, were randomly assigned to receive 0.15 mg SEL-212, 1.0 mg SEL-212, or placebo.
There was a stopping rule for patients who reached a sUA level < 2 mg/dL 1 hour after the infusion.
The primary endpoint was sUA level < 6 mg/dL for at least 80% of the sixth month of the 6-month trial. About 50% of patients on either dose of SEL-212 met this endpoint (vs 4% of those receiving placebo; P < .0001). There was a numerical advantage for the higher dose in both studies.
Patients who completed the 6-month trial were eligible for a 6-month extension, during which they remained on their assigned therapy, including placebo. This phase was also blinded. Patients who met the stopping rule in either the main study or extension did not take the study drug but remained in the study for final analysis.
Of the 265 patients who participated in the main phase of the study, 143 (54%) completed the 6-month extension. Most discontinuations were the result of the stopping rule. Reasons for other patients discontinuing the study included withdrawal of consent in about 10% of each treatment arm and adverse events in 13.8%, 6.8%, and 2.2% of the high-dose, low-dose, and placebo groups, respectively.
At 12 months, when the data from the two trials were pooled, the proportion of patients on therapy and responding remained at about 50% in the high-dose group and 43% in the low-dose group on an intention-to-treat analysis. Relative to the 8% response rate for placebo, the advantage for either dose was highly significant (P < .0001).
In the subgroup of patients with tophi at baseline, representing about half the study group, responses were low at 12 months, whether on high- (41%) or low-dose (43%) SEL-212. The rate of response among placebo patients with baseline tophi was 9%.
Safety of SEL-212
The safety over the 6-month extension did not differ substantially from that observed during the first 6 months, according to Dr. Baraf. This was reiterated in more detail by Alan Kivitz, MD, Altoona Center for Clinical Research, Duncansville, Pennsylvania. He delivered a separate safety presentation focused on DISSOLVE I.
Specifically, there were no serious adverse events thought to be related to treatment. Besides gout flares, which affected approximately 27% of patients regardless of active treatment or placebo assignment, the most common adverse effect was hypertriglyceridemia, which was observed in 5.4% of patients on active treatment vs 0% of those receiving placebo. Independent of the treatment arm, less than 5% of patients developed stomatitis or cellulitis during the 6-month extension period.
In the 6-month extension phase, there were no infusion reactions observed within 1 hour after SEL-212 administration and just two overall that occurred with low-dose SEL-212, according to Kivitz.
New Selective URAT1 Inhibitors
The other potential advance in the treatment of refractory gout is coming from newer selective URAT1 inhibitors. According to the lead investigators of two phase 2 trials evaluating a novel URAT1 inhibitor, the urate transporter protein has long been considered the most promising target for gout treatment. As this protein regulates the absorption of uric acid from the renal tubule, it has a direct uric acid–lowering effect. However, the adverse events of current agents, such as probenecid, benzbromarone, and sulfinpyrazone, have created a need for drugs with a better benefit-to-risk ratio.
In one of two multicenter phase 2 studies on refractory gout, the experimental agent ruzinurad was tested as an adjunct to the xanthine oxidase inhibitor febuxostat. In the other, the objective was to evaluate whether the experimental agent AR882 or AR882 plus allopurinol is better than allopurinol alone for reducing tophi at 12 months.
Ruzinurad Plus Febuxostat
In the ruzinurad trial, 151 patients with symptomatic gout and elevated sUA (> 6 mg/dL) for at least 6 weeks on stable doses of febuxostat were randomized to receive 5 mg ruzinurad, 10 mg ruzinurad, or placebo. All remained on febuxostat. In the active treatment arms, the starting ruzinurad dose was 1 mg before titrating up to the assigned target.
For the primary endpoint of sUA < 6 mg/dL at 12 weeks, the rates were 56.9%, 53.1%, and 13.7% in the high-dose, low-dose, and placebo groups, respectively (P < .0001 for both ruzinurad arms), reported Huihua Ding, MD, a clinician and researcher at Shanghai Jiao Tong University, Shanghai, China.
“Consistently, subgroup analyses based on baseline eGFR [estimated glomerular filtration rate], sUA, and tophus demonstrated superior effective of ruzinurad plus febuxostat over placebo plus febuxostat,” reported Dr. Ding, who noted that previous clinical studies suggested the potential for synergism between ruzinurad and febuxostat.
The proportion of patients achieving the more rigorous target of < 0.5 mg/dL was also higher with the higher and lower doses of ruzinurad vs placebo (43.1% and 38.8% vs 9.8%, respectively).
The proportion of patients with treatment-emergent side effects did not differ between the three groups. The most common were gout flares, which were observed in 39.2%, 49.0%, and 45.1% in the high-dose, low-dose, and placebo groups, respectively. Most adverse events were mild or moderate, and none led to treatment discontinuation.
The favorable benefit-to-risk profile of ruzinurad was attributed by Dr. Ding to its high relative selectivity and potent inhibition of URAT1, an advantage that might be relevant to avoiding side effects at higher doses.
AR882 in Patients With Tophi
In the trial with AR882, 42 patients with refractory gout and at least one subcutaneous tophus were randomized to receive 75 mg AR882, 50 mg AR882 plus allopurinol, or allopurinol alone. All drugs were taken once daily. Doses of allopurinol of up to 300 mg were permitted.
The changes in the target tophus area and crystal volume at month 6 were compared, and patients who completed this phase were invited into a 6-month extension. In the 6-month extension, 75 mg AR882 was additionally provided to those who had been in the single-agent allopurinol arm. The other arms were unchanged.
Tophi measurements were performed with calipers at regular intervals. Change from baseline in sUA levels was also an efficacy measure, according to Robert Keenan, MD, chief medical officer of Arthrosi Therapeutics, which is developing AR882.
From average baseline sUA levels of > 9 mg/dL, all three treatments reduced sUA levels by an average of at least 4.5 mg by month 3. At month 6, complete resolution of at least one target tophus was observed in 29% of the group randomized to receive 75 mg AR882 alone, 8% of those randomized to receive 50 mg AR882 plus allopurinol, and 8% of those on allopurinol alone.
At month 12, the average sUA levels were 4.3 mg/dL for 75 mg AR882, 3.7 mg/dL for 50 mg AR882 plus allopurinol, and 2.9 mg/dL for the 75 mg AR882 plus allopurinol extension-switch arm.
At the 12-month mark, the proportions of patients with complete resolution of any tophus were 50.0% for 75 mg AR882, 12.5% for 50 mg AR882 plus allopurinol, and 36.4% for the 75 mg AR882 plus allopurinol extension-switch arm, according to Dr. Keenan.
Compared with allopurinol alone at 6 months, 75 mg AR882 led to a reduction in total urate crystal volume, and this reduction was sustained at 12 months, he added.
Alone or in combination with allopurinol, AR882 was well tolerated. Gout flares were the most common adverse events, but they declined with continued AR882 treatment, according to Dr. Keenan. Diarrhea, headache, and upper respiratory infections were reported but were of mild or moderate severity.
Again, the take-home message from this study, like the other phase 2 study of a novel URAT1 inhibitor, is that these newer drugs might offer a better benefit-to-risk ratio, particularly in those with refractory disease.
“AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition,” Dr. Keenan said.
Dr. Baraf reported financial relationships with Horizon Therapeutics, Fresenius Kabi, Grünenthal, Olatec, Selecta Biosciences, and Sobi, which provided funding for the trials he discussed. Dr. Kivitz also reported a financial relationship with Sobi, which funded the DISSOLVE trials, along with AbbVie, Amgen, Eli Lilly, Flexion, GlaxoSmithKline, and Sanofi Regeneron. Dr. Ding reported no potential conflicts. The study she discussed was funded by Jiangsu Hengrui Pharmaceuticals. Dr. Keenan is an employee of Arthrosi Therapeutics, which provided funding for the trial he presented.
August 1, 2024 — Editor's note: This article has been updated to reflect the correct number of infusion reactions reported in the 6-month extension phase of the DISSOLVE I trial.
A version of this article appeared on Medscape.com.
FROM EULAR 2024