Rheumatology

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

[email protected]

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

[email protected]

Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.

Bruce Jancin/MDedge News

But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.

He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.

Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
 

RA improvement on an ITIS diet

Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.

However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.

The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.

As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.

At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.

Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.

The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.

Biqi is big in China, gaining ground in the U.S.

Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.

“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.

If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.

In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.

“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.

American RA patients embrace turmeric

Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.

Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.

Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
 

What about osteoarthritis?

Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.

Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.

Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.

Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
 

[email protected]

Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.

Courtesy Dr. Alexis Ogdie

“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.

Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
 

Anxiety and depression

Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.

Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.

“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.

Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.

“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”

Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.

“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.

The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.

Obesity

Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.

The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.

The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.

“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.

Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.

What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.

Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.

Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.

New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.

Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.

[email protected]

Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.

Courtesy Dr. Alexis Ogdie

“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.

Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
 

Anxiety and depression

Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.

Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.

“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.

Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.

“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”

Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.

“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.

The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.

Obesity

Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.

The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.

The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.

“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.

Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.

What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.

Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.

Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.

New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.

Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.

[email protected]

Only about 30% or fewer of patients with psoriatic arthritis (PsA) on therapy achieve disease remission by any definition. One reason for this may be inadequate attention to common comorbid conditions, Alexis Ogdie, MD, MSCE, declared at the 2021 Rheumatology Winter Clinical Symposium.

Courtesy Dr. Alexis Ogdie

“I believe that addressing off-target aspects of disease is really important to improving the patient experience of their disease. We might need to target these directly in order to improve outcomes,” said Dr. Ogdie, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia, who coauthored the current American College of Rheumatology/National Psoriasis Foundation PsA guidelines.

Since rheumatologists are by now well informed about the increased cardiovascular risk associated with PsA, she focused on two common comorbidities that get less attention, both of which are associated with worse clinical outcomes in PsA: obesity and mental health issues.
 

Anxiety and depression

Dr. Ogdie was first author of a large, population-based, longitudinal cohort study of cause-specific mortality in 8,706 U.K. patients with PsA, 41,752 with RA, and more than 81,000 controls. Particularly striking was the finding of elevated mortality because of suicide in the rheumatic disease patients: a 203% increased risk in the PsA population, compared with the general population, and a 147% greater risk in patients with RA.

Overall, 30%-40% of PsA patients have comorbid depression and/or anxiety.

“That’s pretty striking. It’s also true for rheumatoid arthritis and axial spondyloarthritis. And if you’re depressed, you’re much less likely to respond to therapy in the way that we are measuring response to therapy,” Dr. Ogdie said.

Her approach to screening for depression and anxiety in her PsA patients, and indeed in all her other patients, is to begin by normalizing the topic, explaining to them that these affective disorders are common among patients with these disorders. She lets her patients know they can talk to her about it. And she informs them that, while effective treatment of their rheumatic disease may improve their depression or anxiety, managing those is also important for improving their disease. Additionally, understanding whether depression is present is important prior to prescribing certain medications. Apremilast (Otezla), for example, can worsen preexisting depression.

“Ask about signs and symptoms of depression,” Dr. Ogdie urged her colleagues. “I do this at every single visit in my review of symptoms. This is one I don’t skip. I ask: ‘Do you have any symptoms of depression or anxiety?’ ”

Structured evidence-based screening tools, many of which are well suited for completion during a patient’s preappointment check-in survey, include the Patient Health Questionnaire–2, the PHQ-9, the Patient-Reported Outcomes Measure Information System–10, PROMIS–Depression, and Routine Assessment of Patient Index Data 3.

“I also really like the PROMIS-29. It covers many domains of interest: depression and anxiety, sleep, fatigue, pain, physical function. It gives a lot of information about what’s going on in a patient’s life right now,” according to the rheumatologist.

The main thing is to regularly screen for anxiety and depression and then refer symptomatic patients for further assessment and treatment. This is not something that all rheumatologists have been trained to do.

Obesity

Dr. Ogdie was lead author of a national CORRONA Registry study which concluded that obese patients with PsA were only half as likely to achieve remission on a tumor necrosis factor (TNF) inhibitor, compared with nonobese patients. She believes the same holds true for all other types of therapy: Across the board, obesity is associated with a poor response. And obesity is much more common in PsA patients than the general population in every age group. Moreover, obesity is associated with risk factors for cardiovascular disease and is associated with fatty liver disease, two other major comorbid conditions in the PsA population.

The CORRONA Registry findings are supportive of an earlier Italian prospective, observational study of 135 obese and an equal number of normal-weight PsA patients, all of whom started on a TNF inhibitor and were followed for 24 months. In a multivariate-adjusted analysis, obesity was independently associated with a 390% higher risk of not achieving minimal disease activity.

The same Italian group subsequently conducted a prospective dietary intervention study in 138 overweight or obese patients with PsA starting anti-TNF therapy. A total of 59% of participants randomized to either of the two dietary interventions experienced at least a 5% weight loss at 6 months. The key study finding: Compared with the subjects with less than 5% weight loss, those with 5%-10% weight loss were 275% more likely to achieve minimal disease activity at 6 months, and in those with greater than 10% weight loss the likelihood of attaining minimal disease activity increased by 567%.

“We’re talking about a disease where treatments tested in clinical trials have odds ratios in the 1.2 range, compared with other therapies, so this is a really striking difference,” she observed.

Several studies have demonstrated that obesity in psoriasis patients is a risk factor for developing PsA. Recently, U.K. investigators took things a step further, reporting in a huge observational study that obese or overweight psoriasis patients who reduced their body mass index over a 10-year period had a corresponding reduction in the risk of developing PsA, compared with overweight or obese psoriasis patients whose BMI remained steady over the same period.

What’s needed now is access to programs to help patients with PsA lose weight. Health insurers are often unwilling to provide coverage. “We have a really tough time getting the patients in to see a nutritionist unless they’re willing to pay out of pocket,” Dr. Ogdie said.

Physical activity is an important element in successful weight loss. It also is recommended in practice guidelines for patients with inflammatory arthritis because of its salutary effects on disease activity scores, pain and stiffness, sleep, and quality of life. But a recent survey conducted by Dr. Ogdie and coworkers concluded that patients with PsA and other forms of inflammatory arthritis don’t receive much exercise guidance from their rheumatologists. About 60% of subjects were inactive. Those who were physically active typically engaged in aerobic exercise but were much less likely to do the other guideline-recommended forms of exercise, namely flexibility, balance, and resistance training. The patients’ report of low engagement of their physicians “suggests an opportunity for more prescriptive exercise discussions,” according to the investigators.

Diabetes, a critical risk factor for cardiovascular disease, occurs at an increased incidence in PsA. This was demonstrated in a U.K. cohort study coauthored by Dr. Ogdie. The study, which included nearly 4,200 individuals with PsA, concluded that they had a 43% greater incidence of diabetes than the general population in an analysis adjusted for body mass index, smoking, alcohol use, and demographics.

New-onset diabetes can be readily picked up by rheumatologists based upon the laboratory work they often order at patient office visits, or during their review of symptoms, she noted, and added that the U.S. Preventive Services Task Force recommends ordering a hemoglobin A1c test every 3 years.

Dr. Ogdie reported receiving research grants and/or consulting fees from numerous pharmaceutical companies. Her research is also funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Psoriasis Foundation.

[email protected]

People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.

Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.

In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”

The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.

The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.

Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.

As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.

The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.

The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.

However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.

Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.

The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.

People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.

Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.

In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”

The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.

The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.

Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.

As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.

The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.

The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.

However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.

Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.

The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.

People with systemic lupus erythematosus (SLE) experienced significantly higher rates of first severe infections, a higher number of severe infections overall, and greater infection-related mortality, compared with controls, based on data from a population-based cohort study of more than 30,000 individuals.

Infections remain a leading cause of morbidity and early mortality in patients with SLE, wrote Kai Zhao, MSc, of Arthritis Research Canada, Richmond, and colleagues. However, “limitations from existing studies including selected samples, small sizes, and prevalent cohorts can negatively affect the accuracy of both the absolute and relative risk estimates of infections in SLE at the population level,” they said.

In a study published in Rheumatology, the researchers identified 5,169 people newly diagnosed with SLE between Jan. 1, 1997, and March 31, 2015, and matched them with 25,845 non-SLE controls using an administrative health database of all health care services funded in British Columbia during the time period. The investigators said the study is the first “to evaluate the risk of severe infections in a large population-based and incident SLE cohort.”

The average age of the patients was 46.9 at the time of their index SLE diagnosis, and 86% were women. The average follow-up period was approximately 10 years.

The primary outcome was the first severe infection after the onset of SLE that required hospitalization or occurred in the hospital setting. A total of 955 (18.5%) first severe infections occurred in the SLE group, compared with 1,988 (7.7%) in the controls, for incidence rates of 19.7 events per 1,000 person-years and 7.6 events per 1,000 person-years, respectively, yielding an 82% increased risk of severe infection for SLE patients after adjustment for confounding baseline factors.

Secondary outcomes of the total number of severe infections and infection-related mortality both showed significant increases in SLE patients, compared with controls. The total number of severe infections in the SLE and control groups was 1,898 and 3,114, respectively, with an adjusted risk ratio of 2.07.

As for mortality, a total of 539 deaths occurred in SLE patients during the study period, and 114 (21%) were related to severe infection. A total of 1,495 deaths occurred in the control group, including 269 (18%) related to severe infection. The adjusted hazard ratio was 1.61 after adjustment for confounding baseline variables.

The risks for first severe infection, total number of severe infections, and infection-related mortality were “independent of traditional risk factors for infection and the results remain robust in the presence of an unmeasured confounder (smoking) and competing risk of death,” the researchers said. Reasons for the increased risk are uncertain, but likely result from intrinsic factors such as immune system dysfunction and extrinsic factors such as the impact of immunosuppressive medications. “Future research can focus on quantifying the relative contributions of these intrinsic and extrinsic factors on the increased infection risk in SLE patients,” they added.

The study findings were limited by several factors linked to the observational design, including possible misdiagnosis of SLE and inaccurate measure of SLE onset, the researchers noted. In addition, no data were available for certain confounders such as smoking and nonhospitalized infections, they said.

However, the results were strengthened by the large size and general population and the use of sensitivity analyses, they noted. For SLE patients, “increased awareness of the risk of infections can identify their early signs and potentially prevent hospitalizations,” and clinicians can promote infection prevention strategies, including vaccinations when appropriate, they added.

Based on their findings, “we recommend a closer surveillance for severe infections in SLE patients and risk assessment for severe infections for SLE patients after diagnosis,” the researchers emphasized. “Further studies are warranted to further identify risk factors for infections in SLE patients to develop personalized treatment regimens and to select treatment in practice by synthesizing patient information,” they concluded.

The study was supported by the Canadian Institutes for Health Research. The researchers had no financial conflicts to disclose.

Almost one in four men and women diagnosed with kidney stones have osteoporosis or a history of fracture at the time of their diagnosis, yet fewer than 10% undergo bone mineral density (BMD) screening, a retrospective analysis of a Veterans Health Administration database shows.

kgerakis/Getty Images

Because the majority of those analyzed in the VA dataset were men, this means that middle-aged and older men with kidney stones have about the same risk for osteoporosis as postmenopausal women do, but BMD screening for such men is not currently recommended, the study notes.

“These findings suggest that the risk of osteoporosis or fractures in patients with kidney stone disease is not restricted to postmenopausal women but is also observed in men, a group that is less well recognized to be at risk,” Calyani Ganesan, MD, of Stanford (Calif.) University and colleagues say in their article, published online March 3 in the Journal of Bone and Mineral Research.

“We hope this work raises awareness regarding the possibility of reduced bone strength in patients with kidney stones, [and] in our future work, we hope to identify which patients with kidney stones are at higher risk for osteoporosis or fracture to help guide bone density screening efforts by clinicians in this population,” Dr. Ganesan added in a statement.
 

VA dataset: Just 9.1% had DXA after kidney stone diagnosed

A total of 531,431 patients with a history of kidney stone disease were identified in the VA dataset. Of these, 23.6% either had been diagnosed with osteoporosis or had a history of fracture around the time of their kidney stone diagnosis. The most common diagnosis was a non-hip fracture, seen in 19% of patients, Dr. Ganesan and colleagues note, followed by osteoporosis in 6.1%, and hip fracture in 2.1%.

The mean age of the patients who concurrently had received a diagnosis of kidney stone disease and osteoporosis or had a fracture history was 64.2 years. In this cohort, more than 91% were men. The majority of the patients were White.

Among some 462,681 patients who had no prior history of either osteoporosis or fracture before their diagnosis of kidney stones, only 9.1% had undergone dual-energy x-ray absorptiometry (DXA) screening for BMD in the 5 years after their kidney stone diagnosis.

“Of those who completed DXA ... 20% were subsequently diagnosed with osteoporosis,” the authors note – 19% with non-hip fracture, and 2.4% with hip fracture.

Importantly, 85% of patients with kidney stone disease who were screened with DXA and were later diagnosed with osteoporosis were men.

“Given that almost 20% of patients in our cohort had a non-hip fracture, we contend that osteoporosis is underdiagnosed and undertreated in older men with kidney stone disease,” the authors stress.

Perform DXA screen in older men, even in absence of hypercalciuria

The authors also explain that the most common metabolic abnormality associated with kidney stones is high urine calcium excretion, or hypercalciuria.

“In a subset of patients with kidney stones, dysregulated calcium homeostasis may be present in which calcium is resorbed from bone and excreted into the urine, which can lead to osteoporosis and the formation of calcium stones,” they explain.

However, when they carried out a 24-hour assessment of urine calcium excretion on a small subset of patients with kidney stones, “we found no correlation between osteoporosis and the level of 24-hour urine calcium excretion,” they point out.

Even when the authors excluded patients who were taking a thiazide diuretic – a class of drugs that decreases urine calcium excretion – there was no correlation between osteoporosis and the level of 24-hour urine calcium excretion.

The investigators suggest it is possible that, in the majority of patients with kidney stones, the cause of hypercalciuria is more closely related to overabsorption of calcium from the gut, not to overresorption of calcium from the bone.

“Nonetheless, our findings indicate that patients with kidney stone disease could benefit from DXA screening even in the absence of hypercalciuria,” they state.

“And our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, for whom efforts to mitigate risks of osteoporosis and fractures are not commonly emphasized,” they reaffirm.

The study was funded by the VA Merit Review and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have disclosed no relevant financial relationships.

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

Almost one in four men and women diagnosed with kidney stones have osteoporosis or a history of fracture at the time of their diagnosis, yet fewer than 10% undergo bone mineral density (BMD) screening, a retrospective analysis of a Veterans Health Administration database shows.

kgerakis/Getty Images

Because the majority of those analyzed in the VA dataset were men, this means that middle-aged and older men with kidney stones have about the same risk for osteoporosis as postmenopausal women do, but BMD screening for such men is not currently recommended, the study notes.

“These findings suggest that the risk of osteoporosis or fractures in patients with kidney stone disease is not restricted to postmenopausal women but is also observed in men, a group that is less well recognized to be at risk,” Calyani Ganesan, MD, of Stanford (Calif.) University and colleagues say in their article, published online March 3 in the Journal of Bone and Mineral Research.

“We hope this work raises awareness regarding the possibility of reduced bone strength in patients with kidney stones, [and] in our future work, we hope to identify which patients with kidney stones are at higher risk for osteoporosis or fracture to help guide bone density screening efforts by clinicians in this population,” Dr. Ganesan added in a statement.
 

VA dataset: Just 9.1% had DXA after kidney stone diagnosed

A total of 531,431 patients with a history of kidney stone disease were identified in the VA dataset. Of these, 23.6% either had been diagnosed with osteoporosis or had a history of fracture around the time of their kidney stone diagnosis. The most common diagnosis was a non-hip fracture, seen in 19% of patients, Dr. Ganesan and colleagues note, followed by osteoporosis in 6.1%, and hip fracture in 2.1%.

The mean age of the patients who concurrently had received a diagnosis of kidney stone disease and osteoporosis or had a fracture history was 64.2 years. In this cohort, more than 91% were men. The majority of the patients were White.

Among some 462,681 patients who had no prior history of either osteoporosis or fracture before their diagnosis of kidney stones, only 9.1% had undergone dual-energy x-ray absorptiometry (DXA) screening for BMD in the 5 years after their kidney stone diagnosis.

“Of those who completed DXA ... 20% were subsequently diagnosed with osteoporosis,” the authors note – 19% with non-hip fracture, and 2.4% with hip fracture.

Importantly, 85% of patients with kidney stone disease who were screened with DXA and were later diagnosed with osteoporosis were men.

“Given that almost 20% of patients in our cohort had a non-hip fracture, we contend that osteoporosis is underdiagnosed and undertreated in older men with kidney stone disease,” the authors stress.

Perform DXA screen in older men, even in absence of hypercalciuria

The authors also explain that the most common metabolic abnormality associated with kidney stones is high urine calcium excretion, or hypercalciuria.

“In a subset of patients with kidney stones, dysregulated calcium homeostasis may be present in which calcium is resorbed from bone and excreted into the urine, which can lead to osteoporosis and the formation of calcium stones,” they explain.

However, when they carried out a 24-hour assessment of urine calcium excretion on a small subset of patients with kidney stones, “we found no correlation between osteoporosis and the level of 24-hour urine calcium excretion,” they point out.

Even when the authors excluded patients who were taking a thiazide diuretic – a class of drugs that decreases urine calcium excretion – there was no correlation between osteoporosis and the level of 24-hour urine calcium excretion.

The investigators suggest it is possible that, in the majority of patients with kidney stones, the cause of hypercalciuria is more closely related to overabsorption of calcium from the gut, not to overresorption of calcium from the bone.

“Nonetheless, our findings indicate that patients with kidney stone disease could benefit from DXA screening even in the absence of hypercalciuria,” they state.

“And our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, for whom efforts to mitigate risks of osteoporosis and fractures are not commonly emphasized,” they reaffirm.

The study was funded by the VA Merit Review and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have disclosed no relevant financial relationships.

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

Almost one in four men and women diagnosed with kidney stones have osteoporosis or a history of fracture at the time of their diagnosis, yet fewer than 10% undergo bone mineral density (BMD) screening, a retrospective analysis of a Veterans Health Administration database shows.

kgerakis/Getty Images

Because the majority of those analyzed in the VA dataset were men, this means that middle-aged and older men with kidney stones have about the same risk for osteoporosis as postmenopausal women do, but BMD screening for such men is not currently recommended, the study notes.

“These findings suggest that the risk of osteoporosis or fractures in patients with kidney stone disease is not restricted to postmenopausal women but is also observed in men, a group that is less well recognized to be at risk,” Calyani Ganesan, MD, of Stanford (Calif.) University and colleagues say in their article, published online March 3 in the Journal of Bone and Mineral Research.

“We hope this work raises awareness regarding the possibility of reduced bone strength in patients with kidney stones, [and] in our future work, we hope to identify which patients with kidney stones are at higher risk for osteoporosis or fracture to help guide bone density screening efforts by clinicians in this population,” Dr. Ganesan added in a statement.
 

VA dataset: Just 9.1% had DXA after kidney stone diagnosed

A total of 531,431 patients with a history of kidney stone disease were identified in the VA dataset. Of these, 23.6% either had been diagnosed with osteoporosis or had a history of fracture around the time of their kidney stone diagnosis. The most common diagnosis was a non-hip fracture, seen in 19% of patients, Dr. Ganesan and colleagues note, followed by osteoporosis in 6.1%, and hip fracture in 2.1%.

The mean age of the patients who concurrently had received a diagnosis of kidney stone disease and osteoporosis or had a fracture history was 64.2 years. In this cohort, more than 91% were men. The majority of the patients were White.

Among some 462,681 patients who had no prior history of either osteoporosis or fracture before their diagnosis of kidney stones, only 9.1% had undergone dual-energy x-ray absorptiometry (DXA) screening for BMD in the 5 years after their kidney stone diagnosis.

“Of those who completed DXA ... 20% were subsequently diagnosed with osteoporosis,” the authors note – 19% with non-hip fracture, and 2.4% with hip fracture.

Importantly, 85% of patients with kidney stone disease who were screened with DXA and were later diagnosed with osteoporosis were men.

“Given that almost 20% of patients in our cohort had a non-hip fracture, we contend that osteoporosis is underdiagnosed and undertreated in older men with kidney stone disease,” the authors stress.

Perform DXA screen in older men, even in absence of hypercalciuria

The authors also explain that the most common metabolic abnormality associated with kidney stones is high urine calcium excretion, or hypercalciuria.

“In a subset of patients with kidney stones, dysregulated calcium homeostasis may be present in which calcium is resorbed from bone and excreted into the urine, which can lead to osteoporosis and the formation of calcium stones,” they explain.

However, when they carried out a 24-hour assessment of urine calcium excretion on a small subset of patients with kidney stones, “we found no correlation between osteoporosis and the level of 24-hour urine calcium excretion,” they point out.

Even when the authors excluded patients who were taking a thiazide diuretic – a class of drugs that decreases urine calcium excretion – there was no correlation between osteoporosis and the level of 24-hour urine calcium excretion.

The investigators suggest it is possible that, in the majority of patients with kidney stones, the cause of hypercalciuria is more closely related to overabsorption of calcium from the gut, not to overresorption of calcium from the bone.

“Nonetheless, our findings indicate that patients with kidney stone disease could benefit from DXA screening even in the absence of hypercalciuria,” they state.

“And our findings provide support for wider use of bone mineral density screening in patients with kidney stone disease, including middle-aged and older men, for whom efforts to mitigate risks of osteoporosis and fractures are not commonly emphasized,” they reaffirm.

The study was funded by the VA Merit Review and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have disclosed no relevant financial relationships.

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

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

[email protected]

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

[email protected]

It’s been a banner year for treatment advances in systemic lupus erythematosus (SLE), with two drugs gaining approval for lupus nephritis while other promising molecules with novel mechanisms of action advanced smartly through the developmental pipeline, speakers agreed at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“I think the most important thing in rheumatology in the last year is where we are now with lupus. With two drugs being approved for lupus nephritis, I think that’s really huge as we talk about treat-to-target,” said Alvin F. Wells, MD, PhD, a rheumatologist in Franklin, Wisc.

Martin Bergman, MD, concurred.

“Lupus has been blowing up in the past year. We have two new medications for lupus nephritis, we have two or three new mechanisms of action for therapy. I think that was one of the biggest things in rheumatology in the past year,” said Dr. Bergman, a rheumatologist at Drexel University in Philadelphia and in private practice in Ridley Park, Pa.

Together with Roy Fleischmann, MD, Dr. Wells spotlighted promising new molecules for the treatment of SLE, giant cell arteritis, vasculitis, rheumatoid arthritis, and osteoarthritis.
 

SLE

The two drugs approved in recent months specifically for lupus nephritis are voclosporin (Lupkynis) and belimumab (Benlysta), which has been approved for lupus for a decade. Voclosporin, an oral calcineurin inhibitor, is a modification of cyclosporine offering significant advantages over the older drug: It’s more potent, requires no dose titration, has a better safety profile, and is metabolized more quickly.

“A safer and easier-to-use calcineurin inhibitor is going to be huge,” Dr. Wells predicted.

Up for Food and Drug Administration review in the coming year on the basis of the positive phase 3 TULIP-1 and TULIP-2 trials is anifrolumab, a monoclonal antibody that binds to the type 1 interferon receptor subunit 1d. At 52 weeks in the pooled analysis, one or more SLE flares occurred in 33.6% of patients on anifrolumab and 42.9% of placebo-treated controls.

“This is not a blockbuster, but it’s a worthwhile addition, like belimumab,” according to Dr. Fleischmann, a rheumatologist at the University of Texas, Dallas.

Dr. Wells concurred, with a reservation: In a subgroup analysis of the TULIP trials, anifrolumab wasn’t significantly better than placebo in black patients, who tend to have more severe and tough-to-treat renal disease.

“Anifrolumab doesn’t look as effective as some other agents, and I’d be disinclined to give it to my black patients,” the rheumatologist said.

Dr. Fleischmann was far more enthusiastic about obinutuzumab (Gazyva), a humanized anti-CD20 monoclonal antibody already approved for the treatment of chronic lymphocytic leukemia and follicular lymphoma.

Bruce Jancin/MDedge News

A humanized monoclonal antibody known for now as BIIB059 demonstrated efficacy and was well tolerated in the phase 2 LILAC trial. BIIB059 binds to blood dendritic cell antigen 2 (BDCA2), a receptor specific to plasmacytoid dendritic cells, resulting in decreased production of type 1 interferon and other inflammatory cytokines. The LILAC trial included 132 SLE patients with active arthritis and skin disease who received subcutaneous injections of BIIB059 at 450 mg or placebo every 4 weeks, with an extra dose at week 2. The primary endpoint was met, with an absolute 15-joint reduction in the total number of tender or swollen joints from baseline to week 24 in the BIIB059 group, compared to an 11.6-joint reduction with placebo. In addition, the likelihood of an SRI-4 response at week 24 was 3.49-fold greater with BIIB059 than with placebo.

Dr. Wells noted that the BIIB059 group showed continued improvement from week 12 to week 24, unlike the response pattern seen with many biologics for rheumatoid arthritis, where a plateau is reached by 8-12 weeks.

Vasculitis

The positive results for the C5a receptor inhibitor avacopan for treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the phase-3 ADVOCATE trial have been hailed by some rheumatologists as a major breakthrough, but Dr. Fleischmann isn’t so sure.

The trial randomized 331 patients to oral avacopan at 30 mg twice daily or oral prednisone, with all patients on either cyclophosphamide or rituximab. Avacopan was noninferior to prednisone in terms of remission at week 26, but superior to prednisone for sustained taper at week 52. The rate of serious adverse events was 45.1% with prednisone and 42.2% in the avacopan arm.

“This is a drug that’s going to be much, much more expensive than prednisone. There were people in our group who were ecstatic that this drug is going to come, but how much it’s going to be used, I don’t know,” Dr. Fleischmann said.

Dr. Wells said cost-benefit analyses will be needed in order to learn if avacopan’s anticipated high sticker price is offset by the cost of serious corticosteroid side effects such as avascular necrosis.
 

Giant cell arteritis

Mavrilimumab is a human monoclonal antibody that inhibits human granulocyte macrophage colony stimulating factor receptor alpha. It demonstrated impressive efficacy in a phase 2, double-blind, randomized, placebo-controlled trial conducted in 70 patients with biopsy-confirmed giant cell arteritis. Participants were on corticosteroids until they went into remission and were then randomized to mavrilimumab or placebo, with the steroids stopped. By week 26, 19% of patients in the mavrilimumab arm had flared, as compared to 46.4% of controls.

“This is a game changer,” Dr. Wells declared. “I struggle with these patients because I can’t get the IL-6 drugs approved for them. I need something else.”

Dr. Fleischmann has a good idea how he’ll use mavrilimumab, if it wins approval: “I think this is clearly a drug you would use in a patient you can’t get off steroids and you’re having all the steroid toxicity. I don’t know that you’d use it right away.”

Osteoarthritis

Dr. Fleischmann predicted that tanezumab, a monoclonal antibody directed against nerve growth factor, will win FDA approval in 2021 for the treatment of osteoarthritis pain in patients with an inadequate response or intolerance to standard-of-care NSAIDs and opioids. But he cautioned his colleagues not to expect too much from the biologic, which has a long and checkered developmental history.

“It works better than placebo. It does not work better than an NSAID or an opioid. So it should be reasonable in patients who cannot take an NSAID or cannot or will not take an opioid,” he said.

There are safety issues to be aware of with tanezumab, he added: clinically significant increased risks of peripheral neuropathy and joint space narrowing.
 

Rheumatoid arthritis

Dr. Wells thought one of the most interesting novel therapies for RA in the past year didn’t involve a pharmaceutical, but rather noninvasive auricular branch stimulation of the vagus nerve. He cited an open-label, 12-week, uncontrolled study in 27 patients with active RA who wore an ear clip for vagal nerve stimulation for 12 weeks. The mean Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) – the primary study endpoint – improved from 6.30 at baseline to 3.76 at week 12. The number of tender joints dropped from 12.17 to 4.7, while the swollen joint count went from 7.0 to 3.44. Pain scores improved from 75.23 to 43.3. Scores on the Health Assessment Questionnaire Disability Index improved from 1.59 to 1.05. There was no significant change in CRP. All in all, a modest clinical effect achieved noninvasively.

“The thing that did it for me was the effect on MRI from baseline: decreased synovitis, osteitis, and bone erosion scores,” Dr. Wells said. “This is noninvasive, so patients who want to do medical marijuana or CBD can put an earring on their auricular nerve.”

Dr. Fleischmann scoffed. “An open-label study, 27 patients? Let me see the real study,” he quipped.

Dr. Fleischmann reported receiving clinical trial research grants from and serving as a consultant to more than a dozen pharmaceutical companies. Dr. Wells serves as a consultant to MiCare Path.

[email protected]

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

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

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

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

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

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

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.

Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
 

Swedes show biologics may reduce excess lymphoma risk in RA

Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.

The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.

Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.

“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”

Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.

“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”

Bruce Jancin/MDedge News

Beware underappreciated hazards of very-low-dose glucocorticoids

The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.

Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.

Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.

A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.

“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”

Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”

Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?

”Because when we find something that works, we stick to it,” Dr. Cush replied.

RA disease activity predicts VTE risk

The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.

The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.

The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
 

SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy

The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.

The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.

“This study could impact guidelines,” Dr. Cush predicted.

Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.

Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.

This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.

”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.

Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.

“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.

“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”

Making a SELECT-CHOICE in refractory RA

In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.

In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.

“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
 

Make way for machine learning

Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.

“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.

He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.

Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
 

Treat-to-target strategies don’t tame excess mortality in RA

At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.

“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.

“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
 

More trouble for tofacitinib

Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.

The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.

Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.

The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.

“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.

Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.

“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

Bruce Jancin/MDedge News

[email protected]

A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.

Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
 

Swedes show biologics may reduce excess lymphoma risk in RA

Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.

The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.

Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.

“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”

Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.

“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”

Bruce Jancin/MDedge News

Beware underappreciated hazards of very-low-dose glucocorticoids

The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.

Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.

Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.

A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.

“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”

Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”

Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?

”Because when we find something that works, we stick to it,” Dr. Cush replied.

RA disease activity predicts VTE risk

The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.

The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.

The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
 

SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy

The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.

The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.

“This study could impact guidelines,” Dr. Cush predicted.

Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.

Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.

This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.

”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.

Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.

“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.

“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”

Making a SELECT-CHOICE in refractory RA

In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.

In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.

“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
 

Make way for machine learning

Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.

“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.

He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.

Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
 

Treat-to-target strategies don’t tame excess mortality in RA

At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.

“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.

“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
 

More trouble for tofacitinib

Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.

The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.

Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.

The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.

“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.

Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.

“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

Bruce Jancin/MDedge News

[email protected]

A massive Swedish cohort study suggesting that biologic agents reduce the known excess risk of lymphoma in patients with rheumatoid arthritis was hailed as one of the high points of the last year by speakers at the 2021 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

The speakers gave additional shout-outs regarding other key developments in RA during the pandemic year, including two huge studies showing that even low-dose corticosteroids at 5 mg/day or less carry the price of increased risk of cardiovascular disease and serious infections; Swedish data showing that RA disease activity can be used for venous thromboembolism (VTE) risk stratification; evidence from the venerable BeST study showing at 17 years of follow-up that treat-to-target strategies didn’t prevent an increased mortality risk of RA compared to the general population; and a signal that artificial intelligence using machine learning will become useful in clinical practice sooner than many realize.

Also, the speakers offered kudos to the investigators in the SEAM-RA trial, whose results they expect to be practice changing. In addition, they praised the SELECT-CHOICE trial for providing insight into the relative safety and efficacy of upadacitinib (Rinvoq) and abatacept (Orencia) as second- or third-line therapy in RA. And they warned their colleagues of rocky upcoming months for tofacitinib (Xeljanz) as the Food and Drug Administration reviews concerning new data from a long-term postmarketing safety trial.
 

Swedes show biologics may reduce excess lymphoma risk in RA

Decades ago, Swedish investigators harnessed their nation’s comprehensive linked health registries to demonstrate that patients with RA are inherently at greater risk for developing lymphoma. Now the Swedes have used the registries to identify a strong signal that this excess risk of lymphoma is reduced in RA patients treated with biologic drugs.

The study included 16,392 RA patients who initiated treatment with a biologic during the study period, 55,253 who were biologic-naive, and 229,047 age- and sex-matched controls from the general population. During the years 2006-2016, there was an adjusted 31% reduction in the risk of incident lymphoma in RA patients who started a first biologic agent, compared with those who did not, and a 54% reduction in lymphoma in biologic-treated patients, compared with those who switched from one conventional synthetic disease-modifying antirheumatic drug (DMARD) to another.

Moreover, while RA patients with 0-2 years of accumulated time on biologics were at a statistically significant 3.42-fold increased risk of lymphoma, compared with the matched general population, that risk shrunk with longer exposure to these medications, dropping to a nonsignificant 1.53-fold increase with 3-4 years of biologic exposure and a 1.04-fold risk with 5 years or more. The lymphoma risks didn’t vary significantly among the TNF inhibitors, nor with the use of TNF inhibitors versus other biologics.

“I think this is really quite encouraging,” said John J. Cush, MD, professor of internal medicine at the University of Texas, Dallas. “If the lymphoma risk was related to inflammation, I think you’d see results like this. It really does speak to the fact that control of inflammation over time does lessen one’s risk of cancer.”

Arthur Kavanaugh, MD, observed that patients with RA continue to ask their rheumatologists if going on a TNF inhibitor will increase their risk of lymphoma, so these Swedish data are going to be useful in conversations in the clinic.

“I thought this study was very exciting,” said Dr. Kavanaugh, professor of medicine at the University of California, San Diego, and director of RWCS. “Maybe we can make the case now that the longer you’re on biologic therapies and the more recently you’re being treated, the better you do in terms of lymphoma risk.”

Bruce Jancin/MDedge News

Beware underappreciated hazards of very-low-dose glucocorticoids

The increased risk of osteoporotic fractures associated with corticosteroid therapy gets tons of attention. But the past year brought two cautionary studies that newly identified significantly increased risks of cardiovascular events and serious infection as well, even at doses of less than 5 mg/day, which have traditionally been believed safe long term.

Investigators at the University of Leeds (England) conducted a population-based cohort study in which they used the U.K. Clinical Practice Research Datalink to analyze the oral corticosteroid dose-dependent cardiovascular risk in 25,324 patients with RA and 62,470 with five other immune-mediated inflammatory diseases: inflammatory bowel disease, giant cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and vasculitis. None had known cardiovascular disease at baseline. The analysis accounted for changes in oral steroid dose over time and for the use of potentially confounding medications.

Over a median 5 years of follow-up, a strong steroid dose-dependent risk of acute MI, heart failure, atrial fibrillation, cerebrovascular disease, and abdominal aortic aneurysm was evident in patients with any of the six of the immune-mediated inflammatory diseases. The 1-year adjusted cumulative risk of major adverse cardiovascular events jumped from 1.4% during periods of nonuse to 8.9% at a daily dose of 25 mg or more. Notably, when patients were on oral steroids at doses less than 5 mg/day, their risk of one or more of these major adverse cardiovascular events was 74% greater than when off steroids.

A separate red flag regarding low-dose glucocorticoids was raised by a retrospective cohort study of the 1-year risk of hospitalization for serious infection in 172,041 RA patients in the Medicare claims database for the years 2005-2015. After 6 months of stable use of DMARDs, 47.1% of those patients were on corticosteroids. Their 1-year cumulative incidence of severe infection resulting in hospitalization was 11% if their dose was 5 mg/day or less, 14.4% at >5 to 10 mg/day, and 17.7% at >10 mg/day, all significantly greater than the 8.6% rate in patients not on steroids. The same pattern held true when the investigators separately scrutinized 44,118 RA patients in the Optum Clinformatics Data Mart database for the years 2006-2015.

“This is a really important paper telling us what you’ve always known, which is that there’s a dose-related increase in serious infections in people on steroids. Everybody knows that, but usually people think of 10 mg/day and above,” Dr. Cush said. “This is a little bit sobering for those of you who think, ‘Well, I’m doing OK using 2.5 or 4 mg/day.’ In this study, even at doses of 5 mg/day or less, there’s a significant increase in serious hospitalizable infections.”

Taken together, the message of these two huge studies is clear, he added: “The idea is we probably shouldn’t be using steroids.”

Given the large array of therapies now available to address various aspects of the inflammatory and immune responses in RA, Dr. Kavanaugh asked, why do so many rheumatologists still maintain their patients on low-dose steroids?

”Because when we find something that works, we stick to it,” Dr. Cush replied.

RA disease activity predicts VTE risk

The risk of VTE climbs with RA disease activity such that patients with high disease activity – defined using the erythrocyte sedimentation rate-based Disease Activity Score in 28 joints (DAS28-ESR) – have double the VTE risk of those in disease remission, according to a Swedish nationwide cohort study using data from the Swedish Rheumatology Quality Register. The investigators concluded that RA disease activity can be used in clinical practice as an additional tool for VTE risk stratification, alongside such established risk factors as immobilization, age, surgery, and comorbid conditions.

The study included 46,316 patients with RA who collectively experienced 2,241 VTE events within 1 year after one of their collective 322,601 visits to their rheumatologist. The overall cumulative 1-year incidence of VTE in the RA population was 0.71%, versus 0.36% in a control group composed of 215,843 randomly selected age- and sex-matched individuals drawn from the general Swedish population. That translates to an adjusted 1.88-fold increased risk in the RA group.

The VTE incidence was 0.52% in the year following a rheumatologist visit at which RA patients were found to be in DAS28-ESR remission. The adjusted risk for VTE climbed significantly in stepwise fashion with increasing disease activity: 12% greater risk with DAS28-ESR low disease activity, 48% greater risk with moderate disease activity, and 2.03-fold greater risk with high disease activity.
 

SEAM-RA shows which drug to withdraw to maintain remission gained on combo therapy

The SEAM-RA trial presented at the 2020 annual meeting of the American College of Rheumatology (ACR) and published shortly afterward in Arthritis & Rheumatology provides guidance on how to best implement a drug tapering strategy in patients who have achieved sustained remission on combination therapy with etanercept (Enbrel) and methotrexate. The purpose of such a strategy is to reduce patients’ medication burden and exposure to safety concerns inherent in continuing therapy. SEAM-RA included 371 RA patients in sustained disease remission during 24 weeks of open-label treatment with etanercept plus methotrexate. At that point, they were randomized 2:2:1 to 48 weeks of double-blind methotrexate monotherapy with etanercept withdrawal, etanercept monotherapy, or continued combination therapy. Those who experienced disease worsening on double-blind monotherapy were eligible for combination rescue therapy with both drugs.

The primary endpoint was maintenance of remission without disease worsening at week 48. This was accomplished in 52.9% of the combination therapy group, with a similar 49.5% success rate in patients on etanercept monotherapy, both significantly better than the 28.7% rate with methotrexate monotherapy. The inference is that biologic monotherapy might be an advantageous strategy for maintenance after achieving prolonged remission on combination therapy.

“This study could impact guidelines,” Dr. Cush predicted.

Among the key study findings, in his view, was that disease worsening occurred early following the switch to methotrexate monotherapy: typically within the first 2-4 weeks. And combination rescue therapy worked: Almost 75% of patients were able to recapture disease remission regardless of which drug they’d been on as monotherapy, and almost 90% of patients on rescue therapy achieved a low-disease-activity state.

Still, just over half of patients were able to maintain long-term remission after downshifting to etanercept monotherapy, Dr. Kavanaugh noted. “The bedeviling thing is we don’t know which patients can do this,” he said.

This was made abundantly clear in PREDICTRA, a phase 4, double-blind study in which 122 RA patients in sustained remission on 40 mg of adalimumab (Humira) every 2 weeks were randomized 5:1 to adalimumab taper or withdrawal for 36 weeks. Overall, 36% of the taper group and 45% of those who halted the biologic flared within 36 weeks. Nothing on an extensive list of candidate baseline predictors predicted flare in either group.

”I think the interesting thing here is that nothing predicted it, not drug levels, antidrug antibodies, not even MRI evidence of inflammation while in remission. The lack of predictors of who’s going to do well off therapy makes us crazy,” Dr. Kavanaugh said. Also noteworthy was that when full-dose, open-label adalimumab was reinstituted as rescue therapy in patients who flared, only half of them regained remission during the following 4 months, he observed.

Dr. Cush didn’t mince words regarding his view of the concept underlying PREDICTRA.

“Why are we even talking about this? We spend our whole lives trying to get these patients into remission, we’re heavily invested in combination therapy, we’re very proud of our great successes, and now we want to find data to condone, ‘Let’s get off drug therapy?’ ” he argued.

“There are untold consequences to this,” the rheumatologist continued. “There are cardiovascular consequences, and we’ve seen the x-ray studies that show that patients may be doing clinically better but still have x-ray worsening because you’ve withdrawn the TNF inhibitor. I think this is all nonsense, and I’m totally against it.”

Making a SELECT-CHOICE in refractory RA

In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.

In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.

“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
 

Make way for machine learning

Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.

“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.

He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.

Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
 

Treat-to-target strategies don’t tame excess mortality in RA

At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.

“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.

“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
 

More trouble for tofacitinib

Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.

The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.

Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.

The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.

“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.

Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.

“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.

Bruce Jancin/MDedge News

[email protected]

Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.

The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.

The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.

“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.

The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
 

Dosing data

Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.

Risk factor recognition

“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.

In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.

Screening strategies

Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.

Marc Bruxelle/Getty Images

In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.

The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.

“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.

“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.

First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.

Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.

The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.

The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.

“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.

The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
 

Dosing data

Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.

Risk factor recognition

“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.

In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.

Screening strategies

Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.

Marc Bruxelle/Getty Images

In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.

The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.

“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.

“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.

First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.

Hydroxychloroquine can be used safely and effectively with attention to dosing, risk factors, and screening, but communication among physicians, patients, and eye care specialists is key to optimizing outcomes and preventing complications, according to a joint statement from four medical societies.

The American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and the American Academy of Ophthalmology have produced a statement, published in Arthritis & Rheumatology, “to emphasize points of agreement that should be recognized by practitioners in all specialties,” lead author James T. Rosenbaum, MD, of Oregon Health & Science University, Portland, and colleagues wrote.

The statement was developed by a working group that included rheumatologists, ophthalmologists, and dermatologists with records of published studies on the use of hydroxychloroquine (HCQ) and its toxicity. The statement updated elements of the 2016 American Academy of Ophthalmology guidelines for monitoring patients for retinal toxicity when using HCQ.

“The need for collaborative management has triggered this joint statement, which applies only to managing the risk of HCQ retinopathy and does not include consideration of cardiac, muscle, dermatologic, or other toxicities,” the authors noted.

The authors emphasized that HCQ plays a valuable role in controlling many rheumatic diseases, and should not be abandoned out of fear of retinopathy. However, proper dosing, recognition of risk factors, and screening strategies are essential.
 

Dosing data

Data on HCQ dosing and retinopathy are limited, but the authors cited a study of 2,361 rheumatic disease patients with an average HCQ dosing regimen of 5.0 mg/kg per day or less in which the toxicity risk was less than 2% for up to 10 years of use. Although data show some increase in risk with duration of use, “for a patient with a normal screening exam in a given year, the risk of developing retinopathy in the ensuing year is low (e.g., less than 5%), even after 20 years of use,” the authors said.

Risk factor recognition

“High daily [HCQ] dosage relative to body weight and cumulative dose are the primary risk factors for retinopathy,” the authors noted. Reduced renal function is an additional risk factor, and patients with renal insufficiency should be monitored and may need lower doses.

In addition, patients with a phenotype of initial parafoveal toxicity may be at increased risk for advanced disease evidenced by damage to the foveal center. “The phenotype of initial parafoveal toxicity is not universal, and in many patients (East Asians particularly) the retinal changes may appear initially along the pericentral vascular arcades,” so these patients should be screened with additional tests beyond the central macula, they emphasized.

Screening strategies

Patients should receive a baseline retinal exam within a few months of starting HCQ to rule out underlying retinal disease, according to the statement. The goal of screening is “to detect early retinopathy before a bullseye becomes visible on ophthalmoscopy, since at that severe stage the damage tends to progress even after discontinuing the medication and may eventually threaten central vision,” the authors said.

Marc Bruxelle/Getty Images

In the absence of risk factors, patients can defer screening for 5 years, but should be screened annually from 5 years and forward, they said. Examples of underlying retinal disease include “significant macular degeneration, severe diabetic retinopathy, or hereditary disorders of retinal function, but these are judgments best made by the ophthalmologist since mild and stable abnormalities that do not interfere with interpretation of critical diagnostic tests may not be a contraindication” to use of HCQ.

The consensus opinion statement has limitations, notably the shortage of data on optimum HCQ dosage and the lack of prospective studies of toxicity, including the need for studies of the impact of blood levels on toxicity and studies of pharmacogenomics to stratify risk, the authors noted.

“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they said.

“Suggestive or uncertain findings should be discussed with the patient and prescribing physician to justify further examinations, but the drug need not be stopped until evidence for retinopathy is definitive, in particular for patients with active rheumatic or cutaneous disease,” and the overall risk of retinopathy remains low if the principles described in the statement are followed, they concluded.

First author Dr. Rosenbaum disclosed financial relationships with AbbVie, UCB, Gilead, Novartis, Horizon, Roche, Eyevensys, Santen, Corvus, Affibody, Kyverna, Pfizer, Horizon, and UpToDate. Another 5 of the study’s 11 authors also disclosed relationships with multiple companies.

Remote interventions using an Internet-based app and telephone outreach to engage patients with osteoarthritis to self-manage their disease have demonstrated the potential to improve some symptoms, at least in the short term, showing the potential for tools to interact with OA patients without having them come into an office or clinic.

ponsulak/Thinkstock

Remote interaction using these two forms of telemedicine – one a sophisticated digital platform, the other using a device that’s been around for almost 150 years – may have greater utility for keeping physicians connected with their OA patients during the COVID-19 pandemic, OA experts said in an interview.

“This is certainly relevant during the pandemic, but this has been of high interest for years as well, as researchers and clinicians have been seeking the best ways to reach patients with these types of programs,” said Kelli Allen, PhD, a research health scientist at the University of North Carolina at Chapel Hill.

Two separate studies evaluated the telemedicine platforms. In JAMA Internal Medicine, researchers reported that telephone-based cognitive-behavioral therapy (CBT) for patients aged 60 and older with OA and insomnia led to improved sleep, fatigue and, to a lesser extent, pain, in a randomized, controlled trial with 327 patients.

A separate randomized, controlled trial of 105 OA patients at the University of Nottingham (England), published in JAMA Network Open, reported that users of a smartphone-based exercise intervention app had greater improvements in pain and function than did controls.

“I think these two studies represent a first step in terms of moving forward, and certainly the interventions could be refined and potentially combined together for patients in the future,” said C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center in Tucson.

Phone-based CBT study

The telephone-based CBT study consisted of two groups: the CBT group (n = 163) who completed six 20- to 30-minute telephone calls over 8 weeks, kept daily diaries, and received tailored educational materials and an education-only group (n = 164). At 2 months after treatment, Insomnia Severity Index scores decreased 8.1 points on average in the CBT group versus 4.8 points in the education-only patients (P < .001).

That variation between the intervention group and controls was sustained out to a year: 7.7 points lower than baseline versus 4.7 points lower. At the same time point, 56.3% of the CBT group remained in remission with Insomnia Severity Index scores less than 7 versus 25.8% of controls. Fatigue outcomes were similarly disparate between the groups.

Pain outcomes were a different story, however. “Post treatment, significant differences were observed for pain, but these differences were not sustained at 12-month follow-up,” first author Susan M. McCurry, PhD, a clinical psychologist and faculty member at the University of Washington, Seattle, and colleagues wrote.

“I think their positive findings illustrate that remotely delivered interventions can be ‘low tech’ and still effective,” Dr. Allen said of the CBT phone study. She noted that complete case data were available for 282 of 327 patients. “The high rate of session attendance suggests that they chose a delivery modality appropriate for their target patient group.”

The scalability of the telephone model is noteworthy, Dr. Kwoh said. “Having a telemedicine intervention that could be scaled a little more easily rather than an in-person intervention, and having individualized treatment, that’s beneficial, as is targeting two symptoms that are very bothersome and burdensome to patients with OA: insomnia and fatigue.” Following patients out to 12 months is a strength of the study, he added.
 

Smartphone app–based exercise study

The U.K. study evaluated 6-week outcomes of 48 patients with knee OA who used a proprietary app-based exercise program (Joint Academy) and 57 controls who used traditional self-management. The app provided daily exercises and texts, along with email and smartphone reminders. The app was derived from the Better Management of Patients with OA program initiated in Sweden in 2008 that used OA treatment guidelines for education and exercise in person in primary care clinics.

App users showed a 1.5-point reduction in numeric rating scale (NRS) pain score at 6 weeks versus virtually no change in controls (P < .001). In terms of secondary outcomes, pain scores improved 2.2 points on average for app users versus 1.2 for controls (P = .02), with similar improvements recorded in both stiffness and physical function.

Average change in the 30-second sit-to-stand test measured 4.5 for the app users and 1.2 for the usual-care group (P < .001). The study found no difference between the two groups in changes in temporal summation, conditional pain modulation, or Arthritis Research UK Musculoskeletal Health Questionnaire scores.

First author Sameer Akram Gohir, MSc, PhD, and colleagues wrote that the reasons for differences in outcomes between app users and controls aren’t clear. “The superior outcome in the intervention group may depend on the content and context in the app, including a combination of standardized exercises and information, as well as using a digital delivery system.”

Data gathering was cut short because of COVID-19 restrictions in the United Kingdom, as 27 patients missed their in-person follow-up visits. That was one shortcoming of the study, Dr. Kwoh noted.

“Given the caveats certainly they were able to show robust changes in terms of decreased pain, and also improvement in a variety of performance measures. Certainly this may be beneficial – we don’t know – in terms of cost-effectiveness, but it may be beneficial for insurance companies to adapt such a program,” he said, adding that future studies into the cost effectiveness of the digital platform would be in order.

“Certainly, if this program were to decrease physician visits or postpone the need for joint replacement for individuals, then it could be certainly very cost effective,” Dr. Kwoh said.

The completion rate among patients in the study – almost 90% – was “impressive,” Dr. Allen said. “However, this is a relatively short-term study, and I think an important question for future research is whether patients continue with this level of engagement for a longer period of time.”

Dr. McCurry had no relevant financial relationships to disclose. The CBT phone study received funding from the Public Health Service and the National Institute on Aging. Coauthors disclosed relationships with Campbell Alliance Group, Mapi Research Trust, and Pfizer. Dr. Gohir reported no relevant financial relationships. The study received funding from the Versus Arthritis UK Plan Center, the National Institute for Health Research Nottingham Biomedical Research Center, and Pfizer Global. The Joint Academy provided software for the study. A coauthor reported a financial relationships with Pfizer. Dr. Kwoh said that in the past year he has consulted for Express Scripts, Kolon Tissue Gene, LG Chem, and Regeneron. In the past year, he also received institutional grants for clinical trials from AbbVie, Cumberland, Eicos, Eli Lilly, GlaxoSmithKline, Mitsubishi, and Pfizer. Dr. Allen had no relevant financial relationships to disclose.

Remote interventions using an Internet-based app and telephone outreach to engage patients with osteoarthritis to self-manage their disease have demonstrated the potential to improve some symptoms, at least in the short term, showing the potential for tools to interact with OA patients without having them come into an office or clinic.

ponsulak/Thinkstock

Remote interaction using these two forms of telemedicine – one a sophisticated digital platform, the other using a device that’s been around for almost 150 years – may have greater utility for keeping physicians connected with their OA patients during the COVID-19 pandemic, OA experts said in an interview.

“This is certainly relevant during the pandemic, but this has been of high interest for years as well, as researchers and clinicians have been seeking the best ways to reach patients with these types of programs,” said Kelli Allen, PhD, a research health scientist at the University of North Carolina at Chapel Hill.

Two separate studies evaluated the telemedicine platforms. In JAMA Internal Medicine, researchers reported that telephone-based cognitive-behavioral therapy (CBT) for patients aged 60 and older with OA and insomnia led to improved sleep, fatigue and, to a lesser extent, pain, in a randomized, controlled trial with 327 patients.

A separate randomized, controlled trial of 105 OA patients at the University of Nottingham (England), published in JAMA Network Open, reported that users of a smartphone-based exercise intervention app had greater improvements in pain and function than did controls.

“I think these two studies represent a first step in terms of moving forward, and certainly the interventions could be refined and potentially combined together for patients in the future,” said C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center in Tucson.

Phone-based CBT study

The telephone-based CBT study consisted of two groups: the CBT group (n = 163) who completed six 20- to 30-minute telephone calls over 8 weeks, kept daily diaries, and received tailored educational materials and an education-only group (n = 164). At 2 months after treatment, Insomnia Severity Index scores decreased 8.1 points on average in the CBT group versus 4.8 points in the education-only patients (P < .001).

That variation between the intervention group and controls was sustained out to a year: 7.7 points lower than baseline versus 4.7 points lower. At the same time point, 56.3% of the CBT group remained in remission with Insomnia Severity Index scores less than 7 versus 25.8% of controls. Fatigue outcomes were similarly disparate between the groups.

Pain outcomes were a different story, however. “Post treatment, significant differences were observed for pain, but these differences were not sustained at 12-month follow-up,” first author Susan M. McCurry, PhD, a clinical psychologist and faculty member at the University of Washington, Seattle, and colleagues wrote.

“I think their positive findings illustrate that remotely delivered interventions can be ‘low tech’ and still effective,” Dr. Allen said of the CBT phone study. She noted that complete case data were available for 282 of 327 patients. “The high rate of session attendance suggests that they chose a delivery modality appropriate for their target patient group.”

The scalability of the telephone model is noteworthy, Dr. Kwoh said. “Having a telemedicine intervention that could be scaled a little more easily rather than an in-person intervention, and having individualized treatment, that’s beneficial, as is targeting two symptoms that are very bothersome and burdensome to patients with OA: insomnia and fatigue.” Following patients out to 12 months is a strength of the study, he added.
 

Smartphone app–based exercise study

The U.K. study evaluated 6-week outcomes of 48 patients with knee OA who used a proprietary app-based exercise program (Joint Academy) and 57 controls who used traditional self-management. The app provided daily exercises and texts, along with email and smartphone reminders. The app was derived from the Better Management of Patients with OA program initiated in Sweden in 2008 that used OA treatment guidelines for education and exercise in person in primary care clinics.

App users showed a 1.5-point reduction in numeric rating scale (NRS) pain score at 6 weeks versus virtually no change in controls (P < .001). In terms of secondary outcomes, pain scores improved 2.2 points on average for app users versus 1.2 for controls (P = .02), with similar improvements recorded in both stiffness and physical function.

Average change in the 30-second sit-to-stand test measured 4.5 for the app users and 1.2 for the usual-care group (P < .001). The study found no difference between the two groups in changes in temporal summation, conditional pain modulation, or Arthritis Research UK Musculoskeletal Health Questionnaire scores.

First author Sameer Akram Gohir, MSc, PhD, and colleagues wrote that the reasons for differences in outcomes between app users and controls aren’t clear. “The superior outcome in the intervention group may depend on the content and context in the app, including a combination of standardized exercises and information, as well as using a digital delivery system.”

Data gathering was cut short because of COVID-19 restrictions in the United Kingdom, as 27 patients missed their in-person follow-up visits. That was one shortcoming of the study, Dr. Kwoh noted.

“Given the caveats certainly they were able to show robust changes in terms of decreased pain, and also improvement in a variety of performance measures. Certainly this may be beneficial – we don’t know – in terms of cost-effectiveness, but it may be beneficial for insurance companies to adapt such a program,” he said, adding that future studies into the cost effectiveness of the digital platform would be in order.

“Certainly, if this program were to decrease physician visits or postpone the need for joint replacement for individuals, then it could be certainly very cost effective,” Dr. Kwoh said.

The completion rate among patients in the study – almost 90% – was “impressive,” Dr. Allen said. “However, this is a relatively short-term study, and I think an important question for future research is whether patients continue with this level of engagement for a longer period of time.”

Dr. McCurry had no relevant financial relationships to disclose. The CBT phone study received funding from the Public Health Service and the National Institute on Aging. Coauthors disclosed relationships with Campbell Alliance Group, Mapi Research Trust, and Pfizer. Dr. Gohir reported no relevant financial relationships. The study received funding from the Versus Arthritis UK Plan Center, the National Institute for Health Research Nottingham Biomedical Research Center, and Pfizer Global. The Joint Academy provided software for the study. A coauthor reported a financial relationships with Pfizer. Dr. Kwoh said that in the past year he has consulted for Express Scripts, Kolon Tissue Gene, LG Chem, and Regeneron. In the past year, he also received institutional grants for clinical trials from AbbVie, Cumberland, Eicos, Eli Lilly, GlaxoSmithKline, Mitsubishi, and Pfizer. Dr. Allen had no relevant financial relationships to disclose.

Remote interventions using an Internet-based app and telephone outreach to engage patients with osteoarthritis to self-manage their disease have demonstrated the potential to improve some symptoms, at least in the short term, showing the potential for tools to interact with OA patients without having them come into an office or clinic.

ponsulak/Thinkstock

Remote interaction using these two forms of telemedicine – one a sophisticated digital platform, the other using a device that’s been around for almost 150 years – may have greater utility for keeping physicians connected with their OA patients during the COVID-19 pandemic, OA experts said in an interview.

“This is certainly relevant during the pandemic, but this has been of high interest for years as well, as researchers and clinicians have been seeking the best ways to reach patients with these types of programs,” said Kelli Allen, PhD, a research health scientist at the University of North Carolina at Chapel Hill.

Two separate studies evaluated the telemedicine platforms. In JAMA Internal Medicine, researchers reported that telephone-based cognitive-behavioral therapy (CBT) for patients aged 60 and older with OA and insomnia led to improved sleep, fatigue and, to a lesser extent, pain, in a randomized, controlled trial with 327 patients.

A separate randomized, controlled trial of 105 OA patients at the University of Nottingham (England), published in JAMA Network Open, reported that users of a smartphone-based exercise intervention app had greater improvements in pain and function than did controls.

“I think these two studies represent a first step in terms of moving forward, and certainly the interventions could be refined and potentially combined together for patients in the future,” said C. Kent Kwoh, MD, director of the University of Arizona Arthritis Center in Tucson.

Phone-based CBT study

The telephone-based CBT study consisted of two groups: the CBT group (n = 163) who completed six 20- to 30-minute telephone calls over 8 weeks, kept daily diaries, and received tailored educational materials and an education-only group (n = 164). At 2 months after treatment, Insomnia Severity Index scores decreased 8.1 points on average in the CBT group versus 4.8 points in the education-only patients (P < .001).

That variation between the intervention group and controls was sustained out to a year: 7.7 points lower than baseline versus 4.7 points lower. At the same time point, 56.3% of the CBT group remained in remission with Insomnia Severity Index scores less than 7 versus 25.8% of controls. Fatigue outcomes were similarly disparate between the groups.

Pain outcomes were a different story, however. “Post treatment, significant differences were observed for pain, but these differences were not sustained at 12-month follow-up,” first author Susan M. McCurry, PhD, a clinical psychologist and faculty member at the University of Washington, Seattle, and colleagues wrote.

“I think their positive findings illustrate that remotely delivered interventions can be ‘low tech’ and still effective,” Dr. Allen said of the CBT phone study. She noted that complete case data were available for 282 of 327 patients. “The high rate of session attendance suggests that they chose a delivery modality appropriate for their target patient group.”

The scalability of the telephone model is noteworthy, Dr. Kwoh said. “Having a telemedicine intervention that could be scaled a little more easily rather than an in-person intervention, and having individualized treatment, that’s beneficial, as is targeting two symptoms that are very bothersome and burdensome to patients with OA: insomnia and fatigue.” Following patients out to 12 months is a strength of the study, he added.
 

Smartphone app–based exercise study

The U.K. study evaluated 6-week outcomes of 48 patients with knee OA who used a proprietary app-based exercise program (Joint Academy) and 57 controls who used traditional self-management. The app provided daily exercises and texts, along with email and smartphone reminders. The app was derived from the Better Management of Patients with OA program initiated in Sweden in 2008 that used OA treatment guidelines for education and exercise in person in primary care clinics.

App users showed a 1.5-point reduction in numeric rating scale (NRS) pain score at 6 weeks versus virtually no change in controls (P < .001). In terms of secondary outcomes, pain scores improved 2.2 points on average for app users versus 1.2 for controls (P = .02), with similar improvements recorded in both stiffness and physical function.

Average change in the 30-second sit-to-stand test measured 4.5 for the app users and 1.2 for the usual-care group (P < .001). The study found no difference between the two groups in changes in temporal summation, conditional pain modulation, or Arthritis Research UK Musculoskeletal Health Questionnaire scores.

First author Sameer Akram Gohir, MSc, PhD, and colleagues wrote that the reasons for differences in outcomes between app users and controls aren’t clear. “The superior outcome in the intervention group may depend on the content and context in the app, including a combination of standardized exercises and information, as well as using a digital delivery system.”

Data gathering was cut short because of COVID-19 restrictions in the United Kingdom, as 27 patients missed their in-person follow-up visits. That was one shortcoming of the study, Dr. Kwoh noted.

“Given the caveats certainly they were able to show robust changes in terms of decreased pain, and also improvement in a variety of performance measures. Certainly this may be beneficial – we don’t know – in terms of cost-effectiveness, but it may be beneficial for insurance companies to adapt such a program,” he said, adding that future studies into the cost effectiveness of the digital platform would be in order.

“Certainly, if this program were to decrease physician visits or postpone the need for joint replacement for individuals, then it could be certainly very cost effective,” Dr. Kwoh said.

The completion rate among patients in the study – almost 90% – was “impressive,” Dr. Allen said. “However, this is a relatively short-term study, and I think an important question for future research is whether patients continue with this level of engagement for a longer period of time.”

Dr. McCurry had no relevant financial relationships to disclose. The CBT phone study received funding from the Public Health Service and the National Institute on Aging. Coauthors disclosed relationships with Campbell Alliance Group, Mapi Research Trust, and Pfizer. Dr. Gohir reported no relevant financial relationships. The study received funding from the Versus Arthritis UK Plan Center, the National Institute for Health Research Nottingham Biomedical Research Center, and Pfizer Global. The Joint Academy provided software for the study. A coauthor reported a financial relationships with Pfizer. Dr. Kwoh said that in the past year he has consulted for Express Scripts, Kolon Tissue Gene, LG Chem, and Regeneron. In the past year, he also received institutional grants for clinical trials from AbbVie, Cumberland, Eicos, Eli Lilly, GlaxoSmithKline, Mitsubishi, and Pfizer. Dr. Allen had no relevant financial relationships to disclose.