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Novel lupus therapies take center stage
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.
“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.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
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.
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.
“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.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
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.
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.
“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.
“It’s an anti-CD20, like rituximab. But it’s better than rituximab, it’s much more effective,” he said.
He pointed to the phase 2 NOBILITY trial, in which 125 patients with class III/IV lupus nephritis were randomized to a 1,000-mg infusion of obinutuzumab or placebo at weeks 0, 2, 24, and 26 and followed for 2 years. The complete renal response rate at 104 weeks in the obinutuzumab group was 41% and the partial renal response rate was 13%, compared to 23% and 6% in controls. The obinutuzumab group also did significantly better in terms of improvement in complement levels, double-stranded DNA, and estimated glomerular filtration rate. All this was accomplished even though the reduction in peripheral B cells dropped from 93% at week 24 to just 16% at week 104. This suggests that tissue levels of B cells in the kidney, joints, and skin may be more important than circulating B cell levels.
“This looks like a very promising agent for patients with lupus nephritis,” Dr. Wells said. “The fact that they got this long-term effect for 2 years with just four infusions is really impressive.”
Another promising drug is iberdomide, an oral modulator of the E3 ubiquitin ligase complex which decreases plasmacytoid dendritic cells and B cells while increasing T regulatory cells. In a phase 2b clinical trial in 288 patients with active SLE, all on background standard-of-care therapy, a 4-point or greater reduction in the SLE Responder Index (SRI-4) at week 24 was achieved in 54.3% of the group on iberdomide at 0.45 mg/day, a significantly better result than the 34.9% rate with placebo. This absolute 19.4% difference was even greater in the subgroup of patients with a high baseline level of the transcription factor Aiolos, where the absolute improvement over placebo was 32.9%. Similarly, the benefit of iberdomide was also enhanced in patients with a high baseline level of type 1 interferon, where the absolute difference was 26.8%. This raises the prospect that a bioassay could be developed to predict the likelihood of a favorable clinical response to the drug. Iberdomide was well tolerated, with fewer severe adverse events than in the control group.
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.
FROM RWCS 2021
Tocilizumab (Actemra) scores FDA approval for systemic sclerosis–associated interstitial lung disease
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.
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.
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.
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.
ACR, AAD, AAO, RDS issue joint statement on safe use of hydroxychloroquine
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.
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.
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.
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.
FROM ARTHRITIS & rHEUMATOLOGY
COVID-19 vaccination recommended for rheumatology patients
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
People with rheumatic diseases should get vaccinated against SARS-CoV-2 as soon as possible, the American College of Rheumatology (ACR) recommends.
“It may be that people with rheumatic diseases are at increased risk of developing COVID or serious COVID-related complications,” Jonathan Hausmann, MD, assistant professor of medicine at Harvard Medical School, Boston, said in an ACR podcast. “So the need to prevent COVID-19 is incredibly important in this group of patients.”
The guidelines recommend a delay in vaccination only in rare circumstances, such as for patients with very severe illness or who have recently been administered rituximab, Jeffrey R. Curtis, MD, MPH, lead author of the guidelines, said in the podcast.
“Our members have been inundated with questions and concerns from their patients on whether they should receive the vaccine,” ACR President David Karp, MD, PhD, said in a press release.
So the ACR convened a panel of nine rheumatologists, two infectious disease specialists, and two public health experts. Over the course of 8 weeks, the task force reviewed the literature and agreed on recommendations. The organization posted a summary of the guidelines on its website after its board of directors approved it Feb. 8. The paper is pending journal peer review.
Some risks are real
The task force confined its research to the COVID-19 vaccines being offered by Pfizer and Moderna because they are currently the only ones approved by the Food and Drug Administration. It found no reason to distinguish between the two vaccines in its recommendations.
Because little research has directly addressed the question concerning COVID-19 vaccination for patients with rheumatic diseases, the task force extrapolated from data on other vaccinations in people with rheumatic disease and on the COVID-19 vaccinations in other populations.
It analyzed reports that other types of vaccination, such as for influenza, triggered flares of rheumatic conditions. “It is really individual case reports or small cohorts where there may be a somewhat higher incidence of flare, but it’s usually not very large in its magnitude nor duration,” said Dr. Curtis of the University of Alabama at Birmingham.
The task force also considered the possibility that vaccinations could lead to a new autoimmune disorder, such as Guillain-Barré syndrome or Bell palsy. The risk is real, the task force decided, but not significant enough to influence their recommendations.
Likewise, in immunocompromised people, vaccinations with live virus, such as those for shingles, might trigger the infection the vaccination is meant to prevent. But this can’t happen with the Pfizer and Moderna COVID-19 vaccines because they contain messenger RNA instead of live viruses, Dr. Curtis said.
Although it might be optimal to administer the vaccines when rheumatic diseases are quiescent, the urgency of getting vaccinated overrides that consideration, Dr. Curtis said. “By and large, there was a general consensus to not want to delay vaccination until somebody was stable and doing great, because you don’t know how long that’s going to be,” he said.
How well does it work?
One unanswered question is whether the COVID-19 vaccines work as well for patients with rheumatic diseases. The task force was reassured by data showing efficacy across a range of subgroups, including some with immunosenescence, Dr. Curtis said. “But until we have data in rheumatology patients, we’re just not going to know,” he said.
The guidelines specify that some drug regimens be modified when patients are vaccinated.
For patients taking rituximab, vaccination should be delayed, but only for those who are able to maintain safe social distancing to reduce the risk for COVID-19 exposure, Dr. Curtis said. “If somebody has just gotten rituximab recently, it might be more ideal to complete the vaccine series about 2-4 weeks before the next rituximab dose,” he said. “So if you are giving that therapy, say, at 6-month intervals, if you could vaccinate them at around month 5 from the most recent rituximab cycle, that might be more ideal.”
The guidance calls for withholding JAK inhibitors for a week after each vaccine dose is administered.
It calls for holding SQ abatacept 1 week prior and 1 week after the first COVID-19 vaccine dose, with no interruption after the second dose.
For abatacept IV, clinicians should “time vaccine administration so that the first vaccination will occur 4 weeks after abatacept infusion (i.e., the entire dosing interval), and postpone the subsequent abatacept infusion by 1 week (i.e., a 5-week gap in total).” It recommends no medication adjustment for the second vaccine dose.
For cyclophosphamide, the guidance recommends timing administration to occur about a week after each vaccine dose, when feasible.
None of this advice should supersede clinical judgment, Dr. Curtis said.
A version of this article first appeared on Medscape.com.
Frozen sections can guide biopsies for giant cell arteritis, but are they feasible?
Positive findings from frozen sections of a first temporal artery biopsy can effectively identify giant cell arteritis, ruling out in those cases the need to perform a second biopsy on the contralateral side and arguing against the use of simultaneous bilateral biopsies, according to results from a retrospective study of nearly 800 patients who underwent the procedure at the Mayo Clinic during 2010-2018.
Although temporal artery biopsy (TAB) remains the standard diagnostic test for giant cell arteritis (GCA), second TAB procedures are often performed in patients with a high level of suspicion for GCA, which may result in unnecessary treatments and complications, Devon A. Cohen, MD, of the Mayo Clinic, Rochester, Minn., and colleagues wrote. (Dr. Cohen is now a clinical fellow in ophthalmology at the Massachusetts Eye and Ear Infirmary.)
At the Mayo Clinic, TAB specimens are first examined with frozen sections at the time of the biopsy; this process, followed within days by formalin-fixed tissue permanent sections, is unique to Mayo. “A frozen section–guided sequential TAB is commonly performed, with the results of the first biopsy obtained within minutes, which determines the need for evaluation of the contralateral side,” the researchers said. However, the use of frozen sections to evaluate patients with GCA has not been well studied.
In a retrospective cohort study published in JAMA Ophthalmology, the researchers identified TAB patients aged 40 years and older who underwent TAB procedures between Jan. 1, 2010, and Dec. 1, 2018, at the Mayo Clinic. The average age of the patients was 72 years, and 41% were men.
Strong positive predictions from frozen sections
The researchers analyzed 1,162 TABs from 795 patients using frozen and permanent histologic sections.
Overall, 119 patients (15.0%) and 138 TABs had positive permanent section findings, and 103 (86.6%) of these patients also had positive frozen section findings, including 4 false positives and 20 false negatives. The frozen section specificity and sensitivity was 99.4% and 83.2%, respectively, for detecting inflammation suggestive of GCA, and the positive and negative predictive values were 96.1% and 96.6%, respectively. Positive and negative likelihood ratios for frozen section were 140.6 and 0.17, respectively.
In a multivariate analysis, the odds of a positive permanent section TAB significantly increased with age (odds ratio, 1.04), vision loss (OR, 2.72), diplopia (OR, 3.33), headache (OR, 2.32), weight loss (OR, 2.37), and anorexia (OR, 5.65).
A total of 60 patients underwent bilateral TABs, and 307 patients underwent bilateral frozen section–guided sequential TABs; the discordance rates based on permanent sections were 5.0% and 5.5%, respectively.
Those discordance rates are “an important result applying to everyone working with patients suspected for GCA,” Patricia Chévez-Barrios, MD, of Houston Methodist Hospital, wrote in an accompanying editorial. “This is on the low end of what was previously published (3%-40%) and supports the relative low need for bilateral synchronous TAB for the diagnosis of GCA.”
A key issue in GCA diagnosis is the need to confirm inflammation, Dr. Chévez-Barrios said. “The surgeon must obtain a significant portion of the artery, and the pathologist should review several sections and levels of the tissue to confidently say whether there is inflammation or no.”
Frozen sections can spare patients from second procedures
The findings suggest a role for frozen section to help to determine whether a unilateral or bilateral simultaneous TAB should be performed, the study authors noted.
“If the frozen section is positive on the first TAB, a contralateral TAB is deferred, given the very low false-positive rate (0.6%). However, if the frozen section does not align with the permanent section result, in particular if the frozen section is positive but permanent section is negative, the patient returns for a TAB on the contralateral side if the GCA suspicion remains high,” they said.
The use of frozen sections requires ideal conditions in order to be effective, Dr. Chévez-Barrios said. The Mayo Clinic approach “is only possible because of their appropriate hospital setting, the training of the histotechnologists, and the experience of the pathologists interpreting the stains and sections. For most pathology laboratories outside of the Mayo Clinic, frozen sections on arteries are the exception and are used only in specific scenarios.”
In addition, the American College of Rheumatology recommends that patients with a high suspicion of GCA should begin corticosteroids as soon as laboratory studies are obtained; “As a result, if a TAB is performed after treatment begins, the typical active pattern of inflammation in the artery changes,” Dr. Chévez-Barrios said. “This further challenges the diagnosis in a frozen section setting because of the need for immunohistochemistry.” Although frozen sections are feasible in specialized settings such as the Mayo Clinic, most patients receive adequate diagnosis and treatment based on permanent sections.
The study findings were limited by several factors including the use of data from patients at a single center and the unique setup of the Mayo Clinic to perform rapid processing of frozen sections, the researchers noted.
“Additionally, we acknowledge that there is controversy regarding the clinical interpretation of healed arteritis. At our institution, healed arteritis is interpreted in the context of patient clinical characteristics and radiographic findings, which may differ from other institutions and may impact the results of this study,” they said.
Overall, the results support the potential of frozen sections in guiding TAB, although “more studies with a comparative analysis of laboratory results, clinical symptoms, and patient demographic characteristics between positive and negative frozen and permanent TAB results are needed to confirm our findings,” they concluded.
The study received no outside funding. One author reported receiving grants from Eli Lilly and Kiniksa Pharmaceuticals as well as personal fees from Genentech-Roche and Sanofi. Dr. Chévez-Barrios had no financial conflicts to disclose.
Positive findings from frozen sections of a first temporal artery biopsy can effectively identify giant cell arteritis, ruling out in those cases the need to perform a second biopsy on the contralateral side and arguing against the use of simultaneous bilateral biopsies, according to results from a retrospective study of nearly 800 patients who underwent the procedure at the Mayo Clinic during 2010-2018.
Although temporal artery biopsy (TAB) remains the standard diagnostic test for giant cell arteritis (GCA), second TAB procedures are often performed in patients with a high level of suspicion for GCA, which may result in unnecessary treatments and complications, Devon A. Cohen, MD, of the Mayo Clinic, Rochester, Minn., and colleagues wrote. (Dr. Cohen is now a clinical fellow in ophthalmology at the Massachusetts Eye and Ear Infirmary.)
At the Mayo Clinic, TAB specimens are first examined with frozen sections at the time of the biopsy; this process, followed within days by formalin-fixed tissue permanent sections, is unique to Mayo. “A frozen section–guided sequential TAB is commonly performed, with the results of the first biopsy obtained within minutes, which determines the need for evaluation of the contralateral side,” the researchers said. However, the use of frozen sections to evaluate patients with GCA has not been well studied.
In a retrospective cohort study published in JAMA Ophthalmology, the researchers identified TAB patients aged 40 years and older who underwent TAB procedures between Jan. 1, 2010, and Dec. 1, 2018, at the Mayo Clinic. The average age of the patients was 72 years, and 41% were men.
Strong positive predictions from frozen sections
The researchers analyzed 1,162 TABs from 795 patients using frozen and permanent histologic sections.
Overall, 119 patients (15.0%) and 138 TABs had positive permanent section findings, and 103 (86.6%) of these patients also had positive frozen section findings, including 4 false positives and 20 false negatives. The frozen section specificity and sensitivity was 99.4% and 83.2%, respectively, for detecting inflammation suggestive of GCA, and the positive and negative predictive values were 96.1% and 96.6%, respectively. Positive and negative likelihood ratios for frozen section were 140.6 and 0.17, respectively.
In a multivariate analysis, the odds of a positive permanent section TAB significantly increased with age (odds ratio, 1.04), vision loss (OR, 2.72), diplopia (OR, 3.33), headache (OR, 2.32), weight loss (OR, 2.37), and anorexia (OR, 5.65).
A total of 60 patients underwent bilateral TABs, and 307 patients underwent bilateral frozen section–guided sequential TABs; the discordance rates based on permanent sections were 5.0% and 5.5%, respectively.
Those discordance rates are “an important result applying to everyone working with patients suspected for GCA,” Patricia Chévez-Barrios, MD, of Houston Methodist Hospital, wrote in an accompanying editorial. “This is on the low end of what was previously published (3%-40%) and supports the relative low need for bilateral synchronous TAB for the diagnosis of GCA.”
A key issue in GCA diagnosis is the need to confirm inflammation, Dr. Chévez-Barrios said. “The surgeon must obtain a significant portion of the artery, and the pathologist should review several sections and levels of the tissue to confidently say whether there is inflammation or no.”
Frozen sections can spare patients from second procedures
The findings suggest a role for frozen section to help to determine whether a unilateral or bilateral simultaneous TAB should be performed, the study authors noted.
“If the frozen section is positive on the first TAB, a contralateral TAB is deferred, given the very low false-positive rate (0.6%). However, if the frozen section does not align with the permanent section result, in particular if the frozen section is positive but permanent section is negative, the patient returns for a TAB on the contralateral side if the GCA suspicion remains high,” they said.
The use of frozen sections requires ideal conditions in order to be effective, Dr. Chévez-Barrios said. The Mayo Clinic approach “is only possible because of their appropriate hospital setting, the training of the histotechnologists, and the experience of the pathologists interpreting the stains and sections. For most pathology laboratories outside of the Mayo Clinic, frozen sections on arteries are the exception and are used only in specific scenarios.”
In addition, the American College of Rheumatology recommends that patients with a high suspicion of GCA should begin corticosteroids as soon as laboratory studies are obtained; “As a result, if a TAB is performed after treatment begins, the typical active pattern of inflammation in the artery changes,” Dr. Chévez-Barrios said. “This further challenges the diagnosis in a frozen section setting because of the need for immunohistochemistry.” Although frozen sections are feasible in specialized settings such as the Mayo Clinic, most patients receive adequate diagnosis and treatment based on permanent sections.
The study findings were limited by several factors including the use of data from patients at a single center and the unique setup of the Mayo Clinic to perform rapid processing of frozen sections, the researchers noted.
“Additionally, we acknowledge that there is controversy regarding the clinical interpretation of healed arteritis. At our institution, healed arteritis is interpreted in the context of patient clinical characteristics and radiographic findings, which may differ from other institutions and may impact the results of this study,” they said.
Overall, the results support the potential of frozen sections in guiding TAB, although “more studies with a comparative analysis of laboratory results, clinical symptoms, and patient demographic characteristics between positive and negative frozen and permanent TAB results are needed to confirm our findings,” they concluded.
The study received no outside funding. One author reported receiving grants from Eli Lilly and Kiniksa Pharmaceuticals as well as personal fees from Genentech-Roche and Sanofi. Dr. Chévez-Barrios had no financial conflicts to disclose.
Positive findings from frozen sections of a first temporal artery biopsy can effectively identify giant cell arteritis, ruling out in those cases the need to perform a second biopsy on the contralateral side and arguing against the use of simultaneous bilateral biopsies, according to results from a retrospective study of nearly 800 patients who underwent the procedure at the Mayo Clinic during 2010-2018.
Although temporal artery biopsy (TAB) remains the standard diagnostic test for giant cell arteritis (GCA), second TAB procedures are often performed in patients with a high level of suspicion for GCA, which may result in unnecessary treatments and complications, Devon A. Cohen, MD, of the Mayo Clinic, Rochester, Minn., and colleagues wrote. (Dr. Cohen is now a clinical fellow in ophthalmology at the Massachusetts Eye and Ear Infirmary.)
At the Mayo Clinic, TAB specimens are first examined with frozen sections at the time of the biopsy; this process, followed within days by formalin-fixed tissue permanent sections, is unique to Mayo. “A frozen section–guided sequential TAB is commonly performed, with the results of the first biopsy obtained within minutes, which determines the need for evaluation of the contralateral side,” the researchers said. However, the use of frozen sections to evaluate patients with GCA has not been well studied.
In a retrospective cohort study published in JAMA Ophthalmology, the researchers identified TAB patients aged 40 years and older who underwent TAB procedures between Jan. 1, 2010, and Dec. 1, 2018, at the Mayo Clinic. The average age of the patients was 72 years, and 41% were men.
Strong positive predictions from frozen sections
The researchers analyzed 1,162 TABs from 795 patients using frozen and permanent histologic sections.
Overall, 119 patients (15.0%) and 138 TABs had positive permanent section findings, and 103 (86.6%) of these patients also had positive frozen section findings, including 4 false positives and 20 false negatives. The frozen section specificity and sensitivity was 99.4% and 83.2%, respectively, for detecting inflammation suggestive of GCA, and the positive and negative predictive values were 96.1% and 96.6%, respectively. Positive and negative likelihood ratios for frozen section were 140.6 and 0.17, respectively.
In a multivariate analysis, the odds of a positive permanent section TAB significantly increased with age (odds ratio, 1.04), vision loss (OR, 2.72), diplopia (OR, 3.33), headache (OR, 2.32), weight loss (OR, 2.37), and anorexia (OR, 5.65).
A total of 60 patients underwent bilateral TABs, and 307 patients underwent bilateral frozen section–guided sequential TABs; the discordance rates based on permanent sections were 5.0% and 5.5%, respectively.
Those discordance rates are “an important result applying to everyone working with patients suspected for GCA,” Patricia Chévez-Barrios, MD, of Houston Methodist Hospital, wrote in an accompanying editorial. “This is on the low end of what was previously published (3%-40%) and supports the relative low need for bilateral synchronous TAB for the diagnosis of GCA.”
A key issue in GCA diagnosis is the need to confirm inflammation, Dr. Chévez-Barrios said. “The surgeon must obtain a significant portion of the artery, and the pathologist should review several sections and levels of the tissue to confidently say whether there is inflammation or no.”
Frozen sections can spare patients from second procedures
The findings suggest a role for frozen section to help to determine whether a unilateral or bilateral simultaneous TAB should be performed, the study authors noted.
“If the frozen section is positive on the first TAB, a contralateral TAB is deferred, given the very low false-positive rate (0.6%). However, if the frozen section does not align with the permanent section result, in particular if the frozen section is positive but permanent section is negative, the patient returns for a TAB on the contralateral side if the GCA suspicion remains high,” they said.
The use of frozen sections requires ideal conditions in order to be effective, Dr. Chévez-Barrios said. The Mayo Clinic approach “is only possible because of their appropriate hospital setting, the training of the histotechnologists, and the experience of the pathologists interpreting the stains and sections. For most pathology laboratories outside of the Mayo Clinic, frozen sections on arteries are the exception and are used only in specific scenarios.”
In addition, the American College of Rheumatology recommends that patients with a high suspicion of GCA should begin corticosteroids as soon as laboratory studies are obtained; “As a result, if a TAB is performed after treatment begins, the typical active pattern of inflammation in the artery changes,” Dr. Chévez-Barrios said. “This further challenges the diagnosis in a frozen section setting because of the need for immunohistochemistry.” Although frozen sections are feasible in specialized settings such as the Mayo Clinic, most patients receive adequate diagnosis and treatment based on permanent sections.
The study findings were limited by several factors including the use of data from patients at a single center and the unique setup of the Mayo Clinic to perform rapid processing of frozen sections, the researchers noted.
“Additionally, we acknowledge that there is controversy regarding the clinical interpretation of healed arteritis. At our institution, healed arteritis is interpreted in the context of patient clinical characteristics and radiographic findings, which may differ from other institutions and may impact the results of this study,” they said.
Overall, the results support the potential of frozen sections in guiding TAB, although “more studies with a comparative analysis of laboratory results, clinical symptoms, and patient demographic characteristics between positive and negative frozen and permanent TAB results are needed to confirm our findings,” they concluded.
The study received no outside funding. One author reported receiving grants from Eli Lilly and Kiniksa Pharmaceuticals as well as personal fees from Genentech-Roche and Sanofi. Dr. Chévez-Barrios had no financial conflicts to disclose.
FROM JAMA OPHTHALMOLOGY
Outcomes have improved for PAH in connective tissue disease
Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.
In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.
First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.
“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.
The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.
Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.
Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.
Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.
The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
Differential patient survival among PAH etiologies
“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.
When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.
Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.
Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.
The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.
Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.
“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.
‘Still have to be aggressive at identifying the high-risk patients’
Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.
“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”
The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.
“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”
They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.
However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.
The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.
Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.
In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.
First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.
“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.
The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.
Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.
Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.
Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.
The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
Differential patient survival among PAH etiologies
“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.
When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.
Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.
Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.
The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.
Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.
“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.
‘Still have to be aggressive at identifying the high-risk patients’
Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.
“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”
The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.
“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”
They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.
However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.
The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.
Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.
In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.
First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.
“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Dr. Khanna said.
The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.
Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.
Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.
Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.
The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.
Differential patient survival among PAH etiologies
“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.
When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.
Dr. Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.
Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.
The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.
Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.
“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Dr. Khanna said.
‘Still have to be aggressive at identifying the high-risk patients’
Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.
“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Dr. Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”
The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.
“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”
They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.
However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.
The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.
FROM ARTHRITIS & RHEUMATOLOGY
Consider home subcutaneous immune globulin for refractory dermatomyositis
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.
“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.
“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”
A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.
“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
SCIg advantages
SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.
French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.
“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
Available products
Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.
The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.
Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.
“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.
More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.
Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.
Dr. Postolova reported having no financial conflicts regarding her presentation.
FROM RWCS 2021
Tocilizumab may improve lung function in early systemic sclerosis
Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.
A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.
Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.
Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.
Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.
At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.
Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.
When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.
Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.
First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.
“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.
Findings from a specific patient population may not be generalizable
Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.
“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”
The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”
Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.
“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.
The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.
“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.
Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.
Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.
Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.
A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.
Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.
Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.
Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.
At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.
Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.
When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.
Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.
First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.
“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.
Findings from a specific patient population may not be generalizable
Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.
“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”
The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”
Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.
“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.
The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.
“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.
Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.
Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.
Treatment with tocilizumab (Actemra) could stabilize or improve lung function in people with early interstitial lung disease associated with systemic sclerosis (SSc-ILD), a new study has found.
A paper published online Feb. 3 in Arthritis & Rheumatology presents the results of a post hoc analysis of data from a phase 3, placebo-controlled, double-blind trial of subcutaneous tocilizumab in patients with SSc and progressive skin disease, which included high-resolution chest CT to assess lung involvement and fibrosis.
Tocilizumab is a monoclonal antibody that targets interleukin-6 and is currently approved for the treatment of immune-mediated diseases such as rheumatoid arthritis, giant cell arteritis, cytokine release syndrome, and systemic and polyarticular course juvenile idiopathic arthritis.
Two previous studies of tocilizumab in patients with early, diffuse cutaneous SSc had also found that the treatment was associated with preservation of lung function but did not characterize that effect using radiography.
Of the 210 participants in the trial, called focuSSced, 136 were found to have interstitial lung disease at baseline and were randomized to 162 mg tocilizumab weekly or placebo for 48 weeks.
At baseline, around three-quarters of those with interstitial lung disease had moderate to severe lung involvement, defined as ground glass opacities, honeycombing, and fibrotic reticulation across at least 20% of the whole lung.
Those in the tocilizumab group showed a 0.1% mean decline in forced vital capacity (FVC) over the 48-week study, while those in the placebo group had a mean decline of 6.3%.
When stratified by severity of lung involvement, those with mild lung disease group treated with tocilizumab had a 4.1% decline in FVC, compared with a 10% decline in the placebo group; those with moderate disease in the treatment group had an 0.7% mean increase in FVC, compared with a 5.7% decrease in the placebo group, and those with severe lung involvement in the treatment arm had a 2.1% increase in FVC, compared with a 6.7% decrease in the placebo arm.
Those treated with tocilizumab also showed a statistically significant 1.8% improvement in the amount of lung involvement, which was largely seen in those with more extensive lung involvement at baseline. Those with more than 20% of the lung affected had a significant 4.9% reduction in lung area affected, while those in the placebo arm showed a significant increase in fibrosis.
First author David Roofeh, MD, of the University of Michigan Scleroderma Program, and colleagues wrote that most patients with SSc will develop interstitial lung disease – particularly those with early, diffuse cutaneous SSc and elevated markers such as C-reactive protein.
“Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc,” the authors wrote.
Findings from a specific patient population may not be generalizable
Commenting on the findings, Lorinda Chung, MD, of Stanford (Calif.) University, said in an interview that the study demonstrated that tocilizumab could prevent radiographic progression of ILD in early diffuse SSc patients with mild to severe lung disease and evidence of active skin disease, as well as elevated inflammatory markers.
“This was a very specific patient population who was studied in the focuSSced clinical trial, and this paper only evaluated a subset of these patients,” Dr. Chung said. “The results may not be generalizable to all SSc-ILD patients and further studies are needed.”
The authors suggested that the patients with progressive skin disease and elevated acute phase reactants may represent a group in the immunoinflammatory phase of the disease rather than the advanced fibrotic stage, and that this might be a “window of therapeutic opportunity to preserve lung function.”
Dr. Chung noted that the radiographic improvement induced by tocilizumab treatment was greatest in those with the most radiographic disease at baseline.
“This may reflect tocilizumab’s impact on decreasing inflammation, but we are not provided the data on the effects of tocilizumab on the individual components of the QILD [quantitative ILD: summation of ground glass opacities, honeycombing, and fibrotic reticulation],” she said.
The study’s authors also made a point about the utility of screening patients with high-resolution chest CT to detect early signs of ILD.
“Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs [pulmonary function tests] are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease,” they wrote.
Describing the results as ‘hypothesis-generating’ owing to the post hoc nature of the analysis, the authors said that FVC was an indirect measure of the flow-resistive properties of the lung, and that other aspects of SSc – such as hide-bound chest thickness – could cause thoracic restriction.
Two authors were funded by the National Institutes of Health. Six authors declared grants, funding, and other support from the pharmaceutical sector, including Roche, which sponsored the original focuSSced trial.
FROM ARTHRITIS & RHEUMATOLOGY
Checkpoint inhibitors’ ‘big picture’ safety shown with preexisting autoimmune diseases
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
Patients with advanced melanoma and preexisting autoimmune diseases (AIDs) who were treated with immune checkpoint inhibitors (ICIs) responded well and did not suffer more grade 3 or higher immune-related adverse events than patients without an AID, a new study finds, although some concerns were raised regarding patients with inflammatory bowel disease (IBD).
“To our knowledge, this is the first study to bridge this knowledge gap by presenting ‘real-world’ data on the safety and efficacy of ICI on a national scale,” wrote Monique K. van der Kooij, MD, of Leiden (the Netherlands) University Medical Center and coauthors. The study was published online in Annals of Internal Medicine.
To investigate ICI use and response among this specific subset of melanoma patients, the researchers launched a nationwide cohort study set in the Netherlands. Data were gathered via the Dutch Melanoma Treatment Registry (DMTR), in which 4,367 patients with advanced melanoma were enrolled between July 2013 and July 2018.
Within that cohort, 415 (9.5%) had preexisting AIDs. Nearly 55% had rheumatologic AIDs (n = 227) – which included RA, systemic lupus erythematosus, scleroderma, sarcoidosis, and vasculitis – with the next most frequent being endocrine AID (n = 143) and IBD (n = 55). Patients with AID were older than patients without (67 vs. 63 years) and were more likely to be female (53% vs. 41%).
The ICIs used in the study included anti-CTLA4 (ipilimumab), anti–programmed death 1 (PD-1) (nivolumab or pembrolizumab), or a combination of nivolumab and ipilimumab. Of the patients with AID, 55% (n = 228) were treated with ICI, compared with 58% of patients without AID. A total of 87 AID patients were treated with anti-CTLA4, 187 received anti-PD-1, and 34 received the combination. The combination was not readily available in the Netherlands until 2017, the authors stated, acknowledging that it may be wise to revisit its effects in the coming years.
Incidence of immune-related adverse events
The incidence of immune-related adverse events (irAEs) grade 3 and above for patients with and without AID who were given anti-CTLA4 was 30%. The incidence rate of irAEs was also similar for patients with (17%; 95% confidence interval, 12%-23%) and without (13%; 95% CI, 12%-15%) AID on anti-PD-1. Patients with AIDs who took anti-PD-1 therapy discontinued it more often because of toxicity than did the patients without AIDs.
The combination group had irAE incidence rates of 44% (95% CI, 27%-62%) for patients with AID, compared with 48% (95% CI, 43%-53%) for patients without AIDs. Overall, no patients with AIDs on ICIs died of toxicity, compared with three deaths among patients without AID on anti-CTLA4, five deaths among patients on anti-PD-1, and one patient on the combination.
Patients with IBD had a notably higher risk of anti-PD-1–induced colitis (19%; 95% CI, 7%-37%), compared with patients with other AIDs (3%; 95% CI, 0%-6%) and patients without AIDs (2%; 95% CI, 2%-3%). IBD patients were also more likely than all other groups on ICIs to stop treatment because of toxicity, leading the researchers to note that “close monitoring in patients with IBD is advised.”
Overall survival after diagnosis was similar in patients with AIDs (median, 13 months; 95% CI, 10-16 months) and without (median, 14 months; 95% CI, 13-15 months), as was the objective response rate to anti-CTLA4 treatment (10% vs. 16%), anti-PD-1 treatment (40% vs. 44%), and combination therapy (39% vs. 43%).
Study largely bypasses the effects of checkpoint inhibitors on RA patients
“For detail, you can’t look to this study,” Anne R. Bass, MD, of the division of rheumatology at the Hospital for Special Surgery in New York, said in an interview. “But for a big-picture look at ‘how safe are checkpoint inhibitors,’ I think it’s an important one.”
Dr. Bass noted that the investigators lumped certain elements together and bypassed others, including their focus on grade 3 or higher adverse events. That was a decision the authors themselves recognized as a potential limitation of their research.
“Understandably, they were worried about life-threatening adverse events, and that’s fine,” she said. But for patients with arthritis who flare, their events are usually grade 2 or even grade 1 and therefore not captured or analyzed in the study. “This does not really address the risk of flare in an RA patient.”
She also questioned their grouping of AIDs, with a bevy of rheumatic diseases categorized as one cluster and the “other” group being particularly broad in its inclusion of “all AIDs not listed” – though only eight patients were placed into that group.
That said, the researchers relied on an oncology database, not one aimed at AID or adverse events. “The numbers are so much bigger than any other study in this area that’s been done,” she said. “It’s both a strength and a weakness of this kind of database.”
Indeed, the authors considered their use of nationwide, population-based data from the DMTR a benefit, calling it “a strength of our approach.”
The DMTR was funded by a grant from the Netherlands Organization for Health Research and Development and sponsored by Bristol-Myers Squibb, Novartis, Roche Nederland, Merck Sharp & Dohme, and Pierre Fabre via the Dutch Institute for Clinical Auditing.
FROM ANNALS OF INTERNAL MEDICINE
Women increasingly turn to CBD, with or without doc’s blessing
When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.
A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.
Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.
Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.
Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.
Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”
Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.
Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.
Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.
In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
The gray zone
There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.
“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”
One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.
This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”
Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”
The ‘entourage effect’
Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.
In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.
Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
It’s the data
Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”
Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”
Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.
Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”
That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”
A version of this article first appeared on Medscape.com.
When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.
A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.
Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.
Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.
Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.
Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”
Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.
Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.
Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.
In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
The gray zone
There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.
“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”
One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.
This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”
Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”
The ‘entourage effect’
Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.
In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.
Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
It’s the data
Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”
Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”
Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.
Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”
That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”
A version of this article first appeared on Medscape.com.
When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.
A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.
Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.
Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.
Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.
Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”
Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.
Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.
Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.
In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
The gray zone
There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.
“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”
One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.
This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”
Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”
The ‘entourage effect’
Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.
In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.
Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
It’s the data
Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”
Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”
Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.
Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”
That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”
A version of this article first appeared on Medscape.com.