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Asciminib safe and effective in CML patients without treatment alternatives
Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.
Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.
Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.
Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.
Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.
Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.
Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.
Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.
Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.
Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.
Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.
Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.
Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.
Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.
Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.
MR4.5 at imatinib discontinuation improves treatment-free survival in CML
Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.
Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).
Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.
Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.
Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.
Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.
Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).
Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.
Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.
Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.
Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.
Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).
Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.
Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.
Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.
Asian CML-CP patients may need a lower starting dose of dasatinib
Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.
Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).
Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.
Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.
Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.
Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.
Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).
Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.
Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.
Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.
Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.
Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).
Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.
Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.
Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.
CML-CP: 3-year MR status is highly predictive of subsequent relapse
Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.
Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.
Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.
Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.
Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.
Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.
Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.
Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.
Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.
Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.
Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.
Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.
Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.
Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.
Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.
CML-CP: Imatinib at higher dose or in combination with other drugs offers no survival benefit
Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).
Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.
Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).
Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.
Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.
Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).
Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.
Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).
Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.
Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.
Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).
Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.
Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).
Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.
Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.
Checkpoint inhibitor–induced rheumatic complications often arise late
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
Most checkpoint inhibitor–induced rheumatic complications in cancer patients can be treated successfully with corticosteroids, albeit often at considerably higher doses than rheumatologists typically use in managing rheumatoid arthritis, Eric M. Ruderman, MD, observed at the 2021 Rheumatology Winter Clinical Symposium.
“In RA, we’re all used to the idea that 5 or 10 mg of corticosteroids per day can make a tremendous difference. That’s not always the case here. Patients who develop rheumatic immunotherapy-related adverse events often require 20-30 mg/day to get symptoms under control,” according to Dr. Ruderman, professor of medicine (rheumatology) at Northwestern University, Chicago.
This may be in part because oncologists typically don’t refer affected patients to rheumatologists early on. Guidelines from the National Comprehensive Cancer Network and other oncology groups suggest referral only once a patient develops grade 3 immunotherapy-related rheumatic adverse events, meaning the symptoms significantly impair daily activities, he explained.
Checkpoint inhibitors, which induce T-cell activation to fight the patient’s malignancy, can produce a plethora of off-target effects. These adverse events may involve the skin, heart, lungs, kidneys, eyes, blood, GI tract, and endocrine organs. The drugs also can cause rheumatic or neurologic complications. The most common of these adverse events are colitis and rash. Next most common are arthritis and arthralgia. Rheumatic side effects are most common as a consequence of immunotherapy using a CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, but can also occur in association with programmed cell death protein 1 (PD-1) inhibitors and PD-ligand 1 inhibitors. Arthritis and other rheumatic adverse events are more common in patients undergoing combination therapy.
Some form of frank inflammatory arthritis occurs in 5%-10% of cancer patients undergoing checkpoint inhibitor therapy. This can manifest as an RA-like polyarthritis, spondyloarthritis, polymyalgia rheumatica, necrotizing myositis, or vasculitis. Arthralgia occurs in up to 40% of treated patients.
This immunotherapy-related arthritis is typically more inflammatory than RA. It also has a much more abrupt onset. It is usually seronegative and has no gender predisposition, and the limited available evidence to date suggests there is no increased risk of this complication in checkpoint inhibitor–treated patients with a history of prior rheumatic disease, according to Dr. Ruderman.
Delayed onset and resolution of rheumatologic immune-related adverse events
“Onset and resolution of rheumatologic adverse events with immunotherapy may be delayed. This is an important point: While skin rash and colitis often show up pretty early in the course of immunotherapy, some of the arthritic events can happen later. They can actually continue after the immunotherapy is stopped,” the rheumatologist said.
Indeed, a retrospective nationwide Canadian study of 117 patients at nine academic centers who developed 136 rheumatic immune-related adverse events in conjunction with cancer immunotherapy found that the mean time to the first such event was 6.8 months into checkpoint inhibitor therapy. The most common rheumatic complication was symmetric polyarthritis, affecting 45 patients. Other rheumatologic immune-related complications included polymyalgia rheumatica in 17 patients, noninflammatory musculoskeletal symptoms in 18, and myositis in 9.
Seventy-six patients were treated with prednisone for a mean of 8.4 months at a maximum dose of 60 mg/day. Forty-two moved up the treatment ladder to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to manage their symptoms. Only two patients required escalation to biologic therapy. A reassuring finding in this relatively small study was that treatment of the patients’ rheumatic complications didn’t appear to worsen the tumor response to immunotherapy: Twenty-three patients experienced tumor progression prior to treatment of their rheumatic disorder, and 14 did so following treatment.
Flares of preexisting rheumatic diseases
These tend to occur much earlier in the course of immune checkpoint inhibitor therapy for cancer than de novo immunotherapy-related rheumatic adverse events. In a retrospective Australian study of 12 cancer patients with preexisting rheumatic disease before going on a PD-1 inhibitor and 24 others with no such history, all of whom developed rheumatic adverse events while on the checkpoint inhibitor, the mean time to a flare of preexisting rheumatic disease was 6.2 weeks, compared to 21.5 weeks in patients who experienced a de novo rheumatic adverse event.
Dr. Ruderman supports recommendations from the European Alliance of Associations for Rheumatology (EULAR) for the management of rheumatic immune-related adverse events due to cancer immunotherapy, even though the underlying level of evidence is fairly weak. The recommendations call for the use of csDMARDs when corticosteroids don’t adequately control symptoms. And when the response to csDMARDs is insufficient, the next step is a biologic, preferably a tumor necrosis factor inhibitor or interleukin-6 inhibitor.
“At our institution, the oncologists are a little bit nervous about using biologics in cancer patients, but I think more and more they’re going to have to accept it. And so far there isn’t a ton of evidence that suggests the addition of biologics interferes with the efficacy of the immunotherapy,” the rheumatologist said.
He underscored the critical importance of one of the overarching principles of the EULAR guidelines: the need for interdisciplinary coordination between rheumatologists and oncologists regarding the problem of rheumatologic immune-related adverse events.
“Oncologists aren’t good at managing inflammatory arthritis. I think they really need us,” he said.
Dr. Ruderman reported serving as a consultant to and/or receiving a research grant from nine pharmaceutical companies.
FROM RWCS 2021
Evidence grows for food as RA treatment
Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.
But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.
He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.
Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
RA improvement on an ITIS diet
Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.
However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.
The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.
As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.
At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.
Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.
The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.
Biqi is big in China, gaining ground in the U.S.
Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.
“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.
If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.
In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.
“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.
American RA patients embrace turmeric
Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.
Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.
Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
What about osteoarthritis?
Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.
Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.
Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.
Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.
But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.
He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.
Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
RA improvement on an ITIS diet
Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.
However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.
The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.
As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.
At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.
Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.
The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.
Biqi is big in China, gaining ground in the U.S.
Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.
“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.
If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.
In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.
“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.
American RA patients embrace turmeric
Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.
Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.
Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
What about osteoarthritis?
Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.
Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.
Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.
Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
Patients with rheumatoid arthritis are often eager to try dietary interventions in an effort to improve their symptoms. For guidance, they turn to their rheumatologists, who typically can offer little in terms of concrete evidence-based recommendations. That’s because their training didn’t emphasize the role of nutrients in rheumatic diseases, the scientific evidence has historically been sketchy, and the topic of diet and disease is rife with fad diets, inflated Internet claims, and hucksterism.
But that’s changing. Indeed, recent annual meetings of the American College of Rheumatology have featured randomized, controlled trials that bring welcome rigor to the field and provide findings of practical interest to clinicians and their patients, Orrin M. Troum, MD, said at the 2021 Rheumatology Winter Clinical Symposium.
He highlighted some of this work, including positive randomized trials of the dietary supplements Biqi – a traditional Chinese herbal medicine – as well as turmeric, along with reported progress in efforts to design a palatable anti-inflammatory diet that favorably alters the gut microbiome and systemic metabolome while improving clinical outcomes in patients with RA.
Dr. Troum, a rheumatologist at the University of Southern California, Los Angeles, and in private practice in Santa Monica, described a typical patient encounter in his clinic that appeared to resonate with his audience from throughout the country: “You can tell people to take another medicine and they’ll start shaking their head no before you’re finished. But when you say there are natural supplements that can help you, they’re saying ‘Yes!’ ”
RA improvement on an ITIS diet
Many physicians recommend a Mediterranean-style diet, first popularized in the landmark Seven Countries Study launched by the late Dr. Ancel Keys. This familiar plant-based regimen emphasizes liberal consumption of extra-virgin olive oil, legumes, fruits and vegetables, whole grains, fish, nuts, and moderate alcohol intake, with very limited intake of red and processed meats, refined grains, and sugar. There is strong evidence that the Mediterranean diet is cardioprotective, which is relevant to patients with RA since they are known to be at elevated cardiovascular risk.
However, investigators at the University of California, San Diego, became convinced that the Mediterranean diet is lacking in key anti-inflammatory ingredients from other parts of the world. These include ginger, green tea, black pepper, turmeric, miso, flax seeds, and tahini, all of which are backed by evidence – from animal models and/or interventional diet studies in patients – that suggests beneficial effects in pain and joint swelling in RA. The researchers also suspected that certain vegetables embraced in the Mediterranean diet – notably eggplant, tomatoes, and potatoes – might be problematic for RA patients because they contain solanine, thought to increase intestinal permeability, which might have arthritogenic effects on the gut microbiome.
The investigators set out to develop an anti-inflammatory diet they call the ITIS diet, essentially tweaking the Mediterranean-style diet by incorporating these additions and subtractions. Importantly, they designed the ITIS diet in conjunction with a multiracial local group of RA patients strongly enthusiastic about the potential for dietary interventions aimed at improving their symptoms. The patients provided feedback that enabled the investigators to fine-tune the anti-inflammatory diet so as to boost palatability and acceptance.
As an illustrative example of the ITIS diet, a typical day might start off with a homemade smoothie of parsley, pineapple, strawberries, and water, followed by a breakfast consisting of one or two corn tortillas spread with avocado, linseed oil, and sesame seeds, accompanied by green tea. Following a mid-morning snack of plain Greek-style yogurt, lunch might be a choice of a large salad, legumes with vegetables, or whole grains with vegetables. For the afternoon snack: four walnuts plus mango, banana, pear, papaya, apple, or pineapple. And for dinner, the options are vegetable soup and a protein; salad plus a protein; or miso soup, cooked vegetables, and a protein.
At the 2020 ACR annual meeting, Roxana Coras, MD, presented the positive findings of an open-label, pilot study of the ITIS diet in which 17 patients with active RA involving at least three tender and three swollen joints adopted the diet for 2 weeks . The ITIS diet turned out to be not too much of a stretch for Southern California RA patients interested in dietary complementary and alternative medicine. Many had already adopted some elements of the anti-inflammatory diet. Dietary adherence in the study was good, as monitored in food logs and by mass spectrometry metabolic profiling of fecal and plasma samples.
Eleven patients were categorized as responders to the anti-inflammatory diet as defined by at least a 50% improvement in pain scores from baseline to 2 weeks; six patients were nonresponders. In the overall study population, mean pain scores on a 0-10 visual analog scale improved from 3.9 to 2.45. Scores on the Clinical Disease Activity Index (CDAI) also improved significantly on the ITIS diet, from 29 to 12.7, reported Dr. Coras, a rheumatologist at the University of California, San Diego.
The mechanisms for the clinical improvement on the diet are under study. Significant differences in the gut microbiome and metabolome were seen between the responders and nonresponders. For example, Mollicutes were increased and Coriobacteriales decreased in clinical responders versus nonresponders. A significant increase in circulating levels of anti-inflammatory oxylipins was also seen in responders. Longer-term controlled studies of the ITIS diet are planned.
Biqi is big in China, gaining ground in the U.S.
Ayurvedic medicine in India and Chinese traditional herbal medicine have richly documented 4,500-year histories.
“It’s so common in my neck of the woods, where there are large Asian communities, for Chinese or Korean or Japanese or Indian medicines to be combined with our medicines. And if you don’t ask about them, you’re never going to find out what these patients are taking,” Dr. Troum said.
If they’re taking Biqi capsules, readily available on the Internet, be advised that there is randomized trial evidence to show that they’re using an efficacious and safe herbal medicine for RA. In China, the combination of Biqi capsules and a conventional disease-modifying antirheumatic drug such as methotrexate is now widely used for treatment of RA. And at the 2019 ACR annual meeting, Runyue Huang, MD, of Guangzhou University of Chinese Medicine, presented the results of a 24-week, randomized, multicenter, open-label clinical trial in which 70 RA patients were assigned to methotrexate plus a 1.2-g Biqi capsule twice daily or to methotrexate plus leflunomide (Arava) at 20 mg/day. The primary outcome – achievement of a 20% improvement in the ACR criteria, or ACR20 response, at week 24 – was achieved in 77% of the Biqi group, not significantly different from the 83% rate in the comparator group. However, the Biqi plus methotrexate group had significantly fewer adverse events and the combination was better tolerated than was leflunomide plus methotrexate.
In addition, a systematic review of earlier clinical trials concluded that Biqi in combination with methotrexate was more effective and had fewer adverse events than methotrexate alone.
“Biqi capsule with methotrexate appears to be a promising combination for RA if you can rest assured that what’s found in the Biqi capsule is exactly what they say. And that’s the main issue: You don’t really know what you’re getting unless it’s in a trial,” Dr. Troum said.
American RA patients embrace turmeric
Turmeric has played a prominent role in Ayurvedic medicine for millenia. The most medicinally important component of turmeric root is curcumin, which has potent anti-inflammatory and antioxidant properties. Americans with RA have gotten on the bandwagon, as demonstrated in a survey of 291 patients with RA or psoriatic arthritis presented at ACR 2020 by investigators from the University of Central Florida, Orlando. Among the respondents, 37% reported having taken curcumin, with no predilection based upon age, gender, or diagnosis. Fifty-nine percent took their curcumin in the form of capsules, with the rest took it as an oil or powder. Fifty-four percent got their curcumin at a local store.
Thirty-six percent of curcumin users reported improvement in pain after going on the herbal supplement. Twenty-five percent reported reduced swelling, 23% had less stiffness, and 16% reported improvement in fatigue. Patients taking 200-1,000 mg/day reported significantly greater improvement in symptoms than that of those taking less than 200 mg/day. Onset of benefits was slow: Patients on curcumin for a year or longer reported greater symptomatic improvement than did those on the supplement for less time.
Asked what he recommends to his RA patients who express interest in supplements aimed at achieving symptomatic improvement, Dr. Troum replied that he’s comfortable suggesting curcumin capsules at 500 mg twice daily, which should be labeled as containing black pepper extract to aid in absorption. He also recommends fish oil both for its cardioprotective benefits and because of randomized trial evidence that it enhances the chances of achieving ACR remission in patients on conventional disease-modifying antirheumatic drugs.
What about osteoarthritis?
Investigators with the National Institutes of Health–sponsored Osteoarthritis Initiative found in an analysis of the dietary patterns of 2,757 patients with mild to moderate knee OA who were followed annually for 6 years that participants could be grouped into two broad categories: Those who consumed what was termed the prudent diet, with high intake of fruits and vegetables, legumes, fish, and whole grains; and fans of the Western diet, characterized by lots of red meat, refined grains, and liberal consumption of French fries. Knee symptoms increased over time in dose-response fashion with greater adherence to the Western diet and decreased with higher prudent diet scores.
Also at ACR 2019, Australian investigators presented the results of the double-blind CurKOA trial, in which 70 participants with knee OA and moderate baseline effusion/synovitis by ultrasound were randomized to take a capsule containing 500 mg of turmeric root extract or identical placebo twice daily for 12 weeks. The group on turmeric plant extract experienced 9.11-mm greater reduction in knee pain on a 0- to 100-mm visual analog scale than did controls, which translates to a moderate standard effect size deemed by investigators to be “greater than other conventional pharmacologic therapies.” Overall, 63% of the turmeric group achieved a treatment response by OARSI-OMERACT criteria, a significantly better outcome than the 38% rate in controls. However, there was no significant between-group difference in knee structural measures as assessed by MRI in this relatively brief trial.
Anne M. Stevens, MD, PhD, senior director of immunology translational medicine at Janssen Pharmaceuticals and a pediatric rheumatologist at Seattle Children’s Hospital, rose from the audience to share that she recommends that her patients on high-dose curcumin not take NSAIDs because the two share a similar mechanism of action involving COX-2 inhibition, and the combination might therefore increase bleeding risk. But Dr. Troum said he hasn’t seen any increase in bleeding in his patients on both agents.
Dr. Troum has financial relationships with numerous pharmaceutical companies, but reported having no financial conflicts of interest regarding his presentation.
FROM RWCS 2021
The cutaneous benefits of bee venom, Part II: Acupuncture, wound healing, and various potential indications
A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.1 Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.8,9
The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.10 In experimental studies, antinociceptive and anti-inflammatory effects have been reported.11 Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.12
A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.13 Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.14 This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.
Acupuncture
Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.8
In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.15
A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.11
Wound healing
A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.17
In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.18
Alopecia
A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.19
Anticancer and anti-arthritic activity
In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.2
In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.4
Phototoxicity
Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.20
Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.10
Antiwrinkle activity
Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.21
Conclusion
Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.
2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.
3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.
4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.
5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.
10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.
11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.
14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.
15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.
20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.
A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.1 Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.8,9
The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.10 In experimental studies, antinociceptive and anti-inflammatory effects have been reported.11 Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.12
A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.13 Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.14 This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.
Acupuncture
Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.8
In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.15
A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.11
Wound healing
A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.17
In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.18
Alopecia
A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.19
Anticancer and anti-arthritic activity
In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.2
In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.4
Phototoxicity
Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.20
Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.10
Antiwrinkle activity
Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.21
Conclusion
Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.
2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.
3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.
4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.
5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.
10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.
11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.
14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.
15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.
20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.
A wide range of products derived from bees, including honey, propolis, bee pollen, bee bread, royal jelly, beeswax, and bee venom, have been used since ancient times for medical purposes.1 Specifically, bee venom has been used in traditional medicine to treat multiple disorders, including arthritis, cancer, pain, rheumatism, and skin diseases.2,3 The primary active constituent of bee venom is melittin, an amphiphilic peptide containing 26 amino acid residues and known to impart anti-inflammatory, antibacterial, analgesic, and anticancer effects.4-7 Additional anti-inflammatory compounds found in bee venom include adolapin, apamin, and phospholipase A2; melittin and phospholipase A2 are also capable of delivering pro-inflammatory activity.8,9
The anti-aging, anti-inflammatory, and antibacterial properties of bee venom have been cited as justification for its use as a cosmetic ingredient.10 In experimental studies, antinociceptive and anti-inflammatory effects have been reported.11 Bee venom phospholipase A2 has also demonstrated notable success in vitro and in vivo in conferring immunomodulatory effects and is a key component in past and continuing use of bee venom therapy for immune-related disorders, such as arthritis.12
A recent review of the biomedical literature by Nguyen et al. reveals that bee venom is one of the key ingredients in the booming Korean cosmeceuticals industry.13 Kim et al. reviewed the therapeutic applications of bee venom in 2019, noting that anti-inflammatory, antiapoptotic, antifibrotic, antimicrobial, and anticancer properties have been cited in experimental and clinical reports, with cutaneous treatments ranging from acne, alopecia, and atopic dermatitis to melanoma, morphea, photoaging, psoriasis, vitiligo, wounds, and wrinkles.14 This column focuses on the use of bee venom in acupuncture and wound healing, as well as some other potential applications of this bee product used for millennia.
Acupuncture
Bee venom acupuncture entails the application of bee venom to the tips of acupuncture needles, which are then applied to acupoints on the skin. Cherniack and Govorushko state that several small studies in humans show that bee venom acupuncture has been used effectively to treat various musculoskeletal and neurological conditions.8
In 2016, Sur et al. explored the effects of bee venom acupuncture on atopic dermatitis in a mouse model with lesions induced by trimellitic anhydride. Bee venom treatment was found to significantly ease inflammation, lesion thickness, and lymph node weight. Suppression of T-cell proliferation and infiltration, Th1 and Th2 cytokine synthesis, and interleukin (IL)-4 and immunoglobulin E (IgE) production was also noted.15
A case report by Hwang and Kim in 2018 described the successful use of bee venom acupuncture in the treatment of a 64-year-old Korean woman with circumscribed morphea resulting from systemic sclerosis. Subcutaneous bee venom acupuncture along the margins resolved pruritus through 2 months of follow-up.11
Wound healing
A study by Hozzein et al. in 2018 on protecting functional macrophages from apoptosis and improving Nrf2, Ang-1, and Tie-2 signaling in diabetic wound healing in mice revealed that bee venom supports immune function, thus promoting healing from diabetic wounds.(16) Previously, this team had shown that bee venom facilitates wound healing in diabetic mice by inhibiting the activation of transcription factor-3 and inducible nitric oxide synthase-mediated stress.17
In early 2020, Nakashima et al. reported their results showing that bee venom-derived phospholipase A2 augmented poly(I:C)-induced activation in human keratinocytes, suggesting that it could play a role in wound healing promotion through enhanced TLR3 responses.18
Alopecia
A 2016 study on the effect of bee venom on alopecia in C57BL/6 mice by Park et al. showed that the bee toxin dose-dependently stimulated proliferation of several growth factors, including fibroblast growth factors 2 and 7, as compared with the control group. Bee venom also suppressed transition from the anagen to catagen phases, nurtured hair growth, and presented the potential as a strong 5α-reductase inhibitor.19
Anticancer and anti-arthritic activity
In 2007, Son et al. reported that the various peptides (melittin, apamin, adolapin, the mast-cell-degranulating peptide), enzymes (i.e., phospholipase A2), as well as biologically active amines (i.e., histamine and epinephrine) and nonpeptide components in bee venom are thought to account for multiple pharmaceutical properties that yield anti-arthritis, antinociceptive, and anticancer effects.2
In 2019, Lim et al. determined that bee venom and melittin inhibited the growth and migration of melanoma cells (B16F10, A375SM, and SK-MEL-28) by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. They concluded that melittin has the potential for use in preventing and treating malignant melanoma.4
Phototoxicity
Heo et al. conducted phototoxicity and skin sensitization studies of bee venom, as well as a bee venom from which they removed phospholipase A2, and determined that both were nonphototoxic substances and did not act as sensitizers.20
Han et al. assessed the skin safety of bee venom on tests in healthy male Hartley guinea pigs in 2017 and found that bee venom application engendered no toxic reactions, including any signs of cutaneous phototoxicity or skin photosensitization, and is likely safe for inclusion as a topical skin care ingredient.10
Antiwrinkle activity
Han et al. also evaluated the beneficial effects of bee venom serum on facial wrinkles in a small study on humans (22 South Korean women between 30 and 49 years old), finding clinical improvements as seen through reductions in wrinkle count, average wrinkle depth, and total wrinkle area. The authors, noting that this was the first clinical study to assess the results of using bee venom cosmetics on facial skin, also cited the relative safety of the product, which presents nominal irritation potential, and acknowledged its present use in the cosmetics industry.21
Conclusion
Bees play a critical role in the web of life as they pollinate approximately one-third of our food. Perhaps counterintuitively, given our awareness of the painful and potentially serious reactions to bee stings, bee venom has also been found to deliver multiple salutary effects. More research is necessary to ascertain the viability of using bee venom as a reliable treatment for the various cutaneous conditions for which it demonstrates potential benefits. Current evidence presents justification for further investigation.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kurek-Górecka A et al. Molecules. 2020 Jan 28;25(3):556.
2. Son DJ et al. Pharmacol Ther. 2007 Aug;115(2):246-70.
3. Lee G, Bae H. Molecules. 2016 May 11;21(5):616.
4. Lim HN et al. Molecules. 2019 Mar 7;24(5):929.
5. Gu H et al. Mol Med Rep. 2018 Oct;18(4):3711-8. 6. You CE et al. Ann Dermatol. 2016 Oct;28(5):593-9. 7. An HJ et al. Int J Mol Med. 2014 Nov;34(5):1341-8. 8. Cherniack EP, Govorushko S. Toxicon. 2018 Nov;154:74-8. 9. Cornara L et al. Front Pharmacol. 2017 Jun 28;8:412.
10. Han SM et al. J Cosmet Dermatol. 2017 Dec;16(4):e68-e75.
11. Hwang JH, Kim KH. Medicine (Baltimore). 2018 Dec;97(49):e13404. 12. Lee G, Bae H. Toxins (Basel). 2016 Feb 22;8(2):48. 13. Nguyen JK et al. J Cosmet Dermatol. 2020 Jul;19(7):1555-69.
14. Kim H et al. Toxins (Basel). 2019 Jun 27:11(7):374.
15. Sur B et al. BMC Complement Altern Med. 2016 Jan 29;16:38. 16. Hozzein WN et al. Mol Immunol. 2018 Nov;103:322-35. 17. Badr G et al. J Cell Physiol. 2016 Oct;231(10):2159-71. 18. Nakashima A et al. Int Immunol. 2020 May 30;32(6):371-83. 19. Park S et al. Biol Pharm Bull. 2016 Jun 1;39(6):1060-8.
20. Heo Y et al. Evid Based Complement Alternat Med. 2015;2015:157367. 21. Han SM et al. Clin Interv Aging. 2015 Oct 1;10:1587-92.
Liver stiffness predicts hepatic events in NAFLD
Among patients with nonalcoholic fatty liver disease (NAFLD) and compensated advanced chronic liver disease, liver stiffness measurements (LSMs) are associated with risks of hepatic events, according to a retrospective analysis of more than 1,000 patients.
“[N]oninvasive markers that can predict liver disease severity and outcomes in patients with NAFLD and advanced fibrosis are a major unmet need,” wrote lead author Salvatore Petta, MD, of the University of Palermo, Italy, and colleagues. Their report is in Clinical Gastroenterology and Hepatology. “Data about the accuracy of LSM in the prediction of events in NAFLD, and especially in patients with NAFLD and F3-F4 fibrosis, are scarce.”
To address this knowledge gap, the investigators retrospectively analyzed data from 1,039 consecutive patients with NAFLD who had baseline LSMs of more than 10 kPa and/or histologically diagnosed F3-F4 fibrosis. Patients were prospectively recruited at 10 centers in 6 countries, then followed for a median of 35 months, ranging from 19 to 63 months.
All patients had their liver stiffness measured with an M or XL probe at baseline. In addition, approximately half of the patients (n = 533) had a follow-up measurement using the same method, generating a subgroup with changes in liver stiffness. “Improved” liver stiffness was defined as a decrease in LSM greater than 20% from baseline, “impaired” liver stiffness was defined as an increase in LSM greater than 20% from baseline, and “stable” liver stiffness was defined as a change falling between 20% lower and 20% higher than baseline.
At baseline, mean LSM was 17.6 kPa. Cox regression analysis revealed that baseline LSM was independently associated with HCC (hazard ratio, 1.03; 95% confidence interval, 1.00-1.04; P = .003), liver decompensation (HR, 1.03; 95% CI, 1.02-1.04; P < .001), and liver-related death (HR, 1.02; 95% CI, 1.00-1.03; P = .005), but not extrahepatic events.
According to the investigators, the association between LSM at baseline and risk of liver decompensation was maintained after adjustment for the severity of liver disease and for surrogate markers of portal hypertension, they noted. Furthermore, patients with a baseline LSM of at least 21 kPa – which indicates high risk of clinically significant portal hypertension (CSPH) – were at greater risk of liver decompensation than were those with an LSM less than 21 kPa (HR, 3.71; 95% CI, 1.89-6.78; P = .04).
In the subgroup with follow-up measurements, approximately half of the patients had an improved LSM (53.3%), while 27.2% had a stable LSM, and 19.5% had an impaired LSM, a pattern that was significantly associated with diabetes at baseline (P = .01).
“These data agree with the available literature identifying diabetes as a risk factor for liver disease progression and liver-related complications,” the investigators wrote.
Cox regression showed that, among those with follow-up LSM, changes in LSM were independently associated with HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), liver decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = . 04), liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02), and mortality of any cause (HR, 1.73; 95% CI, 1.11-2.69; P = .01).
These risks could be further stratified by level of change in liver stiffness, with greater impairment predicting greater risk: The crude rate of liver decompensation was 14.4% among those with impaired LSM, compared with 6.2% among those with stable LSM and 3.8% among those with LSM improvement. That said, the categories of changes in LSM were not predictive of decompensation among patients with high risk of CSPH at baseline; however, they remained predictive among those with low risk of CSPH at baseline.
“[T]his study … showed that an integrated assessment of baseline LSM or [changes in LSM] can help in stratifying the risk of development of liver-related complications and of both hepatic and overall mortality,” the investigators concluded. “These data, if further validated, could help personalize prognosis and follow-up in NAFLD with [compensated advanced chronic liver disease].”
The investigators disclosed relationships with AbbVie, Novo Nordisk, Gilead, and others.
As the prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, risk-stratifying those who will develop liver-related complications remains a major challenge. Although progression of liver fibrosis is a key risk factor for developing liver-related complications, the clinical application of noninvasive fibrosis markers for prognostication has been largely unexplored in NAFLD.
This study by Dr. Petta and colleagues highlights the potential for liver stiffness measurements (LSMs) as a noninvasive method. Increased LSM that was suggestive of clinically significant portal hypertension (kPa >21) had a nearly fourfold risk of hepatic decompensation. Furthermore, a longitudinal increase in LSM by greater than 20% was associated with a greater than 50% increased risk for hepatic decompensation, hepatocellular carcinoma, and death.
Transient elastography is a widely available and accurate tool for the noninvasive assessment of liver fibrosis for NAFLD in routine clinical practice. Routine serial measurements of LSM with transient elastography during clinic visits can provide clinicians with important information in the management of NAFLD, which can aid in treatment decisions, response to therapy, and monitoring of disease progression.
Further research is needed to validate these findings and to evaluate how longitudinal changes in LSM and other noninvasive fibrosis markers can prognosticate outcomes in NAFLD.
George Cholankeril MD, MS, is an assistant professor in the section of gastroenterology & hepatology of the department of medicine and in the division of abdominal transplantation of the department of surgery at Baylor College of Medicine in Houston. He reported having no conflicts of interest.
As the prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, risk-stratifying those who will develop liver-related complications remains a major challenge. Although progression of liver fibrosis is a key risk factor for developing liver-related complications, the clinical application of noninvasive fibrosis markers for prognostication has been largely unexplored in NAFLD.
This study by Dr. Petta and colleagues highlights the potential for liver stiffness measurements (LSMs) as a noninvasive method. Increased LSM that was suggestive of clinically significant portal hypertension (kPa >21) had a nearly fourfold risk of hepatic decompensation. Furthermore, a longitudinal increase in LSM by greater than 20% was associated with a greater than 50% increased risk for hepatic decompensation, hepatocellular carcinoma, and death.
Transient elastography is a widely available and accurate tool for the noninvasive assessment of liver fibrosis for NAFLD in routine clinical practice. Routine serial measurements of LSM with transient elastography during clinic visits can provide clinicians with important information in the management of NAFLD, which can aid in treatment decisions, response to therapy, and monitoring of disease progression.
Further research is needed to validate these findings and to evaluate how longitudinal changes in LSM and other noninvasive fibrosis markers can prognosticate outcomes in NAFLD.
George Cholankeril MD, MS, is an assistant professor in the section of gastroenterology & hepatology of the department of medicine and in the division of abdominal transplantation of the department of surgery at Baylor College of Medicine in Houston. He reported having no conflicts of interest.
As the prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, risk-stratifying those who will develop liver-related complications remains a major challenge. Although progression of liver fibrosis is a key risk factor for developing liver-related complications, the clinical application of noninvasive fibrosis markers for prognostication has been largely unexplored in NAFLD.
This study by Dr. Petta and colleagues highlights the potential for liver stiffness measurements (LSMs) as a noninvasive method. Increased LSM that was suggestive of clinically significant portal hypertension (kPa >21) had a nearly fourfold risk of hepatic decompensation. Furthermore, a longitudinal increase in LSM by greater than 20% was associated with a greater than 50% increased risk for hepatic decompensation, hepatocellular carcinoma, and death.
Transient elastography is a widely available and accurate tool for the noninvasive assessment of liver fibrosis for NAFLD in routine clinical practice. Routine serial measurements of LSM with transient elastography during clinic visits can provide clinicians with important information in the management of NAFLD, which can aid in treatment decisions, response to therapy, and monitoring of disease progression.
Further research is needed to validate these findings and to evaluate how longitudinal changes in LSM and other noninvasive fibrosis markers can prognosticate outcomes in NAFLD.
George Cholankeril MD, MS, is an assistant professor in the section of gastroenterology & hepatology of the department of medicine and in the division of abdominal transplantation of the department of surgery at Baylor College of Medicine in Houston. He reported having no conflicts of interest.
Among patients with nonalcoholic fatty liver disease (NAFLD) and compensated advanced chronic liver disease, liver stiffness measurements (LSMs) are associated with risks of hepatic events, according to a retrospective analysis of more than 1,000 patients.
“[N]oninvasive markers that can predict liver disease severity and outcomes in patients with NAFLD and advanced fibrosis are a major unmet need,” wrote lead author Salvatore Petta, MD, of the University of Palermo, Italy, and colleagues. Their report is in Clinical Gastroenterology and Hepatology. “Data about the accuracy of LSM in the prediction of events in NAFLD, and especially in patients with NAFLD and F3-F4 fibrosis, are scarce.”
To address this knowledge gap, the investigators retrospectively analyzed data from 1,039 consecutive patients with NAFLD who had baseline LSMs of more than 10 kPa and/or histologically diagnosed F3-F4 fibrosis. Patients were prospectively recruited at 10 centers in 6 countries, then followed for a median of 35 months, ranging from 19 to 63 months.
All patients had their liver stiffness measured with an M or XL probe at baseline. In addition, approximately half of the patients (n = 533) had a follow-up measurement using the same method, generating a subgroup with changes in liver stiffness. “Improved” liver stiffness was defined as a decrease in LSM greater than 20% from baseline, “impaired” liver stiffness was defined as an increase in LSM greater than 20% from baseline, and “stable” liver stiffness was defined as a change falling between 20% lower and 20% higher than baseline.
At baseline, mean LSM was 17.6 kPa. Cox regression analysis revealed that baseline LSM was independently associated with HCC (hazard ratio, 1.03; 95% confidence interval, 1.00-1.04; P = .003), liver decompensation (HR, 1.03; 95% CI, 1.02-1.04; P < .001), and liver-related death (HR, 1.02; 95% CI, 1.00-1.03; P = .005), but not extrahepatic events.
According to the investigators, the association between LSM at baseline and risk of liver decompensation was maintained after adjustment for the severity of liver disease and for surrogate markers of portal hypertension, they noted. Furthermore, patients with a baseline LSM of at least 21 kPa – which indicates high risk of clinically significant portal hypertension (CSPH) – were at greater risk of liver decompensation than were those with an LSM less than 21 kPa (HR, 3.71; 95% CI, 1.89-6.78; P = .04).
In the subgroup with follow-up measurements, approximately half of the patients had an improved LSM (53.3%), while 27.2% had a stable LSM, and 19.5% had an impaired LSM, a pattern that was significantly associated with diabetes at baseline (P = .01).
“These data agree with the available literature identifying diabetes as a risk factor for liver disease progression and liver-related complications,” the investigators wrote.
Cox regression showed that, among those with follow-up LSM, changes in LSM were independently associated with HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), liver decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = . 04), liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02), and mortality of any cause (HR, 1.73; 95% CI, 1.11-2.69; P = .01).
These risks could be further stratified by level of change in liver stiffness, with greater impairment predicting greater risk: The crude rate of liver decompensation was 14.4% among those with impaired LSM, compared with 6.2% among those with stable LSM and 3.8% among those with LSM improvement. That said, the categories of changes in LSM were not predictive of decompensation among patients with high risk of CSPH at baseline; however, they remained predictive among those with low risk of CSPH at baseline.
“[T]his study … showed that an integrated assessment of baseline LSM or [changes in LSM] can help in stratifying the risk of development of liver-related complications and of both hepatic and overall mortality,” the investigators concluded. “These data, if further validated, could help personalize prognosis and follow-up in NAFLD with [compensated advanced chronic liver disease].”
The investigators disclosed relationships with AbbVie, Novo Nordisk, Gilead, and others.
Among patients with nonalcoholic fatty liver disease (NAFLD) and compensated advanced chronic liver disease, liver stiffness measurements (LSMs) are associated with risks of hepatic events, according to a retrospective analysis of more than 1,000 patients.
“[N]oninvasive markers that can predict liver disease severity and outcomes in patients with NAFLD and advanced fibrosis are a major unmet need,” wrote lead author Salvatore Petta, MD, of the University of Palermo, Italy, and colleagues. Their report is in Clinical Gastroenterology and Hepatology. “Data about the accuracy of LSM in the prediction of events in NAFLD, and especially in patients with NAFLD and F3-F4 fibrosis, are scarce.”
To address this knowledge gap, the investigators retrospectively analyzed data from 1,039 consecutive patients with NAFLD who had baseline LSMs of more than 10 kPa and/or histologically diagnosed F3-F4 fibrosis. Patients were prospectively recruited at 10 centers in 6 countries, then followed for a median of 35 months, ranging from 19 to 63 months.
All patients had their liver stiffness measured with an M or XL probe at baseline. In addition, approximately half of the patients (n = 533) had a follow-up measurement using the same method, generating a subgroup with changes in liver stiffness. “Improved” liver stiffness was defined as a decrease in LSM greater than 20% from baseline, “impaired” liver stiffness was defined as an increase in LSM greater than 20% from baseline, and “stable” liver stiffness was defined as a change falling between 20% lower and 20% higher than baseline.
At baseline, mean LSM was 17.6 kPa. Cox regression analysis revealed that baseline LSM was independently associated with HCC (hazard ratio, 1.03; 95% confidence interval, 1.00-1.04; P = .003), liver decompensation (HR, 1.03; 95% CI, 1.02-1.04; P < .001), and liver-related death (HR, 1.02; 95% CI, 1.00-1.03; P = .005), but not extrahepatic events.
According to the investigators, the association between LSM at baseline and risk of liver decompensation was maintained after adjustment for the severity of liver disease and for surrogate markers of portal hypertension, they noted. Furthermore, patients with a baseline LSM of at least 21 kPa – which indicates high risk of clinically significant portal hypertension (CSPH) – were at greater risk of liver decompensation than were those with an LSM less than 21 kPa (HR, 3.71; 95% CI, 1.89-6.78; P = .04).
In the subgroup with follow-up measurements, approximately half of the patients had an improved LSM (53.3%), while 27.2% had a stable LSM, and 19.5% had an impaired LSM, a pattern that was significantly associated with diabetes at baseline (P = .01).
“These data agree with the available literature identifying diabetes as a risk factor for liver disease progression and liver-related complications,” the investigators wrote.
Cox regression showed that, among those with follow-up LSM, changes in LSM were independently associated with HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), liver decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = . 04), liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02), and mortality of any cause (HR, 1.73; 95% CI, 1.11-2.69; P = .01).
These risks could be further stratified by level of change in liver stiffness, with greater impairment predicting greater risk: The crude rate of liver decompensation was 14.4% among those with impaired LSM, compared with 6.2% among those with stable LSM and 3.8% among those with LSM improvement. That said, the categories of changes in LSM were not predictive of decompensation among patients with high risk of CSPH at baseline; however, they remained predictive among those with low risk of CSPH at baseline.
“[T]his study … showed that an integrated assessment of baseline LSM or [changes in LSM] can help in stratifying the risk of development of liver-related complications and of both hepatic and overall mortality,” the investigators concluded. “These data, if further validated, could help personalize prognosis and follow-up in NAFLD with [compensated advanced chronic liver disease].”
The investigators disclosed relationships with AbbVie, Novo Nordisk, Gilead, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
