Article

Key clinical point: Decreased SARS-CoV-2 antibody level is the major contributor to breakthrough SARS-CoV-2 infection in vaccinated patients with multiple sclerosis (MS) on various disease modifying therapies (DMT), with the third dose significantly reducing the risk for infection.

Major finding: After the second vaccine dose, the only significant factor associated with the risk for breakthrough infection was low antibody level (hazard ratio [HR] 0.51; P < .001), with the third dose reducing the risk for infection by 56% (HR 0.44; P = .025) during the Omicron wave.

Study details: Findings are from a prospective study of 1705 patients with MS on various DMT who received 2 doses of BNT162b2 (BioNTech-Pfizer) (n = 1391) or mRNA-1273 (Moderna) (n = 314) SARS-CoV-2 vaccine, with most receiving the third dose.

Disclosures: This study was funded by Fondazione Italiana Sclerosi Multipla. Some authors declared receiving grants, travel compensation, speaker honoraria, or advisory board/lecture and consulting fees from various sources.

Source: Sormani MP et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine. 2022;80:104042 (May 4). Doi: 10.1016/j.ebiom.2022.104042

Key clinical point: Decreased SARS-CoV-2 antibody level is the major contributor to breakthrough SARS-CoV-2 infection in vaccinated patients with multiple sclerosis (MS) on various disease modifying therapies (DMT), with the third dose significantly reducing the risk for infection.

Major finding: After the second vaccine dose, the only significant factor associated with the risk for breakthrough infection was low antibody level (hazard ratio [HR] 0.51; P < .001), with the third dose reducing the risk for infection by 56% (HR 0.44; P = .025) during the Omicron wave.

Study details: Findings are from a prospective study of 1705 patients with MS on various DMT who received 2 doses of BNT162b2 (BioNTech-Pfizer) (n = 1391) or mRNA-1273 (Moderna) (n = 314) SARS-CoV-2 vaccine, with most receiving the third dose.

Disclosures: This study was funded by Fondazione Italiana Sclerosi Multipla. Some authors declared receiving grants, travel compensation, speaker honoraria, or advisory board/lecture and consulting fees from various sources.

Source: Sormani MP et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine. 2022;80:104042 (May 4). Doi: 10.1016/j.ebiom.2022.104042

Key clinical point: Decreased SARS-CoV-2 antibody level is the major contributor to breakthrough SARS-CoV-2 infection in vaccinated patients with multiple sclerosis (MS) on various disease modifying therapies (DMT), with the third dose significantly reducing the risk for infection.

Major finding: After the second vaccine dose, the only significant factor associated with the risk for breakthrough infection was low antibody level (hazard ratio [HR] 0.51; P < .001), with the third dose reducing the risk for infection by 56% (HR 0.44; P = .025) during the Omicron wave.

Study details: Findings are from a prospective study of 1705 patients with MS on various DMT who received 2 doses of BNT162b2 (BioNTech-Pfizer) (n = 1391) or mRNA-1273 (Moderna) (n = 314) SARS-CoV-2 vaccine, with most receiving the third dose.

Disclosures: This study was funded by Fondazione Italiana Sclerosi Multipla. Some authors declared receiving grants, travel compensation, speaker honoraria, or advisory board/lecture and consulting fees from various sources.

Source: Sormani MP et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine. 2022;80:104042 (May 4). Doi: 10.1016/j.ebiom.2022.104042

Key clinical point: In ocrelizumab-treated patients with multiple sclerosis (MS), a third SARS-CoV-2 vaccine boosted the T-cell response, but had no additive effect on the maximal T-cell response.

Major finding: SARS-CoV-2-specific T-cell response in patients treated with ocrelizumab was comparable to those not treated with disease modifying therapy (DMT) and healthy controls (HC) after the second SARS-CoV-2 vaccination; however, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

Study details: This was a prospective longitudinal study including patients with MS treated with ocrelizumab (n = 24), fingolimod (n = 12), or no DMT (n = 10) and HC (n = 12) who received three SARS-CoV-2 vaccine doses (BNT162b2 [BioNTech-Pfizer] or CX-024414 [Moderna]).

Disclosures: This study was funded by The Netherlands Organisation for Health Research and Development. Some authors reported receiving consulting fees and research support from various sources.

Source: Cabeza VP et al. Longitudinal T-cell responses after a third SARS-CoV-2 vaccination in patients with multiple sclerosis on ocrelizumab or fingolimod. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1178 (May 6). Doi: 10.1212/NXI.0000000000001178

Key clinical point: In ocrelizumab-treated patients with multiple sclerosis (MS), a third SARS-CoV-2 vaccine boosted the T-cell response, but had no additive effect on the maximal T-cell response.

Major finding: SARS-CoV-2-specific T-cell response in patients treated with ocrelizumab was comparable to those not treated with disease modifying therapy (DMT) and healthy controls (HC) after the second SARS-CoV-2 vaccination; however, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

Study details: This was a prospective longitudinal study including patients with MS treated with ocrelizumab (n = 24), fingolimod (n = 12), or no DMT (n = 10) and HC (n = 12) who received three SARS-CoV-2 vaccine doses (BNT162b2 [BioNTech-Pfizer] or CX-024414 [Moderna]).

Disclosures: This study was funded by The Netherlands Organisation for Health Research and Development. Some authors reported receiving consulting fees and research support from various sources.

Source: Cabeza VP et al. Longitudinal T-cell responses after a third SARS-CoV-2 vaccination in patients with multiple sclerosis on ocrelizumab or fingolimod. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1178 (May 6). Doi: 10.1212/NXI.0000000000001178

Key clinical point: In ocrelizumab-treated patients with multiple sclerosis (MS), a third SARS-CoV-2 vaccine boosted the T-cell response, but had no additive effect on the maximal T-cell response.

Major finding: SARS-CoV-2-specific T-cell response in patients treated with ocrelizumab was comparable to those not treated with disease modifying therapy (DMT) and healthy controls (HC) after the second SARS-CoV-2 vaccination; however, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

Study details: This was a prospective longitudinal study including patients with MS treated with ocrelizumab (n = 24), fingolimod (n = 12), or no DMT (n = 10) and HC (n = 12) who received three SARS-CoV-2 vaccine doses (BNT162b2 [BioNTech-Pfizer] or CX-024414 [Moderna]).

Disclosures: This study was funded by The Netherlands Organisation for Health Research and Development. Some authors reported receiving consulting fees and research support from various sources.

Source: Cabeza VP et al. Longitudinal T-cell responses after a third SARS-CoV-2 vaccination in patients with multiple sclerosis on ocrelizumab or fingolimod. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1178 (May 6). Doi: 10.1212/NXI.0000000000001178

Key clinical point: Continuous siponimod treatment for up to >5 years showed sustained efficacy and a consistent safety profile in patients with secondary progressive multiple sclerosis (SPMS).

Major finding:  The risk for 6-month confirmed disability progression (CDP) was 22% lower (P = .0026) and confirmed worsening in cognitive processing speed was 23% lower (P = .0047) in patients who received continuous siponimod vs those who switched from placebo to siponimod. Siponimod had a manageable and consistent safety profile.

Study details: Findings are from the phase 3 EXPAND study including the extension phase that included 1220 of 1651 patients with SPMS from the core phase. In the extension phase, patients who had received placebo in the core phase switched to siponimod, whereas those who had received siponimod continued the same treatment.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. Five authors reported being employees of Novartis. Some authors reported receiving consulting or speakers’ fees or personal compensation or serving as a steering committee member or on an advisory board for various sources.

Source: Cree BAC et al. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler. 2022 (Apr 5). Doi: 10.1177/13524585221083194

Key clinical point: Continuous siponimod treatment for up to >5 years showed sustained efficacy and a consistent safety profile in patients with secondary progressive multiple sclerosis (SPMS).

Major finding:  The risk for 6-month confirmed disability progression (CDP) was 22% lower (P = .0026) and confirmed worsening in cognitive processing speed was 23% lower (P = .0047) in patients who received continuous siponimod vs those who switched from placebo to siponimod. Siponimod had a manageable and consistent safety profile.

Study details: Findings are from the phase 3 EXPAND study including the extension phase that included 1220 of 1651 patients with SPMS from the core phase. In the extension phase, patients who had received placebo in the core phase switched to siponimod, whereas those who had received siponimod continued the same treatment.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. Five authors reported being employees of Novartis. Some authors reported receiving consulting or speakers’ fees or personal compensation or serving as a steering committee member or on an advisory board for various sources.

Source: Cree BAC et al. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler. 2022 (Apr 5). Doi: 10.1177/13524585221083194

Key clinical point: Continuous siponimod treatment for up to >5 years showed sustained efficacy and a consistent safety profile in patients with secondary progressive multiple sclerosis (SPMS).

Major finding:  The risk for 6-month confirmed disability progression (CDP) was 22% lower (P = .0026) and confirmed worsening in cognitive processing speed was 23% lower (P = .0047) in patients who received continuous siponimod vs those who switched from placebo to siponimod. Siponimod had a manageable and consistent safety profile.

Study details: Findings are from the phase 3 EXPAND study including the extension phase that included 1220 of 1651 patients with SPMS from the core phase. In the extension phase, patients who had received placebo in the core phase switched to siponimod, whereas those who had received siponimod continued the same treatment.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. Five authors reported being employees of Novartis. Some authors reported receiving consulting or speakers’ fees or personal compensation or serving as a steering committee member or on an advisory board for various sources.

Source: Cree BAC et al. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. Mult Scler. 2022 (Apr 5). Doi: 10.1177/13524585221083194

Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

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. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

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. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

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. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.