Article

Key clinical point: Lower levels of caprylate and acetate in breast milk could be risk factors for infantile atopic dermatitis (AD) in exclusively breastfed infants.

Major finding: Caprylate (P = .034) and acetate (P = .002) levels were significantly lower in breast milk for infants with vs. without AD, with caprylate (P = .021) and acetate (P = .015) levels in breast milk being the factors significantly associated with the presence of infantile AD.

Study details: This prospective, observational study included 94 2- to 4-month-old exclusively breastfed infants. In this group 47 infants were diagnosed with mild (n = 17), moderate (n = 25), or severe (n = 5) AD and 47 infants without AD formed the control group.

Disclosures: This study was supported by National Taiwan University Hospital, Taipei, Taiwan. The authors declared no conflict of interests.

Source: Wang LC et al. Lower caprylate and acetate levels in the breast milk is associated with atopic dermatitis in infancy. Pediatr Allergy Immunol. 2022;33(2) e13744 (Feb 21). Doi:  10.1111/pai.13744

Key clinical point: Lower levels of caprylate and acetate in breast milk could be risk factors for infantile atopic dermatitis (AD) in exclusively breastfed infants.

Major finding: Caprylate (P = .034) and acetate (P = .002) levels were significantly lower in breast milk for infants with vs. without AD, with caprylate (P = .021) and acetate (P = .015) levels in breast milk being the factors significantly associated with the presence of infantile AD.

Study details: This prospective, observational study included 94 2- to 4-month-old exclusively breastfed infants. In this group 47 infants were diagnosed with mild (n = 17), moderate (n = 25), or severe (n = 5) AD and 47 infants without AD formed the control group.

Disclosures: This study was supported by National Taiwan University Hospital, Taipei, Taiwan. The authors declared no conflict of interests.

Source: Wang LC et al. Lower caprylate and acetate levels in the breast milk is associated with atopic dermatitis in infancy. Pediatr Allergy Immunol. 2022;33(2) e13744 (Feb 21). Doi:  10.1111/pai.13744

Key clinical point: Lower levels of caprylate and acetate in breast milk could be risk factors for infantile atopic dermatitis (AD) in exclusively breastfed infants.

Major finding: Caprylate (P = .034) and acetate (P = .002) levels were significantly lower in breast milk for infants with vs. without AD, with caprylate (P = .021) and acetate (P = .015) levels in breast milk being the factors significantly associated with the presence of infantile AD.

Study details: This prospective, observational study included 94 2- to 4-month-old exclusively breastfed infants. In this group 47 infants were diagnosed with mild (n = 17), moderate (n = 25), or severe (n = 5) AD and 47 infants without AD formed the control group.

Disclosures: This study was supported by National Taiwan University Hospital, Taipei, Taiwan. The authors declared no conflict of interests.

Source: Wang LC et al. Lower caprylate and acetate levels in the breast milk is associated with atopic dermatitis in infancy. Pediatr Allergy Immunol. 2022;33(2) e13744 (Feb 21). Doi:  10.1111/pai.13744

Key clinical point: Patients with atopic dermatitis (AD) who initiated dupilumab were at a 2-fold higher risk of developing conjunctivitis within 6 months of treatment initiation vs. those who initiated other systemic therapies, with comorbid asthma further increasing the risk.

Major finding: The risk of developing conjunctivitis within 6 months of treatment initiation was higher with dupilumab vs. methotrexate (relative risk [RR] 2.12; 95% CI 1.56-2.91), mycophenolate (RR 2.43; 95% CI 1.32-4.47), or cyclosporine (RR 1.83; 95% CI 1.05-3.20). Comorbid asthma could be a risk factor for conjunctivitis in dupilumab initiators (RR 2.86; 95% CI 1.24-6.60).

Study details: This population-based longitudinal study included 5,004,117 patients with AD who newly initiated dupilumab or methotrexate (cohort 1, n = 5,770), dupilumab or mycophenolate (cohort 2, n = 4,402), and dupilumab or cyclosporine (cohort 3, n = 4,238).

Disclosures: This study was supported by the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. The authors declared serving as advisors, speakers, consultants, or principal investigators or receiving funding and grants from several sources.

Source: Schneeweiss MC et al. Incidence of bacterial and nonbacterial conjunctivitis in patients with atopic dermatitis treated with dupilumab: A US multidatabase cohort study. Dermatitis. 2022 (Feb 15). Doi: 10.1097/DER.0000000000000843

Key clinical point: Patients with atopic dermatitis (AD) who initiated dupilumab were at a 2-fold higher risk of developing conjunctivitis within 6 months of treatment initiation vs. those who initiated other systemic therapies, with comorbid asthma further increasing the risk.

Major finding: The risk of developing conjunctivitis within 6 months of treatment initiation was higher with dupilumab vs. methotrexate (relative risk [RR] 2.12; 95% CI 1.56-2.91), mycophenolate (RR 2.43; 95% CI 1.32-4.47), or cyclosporine (RR 1.83; 95% CI 1.05-3.20). Comorbid asthma could be a risk factor for conjunctivitis in dupilumab initiators (RR 2.86; 95% CI 1.24-6.60).

Study details: This population-based longitudinal study included 5,004,117 patients with AD who newly initiated dupilumab or methotrexate (cohort 1, n = 5,770), dupilumab or mycophenolate (cohort 2, n = 4,402), and dupilumab or cyclosporine (cohort 3, n = 4,238).

Disclosures: This study was supported by the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. The authors declared serving as advisors, speakers, consultants, or principal investigators or receiving funding and grants from several sources.

Source: Schneeweiss MC et al. Incidence of bacterial and nonbacterial conjunctivitis in patients with atopic dermatitis treated with dupilumab: A US multidatabase cohort study. Dermatitis. 2022 (Feb 15). Doi: 10.1097/DER.0000000000000843

Key clinical point: Patients with atopic dermatitis (AD) who initiated dupilumab were at a 2-fold higher risk of developing conjunctivitis within 6 months of treatment initiation vs. those who initiated other systemic therapies, with comorbid asthma further increasing the risk.

Major finding: The risk of developing conjunctivitis within 6 months of treatment initiation was higher with dupilumab vs. methotrexate (relative risk [RR] 2.12; 95% CI 1.56-2.91), mycophenolate (RR 2.43; 95% CI 1.32-4.47), or cyclosporine (RR 1.83; 95% CI 1.05-3.20). Comorbid asthma could be a risk factor for conjunctivitis in dupilumab initiators (RR 2.86; 95% CI 1.24-6.60).

Study details: This population-based longitudinal study included 5,004,117 patients with AD who newly initiated dupilumab or methotrexate (cohort 1, n = 5,770), dupilumab or mycophenolate (cohort 2, n = 4,402), and dupilumab or cyclosporine (cohort 3, n = 4,238).

Disclosures: This study was supported by the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. The authors declared serving as advisors, speakers, consultants, or principal investigators or receiving funding and grants from several sources.

Source: Schneeweiss MC et al. Incidence of bacterial and nonbacterial conjunctivitis in patients with atopic dermatitis treated with dupilumab: A US multidatabase cohort study. Dermatitis. 2022 (Feb 15). Doi: 10.1097/DER.0000000000000843

Key clinical point: Dupilumab effectively reduced signs and symptoms of atopic dermatitis (AD) along with a tolerable safety profile in a real-world setting during the COVID-19 pandemic.

Major finding: At least 75% improvement in the Eczema Area and Severity Index was achieved by 66.6%, 89.5%, and 95.8% patients at 16 weeks, 1 year, and 2 years of dupilumab therapy, respectively, with persistence rates being >90% throughout the 2 years of therapy. The most reported adverse events were infections, with a mild course of COVID-19 being the most reported (4.7%), followed by ocular complications (2.5%).

Study details: Findings are from a retrospective, multicenter study including 360 adults with severe AD who received ≥1 dose of dupilumab.

Disclosures: This study did not receive any funding. Some authors declared serving as a consultant, speaker, or investigator for several sources.

Source: Kojanova M et al. Dupilumab for the treatment of atopic dermatitis: real-world data from the Czech Republic BIOREP registry. J Dermatolog Treat. 2022 (Feb 21). Doi: 10.1080/09546634.2022.2043545

Key clinical point: Dupilumab effectively reduced signs and symptoms of atopic dermatitis (AD) along with a tolerable safety profile in a real-world setting during the COVID-19 pandemic.

Major finding: At least 75% improvement in the Eczema Area and Severity Index was achieved by 66.6%, 89.5%, and 95.8% patients at 16 weeks, 1 year, and 2 years of dupilumab therapy, respectively, with persistence rates being >90% throughout the 2 years of therapy. The most reported adverse events were infections, with a mild course of COVID-19 being the most reported (4.7%), followed by ocular complications (2.5%).

Study details: Findings are from a retrospective, multicenter study including 360 adults with severe AD who received ≥1 dose of dupilumab.

Disclosures: This study did not receive any funding. Some authors declared serving as a consultant, speaker, or investigator for several sources.

Source: Kojanova M et al. Dupilumab for the treatment of atopic dermatitis: real-world data from the Czech Republic BIOREP registry. J Dermatolog Treat. 2022 (Feb 21). Doi: 10.1080/09546634.2022.2043545

Key clinical point: Dupilumab effectively reduced signs and symptoms of atopic dermatitis (AD) along with a tolerable safety profile in a real-world setting during the COVID-19 pandemic.

Major finding: At least 75% improvement in the Eczema Area and Severity Index was achieved by 66.6%, 89.5%, and 95.8% patients at 16 weeks, 1 year, and 2 years of dupilumab therapy, respectively, with persistence rates being >90% throughout the 2 years of therapy. The most reported adverse events were infections, with a mild course of COVID-19 being the most reported (4.7%), followed by ocular complications (2.5%).

Study details: Findings are from a retrospective, multicenter study including 360 adults with severe AD who received ≥1 dose of dupilumab.

Disclosures: This study did not receive any funding. Some authors declared serving as a consultant, speaker, or investigator for several sources.

Source: Kojanova M et al. Dupilumab for the treatment of atopic dermatitis: real-world data from the Czech Republic BIOREP registry. J Dermatolog Treat. 2022 (Feb 21). Doi: 10.1080/09546634.2022.2043545

Key clinical point: Risk for acne was comparable in adolescents and adults with atopic dermatitis (AD) and matched reference individuals from the general population; however, the risk varied with age and sex, with males and older patients appearing to be at higher risk.

Major finding: Although the overall risk for acne was similar among patients with AD vs. reference individuals (hazard ratio [HR] 0.96; P = .4623), the risk was significantly higher in males with AD (HR 1.22; P = .0234) and in patients aged 30-39 (HR 1.41; P = .0156) and ≥40 (HR 2.07; P = .0002) years.

Study details: Findings are from a prospective cohort study including 6,600 adults and adolescents with AD matched with 66,000 reference individuals without AD.

Disclosures: This study did not receive any funding. The authors declared serving as an advisory board member, investigator, speaker, consultant, or receiving honoraria, fees, research funding, and research support from several sources.

Source: Thyssen JP et al. Incidence, prevalence and risk of acne in adolescent and adult patients with atopic dermatitis: a matched cohort study. J Eur Acad Dermatol Venereol. 2022 (Feb 26). Doi: 10.1111/jdv.18027

Key clinical point: Risk for acne was comparable in adolescents and adults with atopic dermatitis (AD) and matched reference individuals from the general population; however, the risk varied with age and sex, with males and older patients appearing to be at higher risk.

Major finding: Although the overall risk for acne was similar among patients with AD vs. reference individuals (hazard ratio [HR] 0.96; P = .4623), the risk was significantly higher in males with AD (HR 1.22; P = .0234) and in patients aged 30-39 (HR 1.41; P = .0156) and ≥40 (HR 2.07; P = .0002) years.

Study details: Findings are from a prospective cohort study including 6,600 adults and adolescents with AD matched with 66,000 reference individuals without AD.

Disclosures: This study did not receive any funding. The authors declared serving as an advisory board member, investigator, speaker, consultant, or receiving honoraria, fees, research funding, and research support from several sources.

Source: Thyssen JP et al. Incidence, prevalence and risk of acne in adolescent and adult patients with atopic dermatitis: a matched cohort study. J Eur Acad Dermatol Venereol. 2022 (Feb 26). Doi: 10.1111/jdv.18027

Key clinical point: Risk for acne was comparable in adolescents and adults with atopic dermatitis (AD) and matched reference individuals from the general population; however, the risk varied with age and sex, with males and older patients appearing to be at higher risk.

Major finding: Although the overall risk for acne was similar among patients with AD vs. reference individuals (hazard ratio [HR] 0.96; P = .4623), the risk was significantly higher in males with AD (HR 1.22; P = .0234) and in patients aged 30-39 (HR 1.41; P = .0156) and ≥40 (HR 2.07; P = .0002) years.

Study details: Findings are from a prospective cohort study including 6,600 adults and adolescents with AD matched with 66,000 reference individuals without AD.

Disclosures: This study did not receive any funding. The authors declared serving as an advisory board member, investigator, speaker, consultant, or receiving honoraria, fees, research funding, and research support from several sources.

Source: Thyssen JP et al. Incidence, prevalence and risk of acne in adolescent and adult patients with atopic dermatitis: a matched cohort study. J Eur Acad Dermatol Venereol. 2022 (Feb 26). Doi: 10.1111/jdv.18027

Key clinical point: A significant proportion of patients with atopic dermatitis (AD) experience sleep disturbance (SD), which usually improves overtime; however, patients with moderate-to-severe AD are more likely to experience a persistent SD course.

Major finding: At least 3 nights of SD were reported by 34.2% of patients at baseline; however only 12.3% of patients reported persistent SD at the first and second follow-ups, and only 11.5% of patients with severe SD at baseline experienced persistent SD scores at the second follow-up. Severe/very severe AD vs. mild AD was a significant predictor of increased nights of SD by eczema (adjusted odds ratio 16.20; P < .0001).

Study details: This prospective, dermatology practice-based study included 1,295 patients with mild (40.5%), moderate (35.1%), or severe/very severe (24.4%) AD.

Disclosures: This study was supported by the Agency for Healthcare Research and Quality, the Dermatology Foundation, and an unrestricted research grant from Galderma. R Chavda and S Gabriel declared being employees of and JI Silverberg declared being a consultant for Galderma.

Source: Manjunath J et al. longitudinal course of sleep disturbance and relationship with itch in adult atopic dermatitis in clinical practice. Dermatitis. 2022 (Mar 3). Doi: 10.1097/DER.0000000000000859

Key clinical point: A significant proportion of patients with atopic dermatitis (AD) experience sleep disturbance (SD), which usually improves overtime; however, patients with moderate-to-severe AD are more likely to experience a persistent SD course.

Major finding: At least 3 nights of SD were reported by 34.2% of patients at baseline; however only 12.3% of patients reported persistent SD at the first and second follow-ups, and only 11.5% of patients with severe SD at baseline experienced persistent SD scores at the second follow-up. Severe/very severe AD vs. mild AD was a significant predictor of increased nights of SD by eczema (adjusted odds ratio 16.20; P < .0001).

Study details: This prospective, dermatology practice-based study included 1,295 patients with mild (40.5%), moderate (35.1%), or severe/very severe (24.4%) AD.

Disclosures: This study was supported by the Agency for Healthcare Research and Quality, the Dermatology Foundation, and an unrestricted research grant from Galderma. R Chavda and S Gabriel declared being employees of and JI Silverberg declared being a consultant for Galderma.

Source: Manjunath J et al. longitudinal course of sleep disturbance and relationship with itch in adult atopic dermatitis in clinical practice. Dermatitis. 2022 (Mar 3). Doi: 10.1097/DER.0000000000000859

Key clinical point: A significant proportion of patients with atopic dermatitis (AD) experience sleep disturbance (SD), which usually improves overtime; however, patients with moderate-to-severe AD are more likely to experience a persistent SD course.

Major finding: At least 3 nights of SD were reported by 34.2% of patients at baseline; however only 12.3% of patients reported persistent SD at the first and second follow-ups, and only 11.5% of patients with severe SD at baseline experienced persistent SD scores at the second follow-up. Severe/very severe AD vs. mild AD was a significant predictor of increased nights of SD by eczema (adjusted odds ratio 16.20; P < .0001).

Study details: This prospective, dermatology practice-based study included 1,295 patients with mild (40.5%), moderate (35.1%), or severe/very severe (24.4%) AD.

Disclosures: This study was supported by the Agency for Healthcare Research and Quality, the Dermatology Foundation, and an unrestricted research grant from Galderma. R Chavda and S Gabriel declared being employees of and JI Silverberg declared being a consultant for Galderma.

Source: Manjunath J et al. longitudinal course of sleep disturbance and relationship with itch in adult atopic dermatitis in clinical practice. Dermatitis. 2022 (Mar 3). Doi: 10.1097/DER.0000000000000859

Key clinical point: Atopic dermatitis (AD) was negatively associated with some serum lipids, indicating AD being intrinsically protective for dyslipidemia.

Major finding: AD was significantly associated with lower levels of total cholesterol (β −0.004; P < .001), triglycerides (β −0.006; P = .006), and low-density lipoprotein (β −0.004; P < .001) but not with high-density lipoprotein (P = .794).

Study details: The data come from a large-scale, cross-sectional study including 13,822 patients with AD and 67,896 patients with asthma.

Disclosures: This study was supported by the National Key Research and Development Project of China Precision Medicine Initiative and the Program of Introducing Talents of Discipline to Universities. The authors declared no conflict of interests.

Source: Tang Z et al. Association between atopic dermatitis, asthma, and serum lipids: A UK Biobank based observational study and Mendelian randomization analysis. Front Med. 2022 (Feb 21). Doi: 10.3389/fmed.2022.810092

Key clinical point: Atopic dermatitis (AD) was negatively associated with some serum lipids, indicating AD being intrinsically protective for dyslipidemia.

Major finding: AD was significantly associated with lower levels of total cholesterol (β −0.004; P < .001), triglycerides (β −0.006; P = .006), and low-density lipoprotein (β −0.004; P < .001) but not with high-density lipoprotein (P = .794).

Study details: The data come from a large-scale, cross-sectional study including 13,822 patients with AD and 67,896 patients with asthma.

Disclosures: This study was supported by the National Key Research and Development Project of China Precision Medicine Initiative and the Program of Introducing Talents of Discipline to Universities. The authors declared no conflict of interests.

Source: Tang Z et al. Association between atopic dermatitis, asthma, and serum lipids: A UK Biobank based observational study and Mendelian randomization analysis. Front Med. 2022 (Feb 21). Doi: 10.3389/fmed.2022.810092

Key clinical point: Atopic dermatitis (AD) was negatively associated with some serum lipids, indicating AD being intrinsically protective for dyslipidemia.

Major finding: AD was significantly associated with lower levels of total cholesterol (β −0.004; P < .001), triglycerides (β −0.006; P = .006), and low-density lipoprotein (β −0.004; P < .001) but not with high-density lipoprotein (P = .794).

Study details: The data come from a large-scale, cross-sectional study including 13,822 patients with AD and 67,896 patients with asthma.

Disclosures: This study was supported by the National Key Research and Development Project of China Precision Medicine Initiative and the Program of Introducing Talents of Discipline to Universities. The authors declared no conflict of interests.

Source: Tang Z et al. Association between atopic dermatitis, asthma, and serum lipids: A UK Biobank based observational study and Mendelian randomization analysis. Front Med. 2022 (Feb 21). Doi: 10.3389/fmed.2022.810092

Key clinical point: A 4-week treatment with a test cream (TC) containing only 2% urea and 20% glycerol significantly reduced sodium lauryl sulphate-induced skin irritation in patients with atopic dermatitis (AD) compared with a no treatment control (NTC) and two reference creams.

Major finding: After 28 days, there was a significant reduction in transepidermal water loss with TC vs. NTC (P < .001), paraffin cream (P < .001), and glycerol cream (P = .021); objective redness was lower with TC vs. NTC (P = .002) and paraffin cream (P < .001). The TC was well tolerated with no evidence of stinging or redness.

Study details: Findings are from a phase 2 trial including 49 adults with AD who were randomly assigned to receive either a TC containing urea and glycerol, a glycerol-containing moisturizer, a simple paraffin cream containing no humectant, or NTC.

Disclosures: This study was funded by Perrigo Nordic. The authors declared serving as consultants, investigators, or advisory board members for and receiving research grants from several sources. Three authors declared being employees of Perrigo Nordic.

Source: Danby SG et al. Different types of emollient cream exhibit diverse physiological effects on the skin barrier in adults with atopic dermatitis. Clin Exp Dermatol. 2022 (Feb 15). Doi:  10.1111/ced.15141

Key clinical point: A 4-week treatment with a test cream (TC) containing only 2% urea and 20% glycerol significantly reduced sodium lauryl sulphate-induced skin irritation in patients with atopic dermatitis (AD) compared with a no treatment control (NTC) and two reference creams.

Major finding: After 28 days, there was a significant reduction in transepidermal water loss with TC vs. NTC (P < .001), paraffin cream (P < .001), and glycerol cream (P = .021); objective redness was lower with TC vs. NTC (P = .002) and paraffin cream (P < .001). The TC was well tolerated with no evidence of stinging or redness.

Study details: Findings are from a phase 2 trial including 49 adults with AD who were randomly assigned to receive either a TC containing urea and glycerol, a glycerol-containing moisturizer, a simple paraffin cream containing no humectant, or NTC.

Disclosures: This study was funded by Perrigo Nordic. The authors declared serving as consultants, investigators, or advisory board members for and receiving research grants from several sources. Three authors declared being employees of Perrigo Nordic.

Source: Danby SG et al. Different types of emollient cream exhibit diverse physiological effects on the skin barrier in adults with atopic dermatitis. Clin Exp Dermatol. 2022 (Feb 15). Doi:  10.1111/ced.15141

Key clinical point: A 4-week treatment with a test cream (TC) containing only 2% urea and 20% glycerol significantly reduced sodium lauryl sulphate-induced skin irritation in patients with atopic dermatitis (AD) compared with a no treatment control (NTC) and two reference creams.

Major finding: After 28 days, there was a significant reduction in transepidermal water loss with TC vs. NTC (P < .001), paraffin cream (P < .001), and glycerol cream (P = .021); objective redness was lower with TC vs. NTC (P = .002) and paraffin cream (P < .001). The TC was well tolerated with no evidence of stinging or redness.

Study details: Findings are from a phase 2 trial including 49 adults with AD who were randomly assigned to receive either a TC containing urea and glycerol, a glycerol-containing moisturizer, a simple paraffin cream containing no humectant, or NTC.

Disclosures: This study was funded by Perrigo Nordic. The authors declared serving as consultants, investigators, or advisory board members for and receiving research grants from several sources. Three authors declared being employees of Perrigo Nordic.

Source: Danby SG et al. Different types of emollient cream exhibit diverse physiological effects on the skin barrier in adults with atopic dermatitis. Clin Exp Dermatol. 2022 (Feb 15). Doi:  10.1111/ced.15141

Key clinical point: Upadacitinib showed sustained efficacy through 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis (AD) along with an acceptable safety profile.

Major finding: At week 52, a 75% improvement in Eczema Area and Severity Index (EASI75) was achieved by 82.0% and 79.1% of patients continuing 15 mg upadacitinib and 84.9% and 84.3% of patients continuing 30 mg upadacitinib in Measure Up 1 and Measure Up 2, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI75 at week 52. No new adverse events were reported.

Study details: Findings are from a 52-week analysis of two ongoing phase 3 trials, Measure Up 1 and Measure Up 2, including 1,609 adults and adolescents with moderate-to-severe AD who were randomly assigned to receive 15 mg upadacitinib once daily, 30 mg upadacitinib, or placebo.

Disclosures: This study was funded by AbbVie. Three authors reported ties with various sources, including AbbVie, with some receiving payments or personal fees and being employees or stockholders of AbbVie.

Source: Simpson EL et al. Efficacy and safety of upadacitinib in patients with moderate to severe atopic dermatitis: Analysis of follow-up data from the Measure Up 1 and Measure Up 2 randomized clinical trials. JAMA Dermatol. 2022 (Mar 9). Doi: 10.1001/jamadermatol.2022.0029

Key clinical point: Upadacitinib showed sustained efficacy through 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis (AD) along with an acceptable safety profile.

Major finding: At week 52, a 75% improvement in Eczema Area and Severity Index (EASI75) was achieved by 82.0% and 79.1% of patients continuing 15 mg upadacitinib and 84.9% and 84.3% of patients continuing 30 mg upadacitinib in Measure Up 1 and Measure Up 2, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI75 at week 52. No new adverse events were reported.

Study details: Findings are from a 52-week analysis of two ongoing phase 3 trials, Measure Up 1 and Measure Up 2, including 1,609 adults and adolescents with moderate-to-severe AD who were randomly assigned to receive 15 mg upadacitinib once daily, 30 mg upadacitinib, or placebo.

Disclosures: This study was funded by AbbVie. Three authors reported ties with various sources, including AbbVie, with some receiving payments or personal fees and being employees or stockholders of AbbVie.

Source: Simpson EL et al. Efficacy and safety of upadacitinib in patients with moderate to severe atopic dermatitis: Analysis of follow-up data from the Measure Up 1 and Measure Up 2 randomized clinical trials. JAMA Dermatol. 2022 (Mar 9). Doi: 10.1001/jamadermatol.2022.0029

Key clinical point: Upadacitinib showed sustained efficacy through 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis (AD) along with an acceptable safety profile.

Major finding: At week 52, a 75% improvement in Eczema Area and Severity Index (EASI75) was achieved by 82.0% and 79.1% of patients continuing 15 mg upadacitinib and 84.9% and 84.3% of patients continuing 30 mg upadacitinib in Measure Up 1 and Measure Up 2, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI75 at week 52. No new adverse events were reported.

Study details: Findings are from a 52-week analysis of two ongoing phase 3 trials, Measure Up 1 and Measure Up 2, including 1,609 adults and adolescents with moderate-to-severe AD who were randomly assigned to receive 15 mg upadacitinib once daily, 30 mg upadacitinib, or placebo.

Disclosures: This study was funded by AbbVie. Three authors reported ties with various sources, including AbbVie, with some receiving payments or personal fees and being employees or stockholders of AbbVie.

Source: Simpson EL et al. Efficacy and safety of upadacitinib in patients with moderate to severe atopic dermatitis: Analysis of follow-up data from the Measure Up 1 and Measure Up 2 randomized clinical trials. JAMA Dermatol. 2022 (Mar 9). Doi: 10.1001/jamadermatol.2022.0029

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

--

Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis 

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

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Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis 

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

--

Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis