EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A 25-week double-blind, placebo-controlled RCT of 51 nursing home patients (mean age 76 years, range 50 to 95 years; 96% men) in 2000 found no difference in all-cause mortality between the MA treatment group and the placebo group (absolute risk reduction [ARR]=13.4%; 95% confidence interval [CI], -12.9% to 37.3%; number needed to harm [NNH]=7; 95% CI, -8 to 3).¹

A 2007 case-control study of 17,328 nursing home residents (mean age 84 years [standard deviation, 9]; 71% women) found increased mortality for residents treated with at least 6 days of MA (median survival=23.9 months; 95% CI, 20.2-27.5) compared with untreated residents (median survival=31.2 months; 95% CI, 27.8-35.9).² The decrease in median survival remained after adjusting for demographic variables, medical diagnoses, and cognitive and physical functioning (hazard ratio=1.37; 95% CI, 1.17-1.59). Follow-up ranged from 30 days to 44 months.

Risks related to megestrol acetate include deep vein thrombosis

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference in adverse events between the MA group and the placebo group (absolute risk increase=6.3%; 95% CI, -14.7% to 27.3%).¹ No DVTs were reported as adverse events.

A 2003 retrospective chart review of 246 nursing home residents (mean age 87 years, 77% women) who were given MA 400 mg/d found an overall incidence of DVT of 4.1% (10 residents); 3.2% (8) residents were on MA at the time of DVT occurrence.³

A 2000 retrospective chart review of 19 nursing home residents who were prescribed MA (mean age 83 years, range 66 to 92 years; 84% women) found 32% (6) who developed Doppler-confirmed DVT after 50 days of therapy.⁴ DVT was not associated with known risk factors, age, body mass index, numbers of medications, or other medical diagnoses. The authors didn’t report MA dosage.

Patients on megestrol acetate don’t gain weight...

The 2000 double-blind, placebo-controlled RCT of 51 nursing home patients found no difference between the MA (800 mg/d for 12 weeks) and placebo groups in percentage of patients who gained ≥1.82 kg (ARR=-6.6%; 95% CI, -30.2% to 18.2%).¹ At the 25-week follow-up (after the MA patients had been off the therapy for 13 weeks), a statistically, but not clinically, significant difference was observed in the number of MA patients who gained ≥1.82 kg (absolute benefit increase=40.2%; 95% CI, 13.4%-66.9%; number needed to treat [NNT]=2; 95% CI, 1-8). Of note, the authors based their statistics on a weight gain of ≥1.82 kg whereas 5 kg or 5% weight gain is the more commonly used definition for clinical significance.⁵

Megestrol acetate is neither safe nor effective for stimulating appetite in malnourished nursing home residents.

The 2007 case-control cohort study of 17,328 nursing home residents, who had lost 5% of total body weight in 3 months or 10% of total body weight in 6 months, also found no significant difference in weight gain between MA-treated patients (median dose=486 mg, range 20 to 2400 mg; median duration=90 days, range 7 to 934 days; median change=1 lb, interquartile range [IQR]=-8 to 10) and controls (median change=2 lb, IQR=-4 to 9) after 6 months of treatment.²

In a 2005 prospective case series of 17 nursing home residents (mean age 92 years [standard deviation, 6], 88% women), MA (400 mg/d for 63 days) was associated with weight loss (mean=-2.13±9.32 lb).⁶ Nine patients (53%) lost weight (mean=9.3±5.4 lb), and 8 patients (47%) gained weight (mean=5.9±4.9 lb).

A retrospective chart review in 2000 of 14 nursing home residents (mean age 84 years, range 74 to 97 years; 85% women) who received MA 40 to 800 mg/d for one to 15 weeks showed that 43% gained weight (mean=3.1 kg), 43% lost weight (mean=2.0 kg), and 14% had no weight change.⁷

A 2002 retrospective chart review of 50 nursing home residents (mean age 79 years, range 31 to 93 years; 74% women) who were treated with MA 200 to 2400 mg/d for at least 6 months found a mean weight loss of 1.1 to 2.2 kg.⁸ In the 6 months after MA discontinuation, weight gain for available subjects (5 to 16 patients) varied (mean monthly change=-0.17 kg to 3.07 kg). The study had a high attrition rate (26 patients were lost 6 months after MA initiation; 39 were lost 6 months after MA discontinuation).

RECOMMENDATIONS

The 2015 American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults strongly advises against the use of MA because of limited increases in weight and increased risk of thrombotic events.⁹

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

Two weeks ago, I saw a man with a swollen left leg in the office. It took me 2 days to get a Doppler study completed in my busy health care system. Point-of-care ultrasound (POCUS) would have been invaluable for this gentleman. As we know, though, POCUS has been “slow to grow” in primary care. However, as this month’s cover story suggests, things are changing.

Since the 1970s, ultrasound has been a standard diagnostic tool for many conditions. Initially considered the domain of radiologists and cardiologists with extensive training, technologic advances now allow accurate interpretation of ultrasound images by generalist physicians with a modest amount of training.

Hopefully point-of-care ultrasound will become a standard part of family medicine training and practice sooner, rather than later.

One of the first references to POCUS in general practice in the United States was published in 1988.¹ Use of ultrasound in family medicine has developed slowly over the past 30 years, due to the high cost of equipment, a lack of training as a formal component of family medicine residency curricula, and a lack of evidence of its effectiveness in office practice. Only 6% of practicing family physicians (FPs) reported using non-obstetric POCUS in their practices in 2016, and only 2% of family medicine residency programs had established POCUS curricula in 2015.^2,3

Ready for prime time. Although I had considered POCUS to be a relatively new and untested technology for primary care settings, my reading of the POCUS article has convinced me that POCUS is now ready for widespread deployment in family medicine office practice. Bornemann and colleagues review the evidence for the use of POCUS in 4 areas: the heart, the lung, screening for abdominal aortic aneurysm (AAA), and the diagnosis of deep vein thrombosis. They provide more than 30 references that support the accuracy and effectiveness of the use of POCUS by FPs for these areas. The equipment is affordable, there is ample evidence of accuracy and effectiveness, and, as they note, a curriculum for FP training has been published.

I certainly hope that POCUS continues to make its way into FPs’ offices. It would certainly help patients like the one I saw 2 weeks ago, and it would help us to screen for AAA in older male smokers, as recommended by the US Preventive Services Task Force.

I am delighted to see FP pioneers working to advance the use of POCUS in family medicine. Hopefully, it will become a standard part of family medicine training and practice sooner, rather than later.

Two weeks ago, I saw a man with a swollen left leg in the office. It took me 2 days to get a Doppler study completed in my busy health care system. Point-of-care ultrasound (POCUS) would have been invaluable for this gentleman. As we know, though, POCUS has been “slow to grow” in primary care. However, as this month’s cover story suggests, things are changing.

Since the 1970s, ultrasound has been a standard diagnostic tool for many conditions. Initially considered the domain of radiologists and cardiologists with extensive training, technologic advances now allow accurate interpretation of ultrasound images by generalist physicians with a modest amount of training.

Hopefully point-of-care ultrasound will become a standard part of family medicine training and practice sooner, rather than later.

One of the first references to POCUS in general practice in the United States was published in 1988.¹ Use of ultrasound in family medicine has developed slowly over the past 30 years, due to the high cost of equipment, a lack of training as a formal component of family medicine residency curricula, and a lack of evidence of its effectiveness in office practice. Only 6% of practicing family physicians (FPs) reported using non-obstetric POCUS in their practices in 2016, and only 2% of family medicine residency programs had established POCUS curricula in 2015.^2,3

Ready for prime time. Although I had considered POCUS to be a relatively new and untested technology for primary care settings, my reading of the POCUS article has convinced me that POCUS is now ready for widespread deployment in family medicine office practice. Bornemann and colleagues review the evidence for the use of POCUS in 4 areas: the heart, the lung, screening for abdominal aortic aneurysm (AAA), and the diagnosis of deep vein thrombosis. They provide more than 30 references that support the accuracy and effectiveness of the use of POCUS by FPs for these areas. The equipment is affordable, there is ample evidence of accuracy and effectiveness, and, as they note, a curriculum for FP training has been published.

I certainly hope that POCUS continues to make its way into FPs’ offices. It would certainly help patients like the one I saw 2 weeks ago, and it would help us to screen for AAA in older male smokers, as recommended by the US Preventive Services Task Force.

I am delighted to see FP pioneers working to advance the use of POCUS in family medicine. Hopefully, it will become a standard part of family medicine training and practice sooner, rather than later.

Two weeks ago, I saw a man with a swollen left leg in the office. It took me 2 days to get a Doppler study completed in my busy health care system. Point-of-care ultrasound (POCUS) would have been invaluable for this gentleman. As we know, though, POCUS has been “slow to grow” in primary care. However, as this month’s cover story suggests, things are changing.

Since the 1970s, ultrasound has been a standard diagnostic tool for many conditions. Initially considered the domain of radiologists and cardiologists with extensive training, technologic advances now allow accurate interpretation of ultrasound images by generalist physicians with a modest amount of training.

Hopefully point-of-care ultrasound will become a standard part of family medicine training and practice sooner, rather than later.

One of the first references to POCUS in general practice in the United States was published in 1988.¹ Use of ultrasound in family medicine has developed slowly over the past 30 years, due to the high cost of equipment, a lack of training as a formal component of family medicine residency curricula, and a lack of evidence of its effectiveness in office practice. Only 6% of practicing family physicians (FPs) reported using non-obstetric POCUS in their practices in 2016, and only 2% of family medicine residency programs had established POCUS curricula in 2015.^2,3

Ready for prime time. Although I had considered POCUS to be a relatively new and untested technology for primary care settings, my reading of the POCUS article has convinced me that POCUS is now ready for widespread deployment in family medicine office practice. Bornemann and colleagues review the evidence for the use of POCUS in 4 areas: the heart, the lung, screening for abdominal aortic aneurysm (AAA), and the diagnosis of deep vein thrombosis. They provide more than 30 references that support the accuracy and effectiveness of the use of POCUS by FPs for these areas. The equipment is affordable, there is ample evidence of accuracy and effectiveness, and, as they note, a curriculum for FP training has been published.

I certainly hope that POCUS continues to make its way into FPs’ offices. It would certainly help patients like the one I saw 2 weeks ago, and it would help us to screen for AAA in older male smokers, as recommended by the US Preventive Services Task Force.

I am delighted to see FP pioneers working to advance the use of POCUS in family medicine. Hopefully, it will become a standard part of family medicine training and practice sooner, rather than later.

Resources

US Preventive Services Task Force. Final Recommendation Statement: Hormone Therapy in Postmenopausal Women: Primary Prevention of Chronic Conditions. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/menopausal-hormone-therapy-preventive-medication1. Accessed January 5, 2018.

Resources

US Preventive Services Task Force. Final Recommendation Statement: Hormone Therapy in Postmenopausal Women: Primary Prevention of Chronic Conditions. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/menopausal-hormone-therapy-preventive-medication1. Accessed January 5, 2018.

Resources

US Preventive Services Task Force. Final Recommendation Statement: Hormone Therapy in Postmenopausal Women: Primary Prevention of Chronic Conditions. Available at: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/menopausal-hormone-therapy-preventive-medication1. Accessed January 5, 2018.

This month’s column resumes my review of prevention and treatment strategies for aging skin using oral and topical cosmeceutical agents.

Preventing and treating inflammation

Skin aging can result from inflammation through several mechanisms, including the formation of reactive oxygen species. Inflammation itself arises from myriad etiologic pathways, with multiple inflammatory mediators potentially involved, including histamines, cytokines, eicosanoids (for example, prostaglandins, thromboxanes, and leukotrienes), complement cascade components, kinins, fibrinopeptide enzymes, nuclear factor–kappa B, and free radicals.

Medioimages/Photodisc

Preventing and treating glycation

Glycation is produced by the Maillard reaction, a chemical reaction – particularly well known in cooking – between an amino acid and a sugar molecule that typically requires heat. This reaction was first described by Louis Camille Maillard in 1912 when he noted that amino acids can react with sugar to yield brown or golden-brown substances. It took until the 1980s for scientists to understand the importance of glycation in health.

When glycation occurs, sugar molecules attach to proteins, creating cross-linked proteins known as advanced glycation end products (or AGEs) and causing a series of chemical reactions. Glycation occurs in collagen fibers and results in the formation of cross-links that bind collagen fibers to each other, which leaves the skin stiffer. Glycosylated collagen is believed to be a factor in the appearance of aged skin.⁴ Glycation also can affect elastin: Recent research suggests that glycation can engender elastosis, which is elastin that is abnormally clumped together and presents more frequently in aged skin.

Several antiaging skin care products claim to treat glycation, but – unfortunately – glycation is not a reversible reaction. It must be prevented in the first place. Some studies suggest that antioxidants can prevent glycation, but it is more likely that they just divert the process down a different pathway that still leads to glycation. Reducing serum glucose levels is the optimum method of preventing glycation.⁵ Dietary intervention and oral metformin are recommended for lowering glycation.
 

REVERSING SKIN CELL AGING

Epidermal keratinocytes in aging

Young basal stem cells synthesize a plethora of new keratinocytes at a pace that leads to fast cell turnover and vigorous production of protective epidermal constituents. Old keratinocytes display less energy, show reduced responsiveness to cellular signals, and do not synthesize these protective components.^6,7 Keratinocyte stem cell function declines over time while damage accumulates, as seen in a diminished response to growth factors, decreased keratinization, and impaired function.⁸

Dermal fibroblasts in cutaneous aging

Young fibroblasts produce key cellular constituents, including collagen, elastin, hyaluronic acid, and heparan sulfate. This production declines in older fibroblasts. Like aging keratinocytes, old fibroblasts lose energy and responsiveness to growth factors and other cellular signals.^6,7

Rejuvenating aged skin with cosmeceuticals

Gene expression, growth factors, cytokines, chemokines, and receptor activation guide the function of keratinocytes and fibroblasts. To reverse or slow cellular skin aging, old keratinocytes and fibroblasts must be galvanized to respond to such signals or the signals must be enhanced.

Stimulating old keratinocytes and fibroblasts

Essential steps in stimulating aged keratinocytes and fibroblasts include: activating gene expression, adding growth factors, activating cytokines and chemokines, turning on receptors, and making cells more responsive to signals.

Influencing gene expression

Retinoids are known to affect collagen genes and increase activity of procollagen genes, thereby reducing the production of collagenase. Many studies have shown the efficacy of retinoids in treating aged skin and preventing cutaneous aging in both areas frequently exposed to the sun but also those that aren’t.^9,10 Prescription retinoids (tretinoin, adapalene, tazarotene) and over-the-counter retinoids (retinol) are first-line options to treat and prevent aging by stimulating old keratinocytes and fibroblasts.^10,11 However, exposing retinoic acid receptors to retinoids almost invariably leads to erythema and flaking in the first few weeks. Therefore, retinoids should be titrated slowly. Note that retinoid esters, such as retinyl palmitate and retinyl linoleate, do not penetrate well into the dermis;¹² they also are not as effective as retinol, tretinoin, adapalene, and tazarotene. Compliance with retinoids is always an issue with patients. They should receive printed educational material about how to begin use and why it is important to use these products consistently.

The use of cosmetic formulations that contain growth factors can contribute to skin rejuvenation. There are various types of growth factors that have the capacity to stimulate old keratinocytes and fibroblasts to enhance function.¹⁷ Growth factors, which are inactive or vulnerable to degradation in their native, soluble form, can directly energize genes or act as a signaling mechanism. To exert their quintessential functions, growth factors must be transferred to the correct receptor site in order for the cell to respond to their signal.¹⁸

Heparan sulfate

Heparan sulfate (HS) plays a primary role in cell-to-cell communications. It increases cellular response to growth factors by facilitating the response of old, lazy fibroblasts to the cellular signals.¹⁸ HS binds, stores, and protects growth factors, which allows them to complete movement to their targets, and then presents them to the appropriate binding site.^18,19 A topically applied analogue of HS has been demonstrated to rejuvenate aged skin.²⁰

Stem cells

Stem cells included and pointedly marketed in cosmeceutical products are usually plant derived, are too large to penetrate the stratum corneum, display short shelf lives, and do not behave as human stem cells would. As a result, stem cells in cosmeceutical agents are essentially useless.

However, novel technologies have revealed ingredients that can incite native stem cells to repopulate the epidermis and dermis with young cells. Stem cells in skin include basal stem cells and 10 varieties of hair follicle stem cells. The LGR6+ hair follicle cells play a pivotal role in repopulating the epidermis after wounding has occurred.^21,22 Aesthetic physicians have known for several years that inducing skin wounding with lasers, needles, and acidic peels leads to improvement in its appearance. Researchers have provided new data showing that wounding the skin prompts LGR6+ stem cells to repopulate the epidermis. Once wounding occurs, neutrophils release the peptide defensin, which stimulates the LGR6+ stem cells to repopulate the epidermis.²³ Topical defensin that has been formulated to penetrate into hair follicles, where the LGR6+ stem cells reside, has been demonstrated to render a smoother, more youthful appearance to the skin.

Conclusion

It is important for practitioners to identify patients at risk for premature skin aging as early as possible and start them on an appropriate and consistent skin care regimen. This typically will include at least a daily sunscreen with an SPF 15 or higher, a nightly topical retinoid, and oral and topical antioxidants. The patient’s additional skin type proclivities (for example, dryness, inflammation, melanocyte activity) should guide the physician as to how to combine these baseline product types with cleansers, moisturizers, and formulations with hydroxy acids, growth factors, heparan sulfate, and defensin.

Several studies have revealed that patients exhibit poor compliance with recommended regimens.²⁴ Informing patients about the need for skin protection and providing printed instructions can help to improve compliance.²⁵ This can promote healthy lifestyle habits and compliance with scientifically proven antiaging therapies.
 

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 wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

1. Arch Dermatol Res. 2010 Jan;302(1):5-17.

2. Am J Pathol. 2009 Nov;175(5):1952-61.

3. J Dermatol Sci. 2017 Jun;86(3):238-48.

4. Eur J Dermatol. 2007 Jan-Feb;17(1):12-20.

5. “Advanced Glycation End Products (AGEs): Emerging Mediators of Skin Aging,” in Textbook of Aging Skin (Berlin: Springer, 2017, pp. 1675-86).

6. Mech Ageing Dev. 1986 Jul;35(2):185-98.

7. Exp Cell Res. 1996 Sep 15;227(2):252-5.

8. J Cutan Pathol. 2003 Jul;30(6):351-7.

9. PLoS One. 2015 Feb 6;10(2):e0117491.

10. Arch Dermatol. 2007 May;143(5):606-12.

11. JAMA. 1988 Jan 22-29;259(4):527-32.

12. J Invest Dermatol. 1997 Sep;109(3):301-5.

13. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.

14. J Am Acad Dermatol. 1996 Sep;35(3 Pt 1):388-91.

15. Dermatol Surg. 2001 May;27(5):429-33.

16. J Invest Dermatol. 1994 Aug;103(2):228-32.

17. Clin Cosmet Investig Dermatol. 2016 Nov 9;9:411-9.

18. Chem Biol Drug Des. 2008 Dec;72(6):455-82.

19. Front Immunol. 2013 Dec 18;4:470.

20. J Drugs Dermatol. 2015 Jul;14(7):669-74.

21. Science. 2010 Mar 12;327(5971):1385-9.

22. Plast Reconstr Surg. 2014 Mar;133(3):579-90.

23. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

24. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

25. J Am Acad Dermatol. 2013 Mar;68(3):364.e1-10.


 

This month’s column resumes my review of prevention and treatment strategies for aging skin using oral and topical cosmeceutical agents.

Preventing and treating inflammation

Skin aging can result from inflammation through several mechanisms, including the formation of reactive oxygen species. Inflammation itself arises from myriad etiologic pathways, with multiple inflammatory mediators potentially involved, including histamines, cytokines, eicosanoids (for example, prostaglandins, thromboxanes, and leukotrienes), complement cascade components, kinins, fibrinopeptide enzymes, nuclear factor–kappa B, and free radicals.

Medioimages/Photodisc

Preventing and treating glycation

Glycation is produced by the Maillard reaction, a chemical reaction – particularly well known in cooking – between an amino acid and a sugar molecule that typically requires heat. This reaction was first described by Louis Camille Maillard in 1912 when he noted that amino acids can react with sugar to yield brown or golden-brown substances. It took until the 1980s for scientists to understand the importance of glycation in health.

When glycation occurs, sugar molecules attach to proteins, creating cross-linked proteins known as advanced glycation end products (or AGEs) and causing a series of chemical reactions. Glycation occurs in collagen fibers and results in the formation of cross-links that bind collagen fibers to each other, which leaves the skin stiffer. Glycosylated collagen is believed to be a factor in the appearance of aged skin.⁴ Glycation also can affect elastin: Recent research suggests that glycation can engender elastosis, which is elastin that is abnormally clumped together and presents more frequently in aged skin.

Several antiaging skin care products claim to treat glycation, but – unfortunately – glycation is not a reversible reaction. It must be prevented in the first place. Some studies suggest that antioxidants can prevent glycation, but it is more likely that they just divert the process down a different pathway that still leads to glycation. Reducing serum glucose levels is the optimum method of preventing glycation.⁵ Dietary intervention and oral metformin are recommended for lowering glycation.
 

REVERSING SKIN CELL AGING

Epidermal keratinocytes in aging

Young basal stem cells synthesize a plethora of new keratinocytes at a pace that leads to fast cell turnover and vigorous production of protective epidermal constituents. Old keratinocytes display less energy, show reduced responsiveness to cellular signals, and do not synthesize these protective components.^6,7 Keratinocyte stem cell function declines over time while damage accumulates, as seen in a diminished response to growth factors, decreased keratinization, and impaired function.⁸

Dermal fibroblasts in cutaneous aging

Young fibroblasts produce key cellular constituents, including collagen, elastin, hyaluronic acid, and heparan sulfate. This production declines in older fibroblasts. Like aging keratinocytes, old fibroblasts lose energy and responsiveness to growth factors and other cellular signals.^6,7

Rejuvenating aged skin with cosmeceuticals

Gene expression, growth factors, cytokines, chemokines, and receptor activation guide the function of keratinocytes and fibroblasts. To reverse or slow cellular skin aging, old keratinocytes and fibroblasts must be galvanized to respond to such signals or the signals must be enhanced.

Stimulating old keratinocytes and fibroblasts

Essential steps in stimulating aged keratinocytes and fibroblasts include: activating gene expression, adding growth factors, activating cytokines and chemokines, turning on receptors, and making cells more responsive to signals.

Influencing gene expression

Retinoids are known to affect collagen genes and increase activity of procollagen genes, thereby reducing the production of collagenase. Many studies have shown the efficacy of retinoids in treating aged skin and preventing cutaneous aging in both areas frequently exposed to the sun but also those that aren’t.^9,10 Prescription retinoids (tretinoin, adapalene, tazarotene) and over-the-counter retinoids (retinol) are first-line options to treat and prevent aging by stimulating old keratinocytes and fibroblasts.^10,11 However, exposing retinoic acid receptors to retinoids almost invariably leads to erythema and flaking in the first few weeks. Therefore, retinoids should be titrated slowly. Note that retinoid esters, such as retinyl palmitate and retinyl linoleate, do not penetrate well into the dermis;¹² they also are not as effective as retinol, tretinoin, adapalene, and tazarotene. Compliance with retinoids is always an issue with patients. They should receive printed educational material about how to begin use and why it is important to use these products consistently.

The use of cosmetic formulations that contain growth factors can contribute to skin rejuvenation. There are various types of growth factors that have the capacity to stimulate old keratinocytes and fibroblasts to enhance function.¹⁷ Growth factors, which are inactive or vulnerable to degradation in their native, soluble form, can directly energize genes or act as a signaling mechanism. To exert their quintessential functions, growth factors must be transferred to the correct receptor site in order for the cell to respond to their signal.¹⁸

Heparan sulfate

Heparan sulfate (HS) plays a primary role in cell-to-cell communications. It increases cellular response to growth factors by facilitating the response of old, lazy fibroblasts to the cellular signals.¹⁸ HS binds, stores, and protects growth factors, which allows them to complete movement to their targets, and then presents them to the appropriate binding site.^18,19 A topically applied analogue of HS has been demonstrated to rejuvenate aged skin.²⁰

Stem cells

Stem cells included and pointedly marketed in cosmeceutical products are usually plant derived, are too large to penetrate the stratum corneum, display short shelf lives, and do not behave as human stem cells would. As a result, stem cells in cosmeceutical agents are essentially useless.

However, novel technologies have revealed ingredients that can incite native stem cells to repopulate the epidermis and dermis with young cells. Stem cells in skin include basal stem cells and 10 varieties of hair follicle stem cells. The LGR6+ hair follicle cells play a pivotal role in repopulating the epidermis after wounding has occurred.^21,22 Aesthetic physicians have known for several years that inducing skin wounding with lasers, needles, and acidic peels leads to improvement in its appearance. Researchers have provided new data showing that wounding the skin prompts LGR6+ stem cells to repopulate the epidermis. Once wounding occurs, neutrophils release the peptide defensin, which stimulates the LGR6+ stem cells to repopulate the epidermis.²³ Topical defensin that has been formulated to penetrate into hair follicles, where the LGR6+ stem cells reside, has been demonstrated to render a smoother, more youthful appearance to the skin.

Conclusion

It is important for practitioners to identify patients at risk for premature skin aging as early as possible and start them on an appropriate and consistent skin care regimen. This typically will include at least a daily sunscreen with an SPF 15 or higher, a nightly topical retinoid, and oral and topical antioxidants. The patient’s additional skin type proclivities (for example, dryness, inflammation, melanocyte activity) should guide the physician as to how to combine these baseline product types with cleansers, moisturizers, and formulations with hydroxy acids, growth factors, heparan sulfate, and defensin.

Several studies have revealed that patients exhibit poor compliance with recommended regimens.²⁴ Informing patients about the need for skin protection and providing printed instructions can help to improve compliance.²⁵ This can promote healthy lifestyle habits and compliance with scientifically proven antiaging therapies.
 

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 wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

1. Arch Dermatol Res. 2010 Jan;302(1):5-17.

2. Am J Pathol. 2009 Nov;175(5):1952-61.

3. J Dermatol Sci. 2017 Jun;86(3):238-48.

4. Eur J Dermatol. 2007 Jan-Feb;17(1):12-20.

5. “Advanced Glycation End Products (AGEs): Emerging Mediators of Skin Aging,” in Textbook of Aging Skin (Berlin: Springer, 2017, pp. 1675-86).

6. Mech Ageing Dev. 1986 Jul;35(2):185-98.

7. Exp Cell Res. 1996 Sep 15;227(2):252-5.

8. J Cutan Pathol. 2003 Jul;30(6):351-7.

9. PLoS One. 2015 Feb 6;10(2):e0117491.

10. Arch Dermatol. 2007 May;143(5):606-12.

11. JAMA. 1988 Jan 22-29;259(4):527-32.

12. J Invest Dermatol. 1997 Sep;109(3):301-5.

13. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.

14. J Am Acad Dermatol. 1996 Sep;35(3 Pt 1):388-91.

15. Dermatol Surg. 2001 May;27(5):429-33.

16. J Invest Dermatol. 1994 Aug;103(2):228-32.

17. Clin Cosmet Investig Dermatol. 2016 Nov 9;9:411-9.

18. Chem Biol Drug Des. 2008 Dec;72(6):455-82.

19. Front Immunol. 2013 Dec 18;4:470.

20. J Drugs Dermatol. 2015 Jul;14(7):669-74.

21. Science. 2010 Mar 12;327(5971):1385-9.

22. Plast Reconstr Surg. 2014 Mar;133(3):579-90.

23. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

24. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

25. J Am Acad Dermatol. 2013 Mar;68(3):364.e1-10.


 

This month’s column resumes my review of prevention and treatment strategies for aging skin using oral and topical cosmeceutical agents.

Preventing and treating inflammation

Skin aging can result from inflammation through several mechanisms, including the formation of reactive oxygen species. Inflammation itself arises from myriad etiologic pathways, with multiple inflammatory mediators potentially involved, including histamines, cytokines, eicosanoids (for example, prostaglandins, thromboxanes, and leukotrienes), complement cascade components, kinins, fibrinopeptide enzymes, nuclear factor–kappa B, and free radicals.

Medioimages/Photodisc

Preventing and treating glycation

Glycation is produced by the Maillard reaction, a chemical reaction – particularly well known in cooking – between an amino acid and a sugar molecule that typically requires heat. This reaction was first described by Louis Camille Maillard in 1912 when he noted that amino acids can react with sugar to yield brown or golden-brown substances. It took until the 1980s for scientists to understand the importance of glycation in health.

When glycation occurs, sugar molecules attach to proteins, creating cross-linked proteins known as advanced glycation end products (or AGEs) and causing a series of chemical reactions. Glycation occurs in collagen fibers and results in the formation of cross-links that bind collagen fibers to each other, which leaves the skin stiffer. Glycosylated collagen is believed to be a factor in the appearance of aged skin.⁴ Glycation also can affect elastin: Recent research suggests that glycation can engender elastosis, which is elastin that is abnormally clumped together and presents more frequently in aged skin.

Several antiaging skin care products claim to treat glycation, but – unfortunately – glycation is not a reversible reaction. It must be prevented in the first place. Some studies suggest that antioxidants can prevent glycation, but it is more likely that they just divert the process down a different pathway that still leads to glycation. Reducing serum glucose levels is the optimum method of preventing glycation.⁵ Dietary intervention and oral metformin are recommended for lowering glycation.
 

REVERSING SKIN CELL AGING

Epidermal keratinocytes in aging

Young basal stem cells synthesize a plethora of new keratinocytes at a pace that leads to fast cell turnover and vigorous production of protective epidermal constituents. Old keratinocytes display less energy, show reduced responsiveness to cellular signals, and do not synthesize these protective components.^6,7 Keratinocyte stem cell function declines over time while damage accumulates, as seen in a diminished response to growth factors, decreased keratinization, and impaired function.⁸

Dermal fibroblasts in cutaneous aging

Young fibroblasts produce key cellular constituents, including collagen, elastin, hyaluronic acid, and heparan sulfate. This production declines in older fibroblasts. Like aging keratinocytes, old fibroblasts lose energy and responsiveness to growth factors and other cellular signals.^6,7

Rejuvenating aged skin with cosmeceuticals

Gene expression, growth factors, cytokines, chemokines, and receptor activation guide the function of keratinocytes and fibroblasts. To reverse or slow cellular skin aging, old keratinocytes and fibroblasts must be galvanized to respond to such signals or the signals must be enhanced.

Stimulating old keratinocytes and fibroblasts

Essential steps in stimulating aged keratinocytes and fibroblasts include: activating gene expression, adding growth factors, activating cytokines and chemokines, turning on receptors, and making cells more responsive to signals.

Influencing gene expression

Retinoids are known to affect collagen genes and increase activity of procollagen genes, thereby reducing the production of collagenase. Many studies have shown the efficacy of retinoids in treating aged skin and preventing cutaneous aging in both areas frequently exposed to the sun but also those that aren’t.^9,10 Prescription retinoids (tretinoin, adapalene, tazarotene) and over-the-counter retinoids (retinol) are first-line options to treat and prevent aging by stimulating old keratinocytes and fibroblasts.^10,11 However, exposing retinoic acid receptors to retinoids almost invariably leads to erythema and flaking in the first few weeks. Therefore, retinoids should be titrated slowly. Note that retinoid esters, such as retinyl palmitate and retinyl linoleate, do not penetrate well into the dermis;¹² they also are not as effective as retinol, tretinoin, adapalene, and tazarotene. Compliance with retinoids is always an issue with patients. They should receive printed educational material about how to begin use and why it is important to use these products consistently.

The use of cosmetic formulations that contain growth factors can contribute to skin rejuvenation. There are various types of growth factors that have the capacity to stimulate old keratinocytes and fibroblasts to enhance function.¹⁷ Growth factors, which are inactive or vulnerable to degradation in their native, soluble form, can directly energize genes or act as a signaling mechanism. To exert their quintessential functions, growth factors must be transferred to the correct receptor site in order for the cell to respond to their signal.¹⁸

Heparan sulfate

Heparan sulfate (HS) plays a primary role in cell-to-cell communications. It increases cellular response to growth factors by facilitating the response of old, lazy fibroblasts to the cellular signals.¹⁸ HS binds, stores, and protects growth factors, which allows them to complete movement to their targets, and then presents them to the appropriate binding site.^18,19 A topically applied analogue of HS has been demonstrated to rejuvenate aged skin.²⁰

Stem cells

Stem cells included and pointedly marketed in cosmeceutical products are usually plant derived, are too large to penetrate the stratum corneum, display short shelf lives, and do not behave as human stem cells would. As a result, stem cells in cosmeceutical agents are essentially useless.

However, novel technologies have revealed ingredients that can incite native stem cells to repopulate the epidermis and dermis with young cells. Stem cells in skin include basal stem cells and 10 varieties of hair follicle stem cells. The LGR6+ hair follicle cells play a pivotal role in repopulating the epidermis after wounding has occurred.^21,22 Aesthetic physicians have known for several years that inducing skin wounding with lasers, needles, and acidic peels leads to improvement in its appearance. Researchers have provided new data showing that wounding the skin prompts LGR6+ stem cells to repopulate the epidermis. Once wounding occurs, neutrophils release the peptide defensin, which stimulates the LGR6+ stem cells to repopulate the epidermis.²³ Topical defensin that has been formulated to penetrate into hair follicles, where the LGR6+ stem cells reside, has been demonstrated to render a smoother, more youthful appearance to the skin.

Conclusion

It is important for practitioners to identify patients at risk for premature skin aging as early as possible and start them on an appropriate and consistent skin care regimen. This typically will include at least a daily sunscreen with an SPF 15 or higher, a nightly topical retinoid, and oral and topical antioxidants. The patient’s additional skin type proclivities (for example, dryness, inflammation, melanocyte activity) should guide the physician as to how to combine these baseline product types with cleansers, moisturizers, and formulations with hydroxy acids, growth factors, heparan sulfate, and defensin.

Several studies have revealed that patients exhibit poor compliance with recommended regimens.²⁴ Informing patients about the need for skin protection and providing printed instructions can help to improve compliance.²⁵ This can promote healthy lifestyle habits and compliance with scientifically proven antiaging therapies.
 

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 wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

1. Arch Dermatol Res. 2010 Jan;302(1):5-17.

2. Am J Pathol. 2009 Nov;175(5):1952-61.

3. J Dermatol Sci. 2017 Jun;86(3):238-48.

4. Eur J Dermatol. 2007 Jan-Feb;17(1):12-20.

5. “Advanced Glycation End Products (AGEs): Emerging Mediators of Skin Aging,” in Textbook of Aging Skin (Berlin: Springer, 2017, pp. 1675-86).

6. Mech Ageing Dev. 1986 Jul;35(2):185-98.

7. Exp Cell Res. 1996 Sep 15;227(2):252-5.

8. J Cutan Pathol. 2003 Jul;30(6):351-7.

9. PLoS One. 2015 Feb 6;10(2):e0117491.

10. Arch Dermatol. 2007 May;143(5):606-12.

11. JAMA. 1988 Jan 22-29;259(4):527-32.

12. J Invest Dermatol. 1997 Sep;109(3):301-5.

13. J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):187-95.

14. J Am Acad Dermatol. 1996 Sep;35(3 Pt 1):388-91.

15. Dermatol Surg. 2001 May;27(5):429-33.

16. J Invest Dermatol. 1994 Aug;103(2):228-32.

17. Clin Cosmet Investig Dermatol. 2016 Nov 9;9:411-9.

18. Chem Biol Drug Des. 2008 Dec;72(6):455-82.

19. Front Immunol. 2013 Dec 18;4:470.

20. J Drugs Dermatol. 2015 Jul;14(7):669-74.

21. Science. 2010 Mar 12;327(5971):1385-9.

22. Plast Reconstr Surg. 2014 Mar;133(3):579-90.

23. Plast Reconstr Surg. 2013 Nov;132(5):1159-71.

24. J Am Acad Dermatol. 2008 Jul;59(1):27-33.

25. J Am Acad Dermatol. 2013 Mar;68(3):364.e1-10.


 

Mr. E, age 37, has a 20-year history of obsessive-compulsive disorder (OCD), with comorbid generalized anxiety disorder and hypertension. His medication regimen consists of lisinopril, 40 mg/d, to control his blood pressure, and escitalopram, 40 mg/d, for OCD and anxiety symptoms, which he started taking 12 weeks ago. Mr. E also has completed cognitive-behavioral therapy (CBT) with Exposure Response Prevention (ERP) therapy for his OCD symptoms. Although escitalopram and CBT have reduced Mr. E’s OCD symptoms, he still exhibits obsessions, such as fear of contamination, and compulsions, including handwashing, that are time-consuming and cause significant social and occupational distress. His Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score is 24. Mr. E asks his psychiatrist if there is anything else that may provide benefit. He is started on risperidone, 0.5 mg at bedtime, in addition to his existing medications. After 8 weeks of treatment with risperidone, Mr. E’s Y-BOCS score decreases to 21.

Box
Antipsychotics for OCD: What the guidelines recommend

Efficacy

The 2013 National Institute for Health Care and Excellence Evidence Update included a 2010 Cochrane Review of 11 randomized controlled trials (RCTs) of antipsychotics as adjunctive treatment to SSRIs.⁵ All trials were <6 months, and most were limited regarding quality aspects. Two trials found no statistically significant difference with olanzapine in efficacy measures (Y-BOCS mean difference [MD] −2.96; 95% confidence interval [CI] −7.41 to 1.22; effect size d = −2.96 [−7.14, 1.22]). Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was no significant difference between groups (n = 44, 1 RCT, odds ratio [OR] 0.76; 95% CI 0.17 to 3.29; effect size d = 0.76 [0.17, 3.29]). Studies found increased weight gain with olanzapine compared with antidepressant monotherapy.

Statistically significant differences were demonstrated with the addition of quetiapine to antidepressant monotherapy as shown in Y-BOCS score at endpoint (Y-BOCS MD −2.28; 95% CI −4.05 to −0.52; effect size d −2.28 [−4.05, −0.52]). Quetiapine also demonstrated benefit for depressive and anxiety symptoms. Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was a significant difference between groups (n = 80, 2 RCTs, OR 0.27; 95% CI 0.09 to 0.87; effect size d = 0.27 [0.09, 0.87]).

Adjunctive treatment with risperidone was superior to antidepressant mono­therapy for participants without a significant response in OCD symptom severity of at least 25% with validated measures (OR 0.17; 95% CI 0.04 to 0.66; effect size d = 0.17 [0.04, 0.66]), and in depressive and anxiety symptoms. Mean reduction in Y-BOCS scores was not statistically significant with risperidone (MD −3.35; 95% CI −8.25 to 1.55; effect size d = −3.35 [−8.25, 1.55]).⁵

A 2014 meta-analysis by Veale et al³ included double-blind, randomized trials that examined atypical antipsychotics compared with placebo for adults with OCD that used an intention-to-treat analysis. Unlike the Cochrane Review, these studies used the Y-BOCS as a primary outcome measure. Participants had a Y-BOCS score of ≥16; had at least 1 appropriate trial of an SSRI or clomipramine (defined as the maximum dose tolerated for at least 8 weeks); and had to continue taking the SSRI or clomipramine throughout the trial, which was a duration of at least 4 weeks. Of 46 published antipsychotic papers that were identified, 20 were excluded and 12 were duplicates. The primary reason for trial exclusion was open-label study design.

Fourteen articles were included in the meta-analysis, but all had small sample sizes and no long-term follow-up data.³ Antipsychotics in the meta-analysis included risperidone (4 studies), quetiapine (5 studies), olanzapine (2 studies), aripiprazole (2 studies), and paliperidone (1 study).

The overall difference in Y-BOCS score change between drug and placebo groups was 2.34 points, which had an overall effect size of d = 0.40. Those taking antipsychotics had approximately a 10% reduction in Y-BOCS score over time. The overall difference was statistically significant with risperidone (overall mean reduction of 3.89 points on the Y-BOCS; 95% CI 1.43 to 5.48; effect size of d = 0.53) and aripiprazole (difference in Y-BOCS outcome 0.1 scores of 6.29 points; effect size of d = 1.11). One trial of risperidone used a low dose (0.5 mg) and had a larger effect size than the studies that used moderate doses. The overall difference was not statistically significant for quetiapine (difference of Y-BOCS outcome scores of 0.81 points) or olanzapine (difference in Y-BOCS outcome scores of −0.19; indicating <1 point difference on the Y-BOCS).³

Studies included in the meta-analysis ranged in durations from 6 to 16 weeks; duration of ≥4 weeks did not make a difference in response. One study demonstrated a worsening of symptoms in the quetiapine group between weeks 4 and 12. Only 4 studies included most patients that had a previous trial of CBT. One study with an additional treatment arm evaluating CBT found that adding CBT was superior to adjunctive risperidone or placebo. Another study found that adding clomipramine or placebo to fluoxetine was superior to treatment with quetiapine. All study participants had Y-BOCS scores that indicated moderate OCD severity (16 to 23). Those with higher baseline Y-BOCS scores had a larger effect size for risperidone and quetiapine.³

Two studies included in the meta-analysis classified OCD symptoms by subtype, such as by dimensions of checking; symmetry, ordering, counting, and repeating; contamination and cleaning; and hoarding. Currently, no clinically significant predictor of outcome of antipsychotic therapy has been identified. Two studies included in the meta-analysis assessed patients with comorbid tic disorders and found no difference by treatment. One study demonstrated benefit of haloperidol in patients with comorbid tic disorders compared with those without comorbid tic disorders. Of note, none of the studies included in the meta-analysis excluded patients with hoarding characteristics, which generally indicate a worse prognosis with treatment.³

In 2015, Dold et al⁶ provided an update to a 2013 meta-analysis⁷ assessing antipsychotic augmentation of SSRIs in treatment-resistant OCD. This update included 2 new RCTs. The 2013 analysis⁷ concluded that risperidone should be considered first-line and is preferred over olanzapine and quetiapine. However, the update found the highest effect size for aripiprazole (d = −1.35), followed by haloperidol (d = −0.82), risperidone (d = −0.59), quetiapine (d = −0.50), olanzapine (d = −0.49), and paliperidone (d = −0.21).^6,7

The 2015 update⁶ concluded that the antipsychotic doses used in trials were moderate and that there was no association between dose and treatment response, indicating that high doses of antipsychotics may not be more effective. Dold et al⁶ postulated that the antipsychotic doses required for treating OCD are similar to those used in treating major depressive disorder and lower than doses used in treating schizophrenia. The 2013 meta-analysis demonstrated that moderate doses of antipsychotics resulted in statistically significant efficacy (relative risk [RR] = 3.99, 95% CI 1.92 to 8.27), while low doses did not demonstrate statistical significance (RR = 1.06, 95% CI 0.45 to 2.53).^6,7

The 2015 subgroup analysis update evaluated the duration of SSRI treatment prior to the antipsychotic augmentation phase, but did not demonstrate statistically significant efficacy for studies with <8 weeks’ duration of SSRI treatment, further highlighting the need for extended duration of treatment with an SSRI prior to augmentation.⁶

The 2013 meta-analysis discussed populations with comorbid tic disorders, including a study that found that patients with OCD and comorbid tic disorders benefit more from adjunctive antipsychotic therapy than those without the comorbidity. The 2015 update excluded trials that included patients with comorbid tic disorders to reduce bias, which did not affect the overall effect sizes of the data.^6,7

In summary, efficacy has been demonstrated for risperidone and aripiprazole. There has been no benefit demonstrated with olanzapine and limited benefit with quetiapine. One study suggested worsening of symptoms with quetiapine the longer that treatment persisted.^3,5-7

Safety

Assessing potential harms related to the use of antipsychotics in treating OCD is complicated, because this information is not always assessed in trials. Instead, researchers often focus on exploring potential benefits because long-term effects of antipsychotics, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects, are well documented.³

Trials included in the meta-analysis by Veale et al³ had a maximum duration of 16 weeks, so it is likely that many of the potential harms of antipsychotic use would not yet have been measurable. The authors cautioned that, although aripiprazole and risperidone demonstrated benefit, their benefit must be weighed against the potential physical risks of long-term antipsychotic use.³One study that was not included in the meta-analysis by Veale et al³ evaluated individuals who did not respond to a SSRI, and randomly assigned them to quetiapine, olanzapine, or risperidone plus CBT. At 1-year follow-up, 50% of participants receiving an antipsychotic had an increase of >10% in body mass index (BMI) and had higher fasting blood sugars compared with only 15.2% of participants with increased BMI in the comparison group (SSRI responders).³

Foa et al⁸ investigated long-term outcomes (ie, 6 months) of SSRI augmentation with ERP or risperidone in patients with OCD. Forty patients were randomized to receive risperidone, and 9 were considered responders. Only 8 chose to enter the maintenance phase, and of those participants, 5 did not complete the study. Two withdrew due to worsening depression, 2 withdrew due to intolerable adverse effects, and 1 was lost to follow-up. Unfortunately, there was no further discussion of what the intolerable adverse effects were.⁸

Patients with comorbid schizophrenia and OCD face additional risks. Lifetime prevalence rates of OCD are greater in persons with schizophrenia compared with the general population (26% vs 8%, respectively). Most studies have demonstrated poor prognosis and medication adherence among patients with comorbid schizophrenia and OCD. Fonseka et al⁹ assessed the risk of antipsychotic induction and exacerbation of OCD symptoms in patients with schizophrenia. Induction and exacerbation of OCD symptoms with clozapine was evident in several case reports, series, and retrospective reviews. A dose-dependent relationship is demonstrated in the literature as well. It is thought that this risk is related to clozapine’s action at the 5-HT2 receptor. Although evidence is limited, it appears that compared with other antipsychotics, clozapine is associated with the greatest risk of induction and exacerbation of OCD symptoms, with 20% to 28% of clozapine-treated patients exhibiting induction of OCD symptoms and 10% to 18% exhibiting an exacerbation of existing OCD symptoms.

Evidence of olanzapine induction and exacerbation of OCD symptoms is also limited to case reports and retrospective studies. However, some studies have estimated induction of OCD symptoms with olanzapine in 11% to 20% of patients.⁹ There is insufficient evidence to form conclusions regarding other antipsychotics. Fonseka et al⁹ recommends switching to an antipsychotic with lower 5HT-2 binding affinity or adding an SSRI, such as fluvoxamine, if induction or exacerbation of OCD symptoms occurs.

Consider long-term risks

The evidence for benefits with antipsy­chotics in treatment-resistant OCD is limited by different populations recruited, small sample sizes, and lack of long-term follow-up. Most evidence supports using ERP over antipsychotics for treating OCD symptoms that have not responded to SSRIs. However, ERP poses its own challenges that may limit clinical utility, such as economic and time restraints. Therefore, benefits with antipsychotics, such as risperidone and aripiprazole, must be weighed against potential long-term risks of treatment, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects.

Regarding Mr. E’s case, because he had been maximized on SSRI therapy for an adequate duration (escitalopram, 40 mg/d, for 12 weeks) and completed CBT with ERP with a partial response, adding risperidone, 0.5 mg at bedtime, was an appropriate treatment option that is supported by the available guidelines and evidence. The risperidone dose is reflective of the initial dosing strategies used in clinical trials. It is recommended to assess efficacy of treatment at 8 weeks with a validated measure, such as the Y-BOCS. A dose increase may be needed to achieve clinically significant symptom improvement, because moderate doses of risperidone have demonstrated efficacy in trials; however, high doses of risperidone are unlikely to provide additional benefit and increase the risk of adverse effects. If risperidone does not provide a clinically favorable risk–benefit ratio for Mr. E, aripiprazole is a potential alternative.

Mr. E, age 37, has a 20-year history of obsessive-compulsive disorder (OCD), with comorbid generalized anxiety disorder and hypertension. His medication regimen consists of lisinopril, 40 mg/d, to control his blood pressure, and escitalopram, 40 mg/d, for OCD and anxiety symptoms, which he started taking 12 weeks ago. Mr. E also has completed cognitive-behavioral therapy (CBT) with Exposure Response Prevention (ERP) therapy for his OCD symptoms. Although escitalopram and CBT have reduced Mr. E’s OCD symptoms, he still exhibits obsessions, such as fear of contamination, and compulsions, including handwashing, that are time-consuming and cause significant social and occupational distress. His Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score is 24. Mr. E asks his psychiatrist if there is anything else that may provide benefit. He is started on risperidone, 0.5 mg at bedtime, in addition to his existing medications. After 8 weeks of treatment with risperidone, Mr. E’s Y-BOCS score decreases to 21.

Box
Antipsychotics for OCD: What the guidelines recommend

Efficacy

The 2013 National Institute for Health Care and Excellence Evidence Update included a 2010 Cochrane Review of 11 randomized controlled trials (RCTs) of antipsychotics as adjunctive treatment to SSRIs.⁵ All trials were <6 months, and most were limited regarding quality aspects. Two trials found no statistically significant difference with olanzapine in efficacy measures (Y-BOCS mean difference [MD] −2.96; 95% confidence interval [CI] −7.41 to 1.22; effect size d = −2.96 [−7.14, 1.22]). Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was no significant difference between groups (n = 44, 1 RCT, odds ratio [OR] 0.76; 95% CI 0.17 to 3.29; effect size d = 0.76 [0.17, 3.29]). Studies found increased weight gain with olanzapine compared with antidepressant monotherapy.

Statistically significant differences were demonstrated with the addition of quetiapine to antidepressant monotherapy as shown in Y-BOCS score at endpoint (Y-BOCS MD −2.28; 95% CI −4.05 to −0.52; effect size d −2.28 [−4.05, −0.52]). Quetiapine also demonstrated benefit for depressive and anxiety symptoms. Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was a significant difference between groups (n = 80, 2 RCTs, OR 0.27; 95% CI 0.09 to 0.87; effect size d = 0.27 [0.09, 0.87]).

Adjunctive treatment with risperidone was superior to antidepressant mono­therapy for participants without a significant response in OCD symptom severity of at least 25% with validated measures (OR 0.17; 95% CI 0.04 to 0.66; effect size d = 0.17 [0.04, 0.66]), and in depressive and anxiety symptoms. Mean reduction in Y-BOCS scores was not statistically significant with risperidone (MD −3.35; 95% CI −8.25 to 1.55; effect size d = −3.35 [−8.25, 1.55]).⁵

A 2014 meta-analysis by Veale et al³ included double-blind, randomized trials that examined atypical antipsychotics compared with placebo for adults with OCD that used an intention-to-treat analysis. Unlike the Cochrane Review, these studies used the Y-BOCS as a primary outcome measure. Participants had a Y-BOCS score of ≥16; had at least 1 appropriate trial of an SSRI or clomipramine (defined as the maximum dose tolerated for at least 8 weeks); and had to continue taking the SSRI or clomipramine throughout the trial, which was a duration of at least 4 weeks. Of 46 published antipsychotic papers that were identified, 20 were excluded and 12 were duplicates. The primary reason for trial exclusion was open-label study design.

Fourteen articles were included in the meta-analysis, but all had small sample sizes and no long-term follow-up data.³ Antipsychotics in the meta-analysis included risperidone (4 studies), quetiapine (5 studies), olanzapine (2 studies), aripiprazole (2 studies), and paliperidone (1 study).

The overall difference in Y-BOCS score change between drug and placebo groups was 2.34 points, which had an overall effect size of d = 0.40. Those taking antipsychotics had approximately a 10% reduction in Y-BOCS score over time. The overall difference was statistically significant with risperidone (overall mean reduction of 3.89 points on the Y-BOCS; 95% CI 1.43 to 5.48; effect size of d = 0.53) and aripiprazole (difference in Y-BOCS outcome 0.1 scores of 6.29 points; effect size of d = 1.11). One trial of risperidone used a low dose (0.5 mg) and had a larger effect size than the studies that used moderate doses. The overall difference was not statistically significant for quetiapine (difference of Y-BOCS outcome scores of 0.81 points) or olanzapine (difference in Y-BOCS outcome scores of −0.19; indicating <1 point difference on the Y-BOCS).³

Studies included in the meta-analysis ranged in durations from 6 to 16 weeks; duration of ≥4 weeks did not make a difference in response. One study demonstrated a worsening of symptoms in the quetiapine group between weeks 4 and 12. Only 4 studies included most patients that had a previous trial of CBT. One study with an additional treatment arm evaluating CBT found that adding CBT was superior to adjunctive risperidone or placebo. Another study found that adding clomipramine or placebo to fluoxetine was superior to treatment with quetiapine. All study participants had Y-BOCS scores that indicated moderate OCD severity (16 to 23). Those with higher baseline Y-BOCS scores had a larger effect size for risperidone and quetiapine.³

Two studies included in the meta-analysis classified OCD symptoms by subtype, such as by dimensions of checking; symmetry, ordering, counting, and repeating; contamination and cleaning; and hoarding. Currently, no clinically significant predictor of outcome of antipsychotic therapy has been identified. Two studies included in the meta-analysis assessed patients with comorbid tic disorders and found no difference by treatment. One study demonstrated benefit of haloperidol in patients with comorbid tic disorders compared with those without comorbid tic disorders. Of note, none of the studies included in the meta-analysis excluded patients with hoarding characteristics, which generally indicate a worse prognosis with treatment.³

In 2015, Dold et al⁶ provided an update to a 2013 meta-analysis⁷ assessing antipsychotic augmentation of SSRIs in treatment-resistant OCD. This update included 2 new RCTs. The 2013 analysis⁷ concluded that risperidone should be considered first-line and is preferred over olanzapine and quetiapine. However, the update found the highest effect size for aripiprazole (d = −1.35), followed by haloperidol (d = −0.82), risperidone (d = −0.59), quetiapine (d = −0.50), olanzapine (d = −0.49), and paliperidone (d = −0.21).^6,7

The 2015 update⁶ concluded that the antipsychotic doses used in trials were moderate and that there was no association between dose and treatment response, indicating that high doses of antipsychotics may not be more effective. Dold et al⁶ postulated that the antipsychotic doses required for treating OCD are similar to those used in treating major depressive disorder and lower than doses used in treating schizophrenia. The 2013 meta-analysis demonstrated that moderate doses of antipsychotics resulted in statistically significant efficacy (relative risk [RR] = 3.99, 95% CI 1.92 to 8.27), while low doses did not demonstrate statistical significance (RR = 1.06, 95% CI 0.45 to 2.53).^6,7

The 2015 subgroup analysis update evaluated the duration of SSRI treatment prior to the antipsychotic augmentation phase, but did not demonstrate statistically significant efficacy for studies with <8 weeks’ duration of SSRI treatment, further highlighting the need for extended duration of treatment with an SSRI prior to augmentation.⁶

The 2013 meta-analysis discussed populations with comorbid tic disorders, including a study that found that patients with OCD and comorbid tic disorders benefit more from adjunctive antipsychotic therapy than those without the comorbidity. The 2015 update excluded trials that included patients with comorbid tic disorders to reduce bias, which did not affect the overall effect sizes of the data.^6,7

In summary, efficacy has been demonstrated for risperidone and aripiprazole. There has been no benefit demonstrated with olanzapine and limited benefit with quetiapine. One study suggested worsening of symptoms with quetiapine the longer that treatment persisted.^3,5-7

Safety

Assessing potential harms related to the use of antipsychotics in treating OCD is complicated, because this information is not always assessed in trials. Instead, researchers often focus on exploring potential benefits because long-term effects of antipsychotics, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects, are well documented.³

Trials included in the meta-analysis by Veale et al³ had a maximum duration of 16 weeks, so it is likely that many of the potential harms of antipsychotic use would not yet have been measurable. The authors cautioned that, although aripiprazole and risperidone demonstrated benefit, their benefit must be weighed against the potential physical risks of long-term antipsychotic use.³One study that was not included in the meta-analysis by Veale et al³ evaluated individuals who did not respond to a SSRI, and randomly assigned them to quetiapine, olanzapine, or risperidone plus CBT. At 1-year follow-up, 50% of participants receiving an antipsychotic had an increase of >10% in body mass index (BMI) and had higher fasting blood sugars compared with only 15.2% of participants with increased BMI in the comparison group (SSRI responders).³

Foa et al⁸ investigated long-term outcomes (ie, 6 months) of SSRI augmentation with ERP or risperidone in patients with OCD. Forty patients were randomized to receive risperidone, and 9 were considered responders. Only 8 chose to enter the maintenance phase, and of those participants, 5 did not complete the study. Two withdrew due to worsening depression, 2 withdrew due to intolerable adverse effects, and 1 was lost to follow-up. Unfortunately, there was no further discussion of what the intolerable adverse effects were.⁸

Patients with comorbid schizophrenia and OCD face additional risks. Lifetime prevalence rates of OCD are greater in persons with schizophrenia compared with the general population (26% vs 8%, respectively). Most studies have demonstrated poor prognosis and medication adherence among patients with comorbid schizophrenia and OCD. Fonseka et al⁹ assessed the risk of antipsychotic induction and exacerbation of OCD symptoms in patients with schizophrenia. Induction and exacerbation of OCD symptoms with clozapine was evident in several case reports, series, and retrospective reviews. A dose-dependent relationship is demonstrated in the literature as well. It is thought that this risk is related to clozapine’s action at the 5-HT2 receptor. Although evidence is limited, it appears that compared with other antipsychotics, clozapine is associated with the greatest risk of induction and exacerbation of OCD symptoms, with 20% to 28% of clozapine-treated patients exhibiting induction of OCD symptoms and 10% to 18% exhibiting an exacerbation of existing OCD symptoms.

Evidence of olanzapine induction and exacerbation of OCD symptoms is also limited to case reports and retrospective studies. However, some studies have estimated induction of OCD symptoms with olanzapine in 11% to 20% of patients.⁹ There is insufficient evidence to form conclusions regarding other antipsychotics. Fonseka et al⁹ recommends switching to an antipsychotic with lower 5HT-2 binding affinity or adding an SSRI, such as fluvoxamine, if induction or exacerbation of OCD symptoms occurs.

Consider long-term risks

The evidence for benefits with antipsy­chotics in treatment-resistant OCD is limited by different populations recruited, small sample sizes, and lack of long-term follow-up. Most evidence supports using ERP over antipsychotics for treating OCD symptoms that have not responded to SSRIs. However, ERP poses its own challenges that may limit clinical utility, such as economic and time restraints. Therefore, benefits with antipsychotics, such as risperidone and aripiprazole, must be weighed against potential long-term risks of treatment, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects.

Regarding Mr. E’s case, because he had been maximized on SSRI therapy for an adequate duration (escitalopram, 40 mg/d, for 12 weeks) and completed CBT with ERP with a partial response, adding risperidone, 0.5 mg at bedtime, was an appropriate treatment option that is supported by the available guidelines and evidence. The risperidone dose is reflective of the initial dosing strategies used in clinical trials. It is recommended to assess efficacy of treatment at 8 weeks with a validated measure, such as the Y-BOCS. A dose increase may be needed to achieve clinically significant symptom improvement, because moderate doses of risperidone have demonstrated efficacy in trials; however, high doses of risperidone are unlikely to provide additional benefit and increase the risk of adverse effects. If risperidone does not provide a clinically favorable risk–benefit ratio for Mr. E, aripiprazole is a potential alternative.

Mr. E, age 37, has a 20-year history of obsessive-compulsive disorder (OCD), with comorbid generalized anxiety disorder and hypertension. His medication regimen consists of lisinopril, 40 mg/d, to control his blood pressure, and escitalopram, 40 mg/d, for OCD and anxiety symptoms, which he started taking 12 weeks ago. Mr. E also has completed cognitive-behavioral therapy (CBT) with Exposure Response Prevention (ERP) therapy for his OCD symptoms. Although escitalopram and CBT have reduced Mr. E’s OCD symptoms, he still exhibits obsessions, such as fear of contamination, and compulsions, including handwashing, that are time-consuming and cause significant social and occupational distress. His Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score is 24. Mr. E asks his psychiatrist if there is anything else that may provide benefit. He is started on risperidone, 0.5 mg at bedtime, in addition to his existing medications. After 8 weeks of treatment with risperidone, Mr. E’s Y-BOCS score decreases to 21.

Box
Antipsychotics for OCD: What the guidelines recommend

Efficacy

The 2013 National Institute for Health Care and Excellence Evidence Update included a 2010 Cochrane Review of 11 randomized controlled trials (RCTs) of antipsychotics as adjunctive treatment to SSRIs.⁵ All trials were <6 months, and most were limited regarding quality aspects. Two trials found no statistically significant difference with olanzapine in efficacy measures (Y-BOCS mean difference [MD] −2.96; 95% confidence interval [CI] −7.41 to 1.22; effect size d = −2.96 [−7.14, 1.22]). Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was no significant difference between groups (n = 44, 1 RCT, odds ratio [OR] 0.76; 95% CI 0.17 to 3.29; effect size d = 0.76 [0.17, 3.29]). Studies found increased weight gain with olanzapine compared with antidepressant monotherapy.

Statistically significant differences were demonstrated with the addition of quetiapine to antidepressant monotherapy as shown in Y-BOCS score at endpoint (Y-BOCS MD −2.28; 95% CI −4.05 to −0.52; effect size d −2.28 [−4.05, −0.52]). Quetiapine also demonstrated benefit for depressive and anxiety symptoms. Among patients with no clinically significant change (defined as ≤35% reduction in Y-BOCS), there was a significant difference between groups (n = 80, 2 RCTs, OR 0.27; 95% CI 0.09 to 0.87; effect size d = 0.27 [0.09, 0.87]).

Adjunctive treatment with risperidone was superior to antidepressant mono­therapy for participants without a significant response in OCD symptom severity of at least 25% with validated measures (OR 0.17; 95% CI 0.04 to 0.66; effect size d = 0.17 [0.04, 0.66]), and in depressive and anxiety symptoms. Mean reduction in Y-BOCS scores was not statistically significant with risperidone (MD −3.35; 95% CI −8.25 to 1.55; effect size d = −3.35 [−8.25, 1.55]).⁵

A 2014 meta-analysis by Veale et al³ included double-blind, randomized trials that examined atypical antipsychotics compared with placebo for adults with OCD that used an intention-to-treat analysis. Unlike the Cochrane Review, these studies used the Y-BOCS as a primary outcome measure. Participants had a Y-BOCS score of ≥16; had at least 1 appropriate trial of an SSRI or clomipramine (defined as the maximum dose tolerated for at least 8 weeks); and had to continue taking the SSRI or clomipramine throughout the trial, which was a duration of at least 4 weeks. Of 46 published antipsychotic papers that were identified, 20 were excluded and 12 were duplicates. The primary reason for trial exclusion was open-label study design.

Fourteen articles were included in the meta-analysis, but all had small sample sizes and no long-term follow-up data.³ Antipsychotics in the meta-analysis included risperidone (4 studies), quetiapine (5 studies), olanzapine (2 studies), aripiprazole (2 studies), and paliperidone (1 study).

The overall difference in Y-BOCS score change between drug and placebo groups was 2.34 points, which had an overall effect size of d = 0.40. Those taking antipsychotics had approximately a 10% reduction in Y-BOCS score over time. The overall difference was statistically significant with risperidone (overall mean reduction of 3.89 points on the Y-BOCS; 95% CI 1.43 to 5.48; effect size of d = 0.53) and aripiprazole (difference in Y-BOCS outcome 0.1 scores of 6.29 points; effect size of d = 1.11). One trial of risperidone used a low dose (0.5 mg) and had a larger effect size than the studies that used moderate doses. The overall difference was not statistically significant for quetiapine (difference of Y-BOCS outcome scores of 0.81 points) or olanzapine (difference in Y-BOCS outcome scores of −0.19; indicating <1 point difference on the Y-BOCS).³

Studies included in the meta-analysis ranged in durations from 6 to 16 weeks; duration of ≥4 weeks did not make a difference in response. One study demonstrated a worsening of symptoms in the quetiapine group between weeks 4 and 12. Only 4 studies included most patients that had a previous trial of CBT. One study with an additional treatment arm evaluating CBT found that adding CBT was superior to adjunctive risperidone or placebo. Another study found that adding clomipramine or placebo to fluoxetine was superior to treatment with quetiapine. All study participants had Y-BOCS scores that indicated moderate OCD severity (16 to 23). Those with higher baseline Y-BOCS scores had a larger effect size for risperidone and quetiapine.³

Two studies included in the meta-analysis classified OCD symptoms by subtype, such as by dimensions of checking; symmetry, ordering, counting, and repeating; contamination and cleaning; and hoarding. Currently, no clinically significant predictor of outcome of antipsychotic therapy has been identified. Two studies included in the meta-analysis assessed patients with comorbid tic disorders and found no difference by treatment. One study demonstrated benefit of haloperidol in patients with comorbid tic disorders compared with those without comorbid tic disorders. Of note, none of the studies included in the meta-analysis excluded patients with hoarding characteristics, which generally indicate a worse prognosis with treatment.³

In 2015, Dold et al⁶ provided an update to a 2013 meta-analysis⁷ assessing antipsychotic augmentation of SSRIs in treatment-resistant OCD. This update included 2 new RCTs. The 2013 analysis⁷ concluded that risperidone should be considered first-line and is preferred over olanzapine and quetiapine. However, the update found the highest effect size for aripiprazole (d = −1.35), followed by haloperidol (d = −0.82), risperidone (d = −0.59), quetiapine (d = −0.50), olanzapine (d = −0.49), and paliperidone (d = −0.21).^6,7

The 2015 update⁶ concluded that the antipsychotic doses used in trials were moderate and that there was no association between dose and treatment response, indicating that high doses of antipsychotics may not be more effective. Dold et al⁶ postulated that the antipsychotic doses required for treating OCD are similar to those used in treating major depressive disorder and lower than doses used in treating schizophrenia. The 2013 meta-analysis demonstrated that moderate doses of antipsychotics resulted in statistically significant efficacy (relative risk [RR] = 3.99, 95% CI 1.92 to 8.27), while low doses did not demonstrate statistical significance (RR = 1.06, 95% CI 0.45 to 2.53).^6,7

The 2015 subgroup analysis update evaluated the duration of SSRI treatment prior to the antipsychotic augmentation phase, but did not demonstrate statistically significant efficacy for studies with <8 weeks’ duration of SSRI treatment, further highlighting the need for extended duration of treatment with an SSRI prior to augmentation.⁶

The 2013 meta-analysis discussed populations with comorbid tic disorders, including a study that found that patients with OCD and comorbid tic disorders benefit more from adjunctive antipsychotic therapy than those without the comorbidity. The 2015 update excluded trials that included patients with comorbid tic disorders to reduce bias, which did not affect the overall effect sizes of the data.^6,7

In summary, efficacy has been demonstrated for risperidone and aripiprazole. There has been no benefit demonstrated with olanzapine and limited benefit with quetiapine. One study suggested worsening of symptoms with quetiapine the longer that treatment persisted.^3,5-7

Safety

Assessing potential harms related to the use of antipsychotics in treating OCD is complicated, because this information is not always assessed in trials. Instead, researchers often focus on exploring potential benefits because long-term effects of antipsychotics, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects, are well documented.³

Trials included in the meta-analysis by Veale et al³ had a maximum duration of 16 weeks, so it is likely that many of the potential harms of antipsychotic use would not yet have been measurable. The authors cautioned that, although aripiprazole and risperidone demonstrated benefit, their benefit must be weighed against the potential physical risks of long-term antipsychotic use.³One study that was not included in the meta-analysis by Veale et al³ evaluated individuals who did not respond to a SSRI, and randomly assigned them to quetiapine, olanzapine, or risperidone plus CBT. At 1-year follow-up, 50% of participants receiving an antipsychotic had an increase of >10% in body mass index (BMI) and had higher fasting blood sugars compared with only 15.2% of participants with increased BMI in the comparison group (SSRI responders).³

Foa et al⁸ investigated long-term outcomes (ie, 6 months) of SSRI augmentation with ERP or risperidone in patients with OCD. Forty patients were randomized to receive risperidone, and 9 were considered responders. Only 8 chose to enter the maintenance phase, and of those participants, 5 did not complete the study. Two withdrew due to worsening depression, 2 withdrew due to intolerable adverse effects, and 1 was lost to follow-up. Unfortunately, there was no further discussion of what the intolerable adverse effects were.⁸

Patients with comorbid schizophrenia and OCD face additional risks. Lifetime prevalence rates of OCD are greater in persons with schizophrenia compared with the general population (26% vs 8%, respectively). Most studies have demonstrated poor prognosis and medication adherence among patients with comorbid schizophrenia and OCD. Fonseka et al⁹ assessed the risk of antipsychotic induction and exacerbation of OCD symptoms in patients with schizophrenia. Induction and exacerbation of OCD symptoms with clozapine was evident in several case reports, series, and retrospective reviews. A dose-dependent relationship is demonstrated in the literature as well. It is thought that this risk is related to clozapine’s action at the 5-HT2 receptor. Although evidence is limited, it appears that compared with other antipsychotics, clozapine is associated with the greatest risk of induction and exacerbation of OCD symptoms, with 20% to 28% of clozapine-treated patients exhibiting induction of OCD symptoms and 10% to 18% exhibiting an exacerbation of existing OCD symptoms.

Evidence of olanzapine induction and exacerbation of OCD symptoms is also limited to case reports and retrospective studies. However, some studies have estimated induction of OCD symptoms with olanzapine in 11% to 20% of patients.⁹ There is insufficient evidence to form conclusions regarding other antipsychotics. Fonseka et al⁹ recommends switching to an antipsychotic with lower 5HT-2 binding affinity or adding an SSRI, such as fluvoxamine, if induction or exacerbation of OCD symptoms occurs.

Consider long-term risks

The evidence for benefits with antipsy­chotics in treatment-resistant OCD is limited by different populations recruited, small sample sizes, and lack of long-term follow-up. Most evidence supports using ERP over antipsychotics for treating OCD symptoms that have not responded to SSRIs. However, ERP poses its own challenges that may limit clinical utility, such as economic and time restraints. Therefore, benefits with antipsychotics, such as risperidone and aripiprazole, must be weighed against potential long-term risks of treatment, including sedation, weight gain, metabolic syndrome, and extrapyramidal side effects.

Regarding Mr. E’s case, because he had been maximized on SSRI therapy for an adequate duration (escitalopram, 40 mg/d, for 12 weeks) and completed CBT with ERP with a partial response, adding risperidone, 0.5 mg at bedtime, was an appropriate treatment option that is supported by the available guidelines and evidence. The risperidone dose is reflective of the initial dosing strategies used in clinical trials. It is recommended to assess efficacy of treatment at 8 weeks with a validated measure, such as the Y-BOCS. A dose increase may be needed to achieve clinically significant symptom improvement, because moderate doses of risperidone have demonstrated efficacy in trials; however, high doses of risperidone are unlikely to provide additional benefit and increase the risk of adverse effects. If risperidone does not provide a clinically favorable risk–benefit ratio for Mr. E, aripiprazole is a potential alternative.

Dear Colleagues,

It is with great excitement that I introduce the first e-newsletter version of The New Gastroenterologist! As more content in medicine, and life in general, is moving toward digital platforms, we at the AGA believe this transition will improve both content dissemination and accessibility to all our readers. In this new format, we will continue to provide articles on topics of importance to the early-career community, expand our offerings by including the new “In Focus” articles (concise overviews of GI topics) both digitally and in GI & Hepatology News print issues, as well as increase the use of multimedia resources, such as videos, to further enhance our content.

In this issue of The New Gastroenterologist, our In Focus article provides a practical overview of the management of chronic constipation. This article, written by Nitin Ahuja and James Reynolds from the Neurogastroenterology and Motility Program at the University of Pennsylvania, Philadelphia, addresses a common topic in our field, and can also be found in the February print issue of GI & Hepatology News. To complement this article, there is a corresponding video abstract that can be viewed.

Also in this issue, Richard Peek (Vanderbilt University, Nashville, Tenn.) – one of the Coeditors in Chief of Gastroenterology – provides a summary of the newly created 1-year editorial fellowship for the AGA’s flagship journal. This is a fantastic new opportunity and you can learn firsthand about the experience of the inaugural editorial fellow, Eric Shah (University of Michigan, Ann Arbor), in an accompanying video. Additionally, as helping patients make a successful transition from a pediatric GI practice to an adult GI practice can be very challenging, in this issue Manreet Kaur and Allyson Wyatt (Baylor College of Medicine, Houston) provide a primer on how to successfully aid in this transition.

Are you considering a career in hospital administration? If so, you will enjoy reading about pursuing a career in hospital administration from Brijen Shah, who is the chief medical officer of Mount Sinai Queens (Icahn School of Medicine at Mount Sinai, New York). Have you been to one of the AGA’s Regional Practice Skills Workshops? These workshops are sponsored by the AGA Trainee and Early Career Committee and held in a growing number of cities across the country. In this issue, Munish Ashat (University of Iowa, Iowa City) provides a recap of the workshop he attended, complete with many useful career pearls.

I hope that you also enjoy the other features in the new e-newsletter format of The New Gastroenterologist. I especially want to point out one of our new sections entitled “In Case You Missed It.” As we all undoubtedly experience information overload with so many new articles released each month, this section collects relevant articles from the numerous AGA publications and consolidates them to ensure you don’t miss any of this great content.

If you are interested in contributing to future issues of The New Gastroenterologist or if there are topics that would interest you, please let us know. You can contact me ([email protected]) or the managing editor of The New Gastroenterologist, Ryan Farrell ([email protected]).

Sincerely,

Bryson W. Katona, MD, PhD
Editor in Chief

Dr. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia.

Dear Colleagues,

It is with great excitement that I introduce the first e-newsletter version of The New Gastroenterologist! As more content in medicine, and life in general, is moving toward digital platforms, we at the AGA believe this transition will improve both content dissemination and accessibility to all our readers. In this new format, we will continue to provide articles on topics of importance to the early-career community, expand our offerings by including the new “In Focus” articles (concise overviews of GI topics) both digitally and in GI & Hepatology News print issues, as well as increase the use of multimedia resources, such as videos, to further enhance our content.

In this issue of The New Gastroenterologist, our In Focus article provides a practical overview of the management of chronic constipation. This article, written by Nitin Ahuja and James Reynolds from the Neurogastroenterology and Motility Program at the University of Pennsylvania, Philadelphia, addresses a common topic in our field, and can also be found in the February print issue of GI & Hepatology News. To complement this article, there is a corresponding video abstract that can be viewed.

Also in this issue, Richard Peek (Vanderbilt University, Nashville, Tenn.) – one of the Coeditors in Chief of Gastroenterology – provides a summary of the newly created 1-year editorial fellowship for the AGA’s flagship journal. This is a fantastic new opportunity and you can learn firsthand about the experience of the inaugural editorial fellow, Eric Shah (University of Michigan, Ann Arbor), in an accompanying video. Additionally, as helping patients make a successful transition from a pediatric GI practice to an adult GI practice can be very challenging, in this issue Manreet Kaur and Allyson Wyatt (Baylor College of Medicine, Houston) provide a primer on how to successfully aid in this transition.

Are you considering a career in hospital administration? If so, you will enjoy reading about pursuing a career in hospital administration from Brijen Shah, who is the chief medical officer of Mount Sinai Queens (Icahn School of Medicine at Mount Sinai, New York). Have you been to one of the AGA’s Regional Practice Skills Workshops? These workshops are sponsored by the AGA Trainee and Early Career Committee and held in a growing number of cities across the country. In this issue, Munish Ashat (University of Iowa, Iowa City) provides a recap of the workshop he attended, complete with many useful career pearls.

I hope that you also enjoy the other features in the new e-newsletter format of The New Gastroenterologist. I especially want to point out one of our new sections entitled “In Case You Missed It.” As we all undoubtedly experience information overload with so many new articles released each month, this section collects relevant articles from the numerous AGA publications and consolidates them to ensure you don’t miss any of this great content.

If you are interested in contributing to future issues of The New Gastroenterologist or if there are topics that would interest you, please let us know. You can contact me ([email protected]) or the managing editor of The New Gastroenterologist, Ryan Farrell ([email protected]).

Sincerely,

Bryson W. Katona, MD, PhD
Editor in Chief

Dr. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia.

Dear Colleagues,

It is with great excitement that I introduce the first e-newsletter version of The New Gastroenterologist! As more content in medicine, and life in general, is moving toward digital platforms, we at the AGA believe this transition will improve both content dissemination and accessibility to all our readers. In this new format, we will continue to provide articles on topics of importance to the early-career community, expand our offerings by including the new “In Focus” articles (concise overviews of GI topics) both digitally and in GI & Hepatology News print issues, as well as increase the use of multimedia resources, such as videos, to further enhance our content.

In this issue of The New Gastroenterologist, our In Focus article provides a practical overview of the management of chronic constipation. This article, written by Nitin Ahuja and James Reynolds from the Neurogastroenterology and Motility Program at the University of Pennsylvania, Philadelphia, addresses a common topic in our field, and can also be found in the February print issue of GI & Hepatology News. To complement this article, there is a corresponding video abstract that can be viewed.

Also in this issue, Richard Peek (Vanderbilt University, Nashville, Tenn.) – one of the Coeditors in Chief of Gastroenterology – provides a summary of the newly created 1-year editorial fellowship for the AGA’s flagship journal. This is a fantastic new opportunity and you can learn firsthand about the experience of the inaugural editorial fellow, Eric Shah (University of Michigan, Ann Arbor), in an accompanying video. Additionally, as helping patients make a successful transition from a pediatric GI practice to an adult GI practice can be very challenging, in this issue Manreet Kaur and Allyson Wyatt (Baylor College of Medicine, Houston) provide a primer on how to successfully aid in this transition.

Are you considering a career in hospital administration? If so, you will enjoy reading about pursuing a career in hospital administration from Brijen Shah, who is the chief medical officer of Mount Sinai Queens (Icahn School of Medicine at Mount Sinai, New York). Have you been to one of the AGA’s Regional Practice Skills Workshops? These workshops are sponsored by the AGA Trainee and Early Career Committee and held in a growing number of cities across the country. In this issue, Munish Ashat (University of Iowa, Iowa City) provides a recap of the workshop he attended, complete with many useful career pearls.

I hope that you also enjoy the other features in the new e-newsletter format of The New Gastroenterologist. I especially want to point out one of our new sections entitled “In Case You Missed It.” As we all undoubtedly experience information overload with so many new articles released each month, this section collects relevant articles from the numerous AGA publications and consolidates them to ensure you don’t miss any of this great content.

If you are interested in contributing to future issues of The New Gastroenterologist or if there are topics that would interest you, please let us know. You can contact me ([email protected]) or the managing editor of The New Gastroenterologist, Ryan Farrell ([email protected]).

Sincerely,

Bryson W. Katona, MD, PhD
Editor in Chief

Dr. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia.

Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.

While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.

Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.

For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”

To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.

Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).

Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.

Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).

The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.

SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.

Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.

While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.

Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.

For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”

To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.

Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).

Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.

Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).

The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.

SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.

Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) grew at a median annual rate of 0.8 mm in a retrospective study of 1,369 patients.

While most of these cysts were “indolent and dormant,” some grew rapidly and developed “other worrisome features,” Youngmin Han, MS, of Seoul (South Korea) National University reported with his associates in the February issue of Gastroenterology. Therefore, clinicians should plan follow-up surveillance based on initial cyst size and growth rate, they concluded.

Based on their findings, the researchers recommended surgery for young, fit, asymptomatic patients who have BD-IPMNs with a diameter of least 30 mm or with thickened cyst walls or those who have a main pancreatic duct measuring 5-9 mm. Surgery also should be considered when patients have lymphadenopathy, high tumor marker levels, or an abrupt change in pancreatic duct caliber with distal pancreatic atrophy or a rapidly growing cyst, they said.

For asymptomatic patients whose cysts are under 10 mm and who do not have worrisome features, they recommended follow-up with CT or MRI at 6 months and then every 2 years after that. Cysts of 10-20 mm should be imaged at 6 months, at 12 months, and then every 1.5-2 years after that, they said. Patients with cyst diameters greater than 20 mm “should undergo MRI or CT or EUS [endoscopic ultrasound] every 6 months for 1 year and then annually thereafter, until the cyst size and features become stable,” they added. Patients whose cysts have a diameter of 30 mm or greater “should be closely monitored with MRI or CT or EUS every 6 months. Surgical resection can be considered in younger patients or those with other combined worrisome features.”

To characterize the natural history of BD-IPMN, the investigators evaluated clinical and imaging data collected between 2001 and 2016 from patients with classical features of BD-IPMN. Each patient included in the study provided 3 or more years of CT, MRI, EUS, and endoscopic retrograde cholangiopancreatography data. The researchers used regression models to estimate changes in sizes of cysts and main pancreatic ducts.

Median follow-up time was 61 months (range, 36-189 months). Cyst diameter averaged 12.8 mm (standard deviation, 6.5 mm) at baseline and 17 mm (SD, 9.2 mm) at final measurement. Larger baseline diameter was associated with faster growth (P = .046): Cysts measuring less than 10 mm at baseline grew at a median annual rate of 0.8 mm (SD, 1.1 mm), while those measuring at least 30 mm grew at a median annual rate of 1.2 mm (SD, 2.1 mm).

Worrisome features were present in 59 patients at baseline and emerged in another 150 patients during follow-up. At baseline, only 2.3% of cysts exceeded 30 mm in diameter, but 8.0% did at final measurement. Cyst wall thickening was found in 0.5% of patients at baseline and 3.7% of patients at final measurement. Main pancreatic ducts measured 5-9 mm in 1.9% of patients at baseline and in 5.6% of patients at final measurement. Additionally, the prevalence of mural nodules rose from 0.4% at baseline to 3.1% at final measurement.

Main pancreatic ducts averaged 1.8 mm (SD, 1.0 mm) at baseline and 2.4 mm (SD, 1.8 mm) at final measurement. Compared with the values seen with smaller cysts, larger baseline cyst diameter correlated significantly with larger main pancreatic ducts, more cases of cyst wall thickening, and more cases with mural nodules (P less than .001 for all comparisons).

The study was funded by a grant from Korean Health Technology R&D Project of Ministry of Health and Welfare, Republic of Korea. The investigators reported having no conflicts of interest.

SOURCE: Han Y et al. Gastroenterology. 2018. doi: 10.1053/j.gastro.2017.10.013.

About 20% of patients whose Crohn’s disease was stable and remitted on infliximab-antimetabolite combination therapy developed major complications within 7 years after infliximab withdrawal, according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).

About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 10⁹ per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.

Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).

About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.

Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.

Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.

The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
 

SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).

About 20% of patients whose Crohn’s disease was stable and remitted on infliximab-antimetabolite combination therapy developed major complications within 7 years after infliximab withdrawal, according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).

About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 10⁹ per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.

Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).

About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.

Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.

Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.

The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
 

SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).

About 20% of patients whose Crohn’s disease was stable and remitted on infliximab-antimetabolite combination therapy developed major complications within 7 years after infliximab withdrawal, according to research published in the February issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.09.061).

About 70% of patients remained free of both infliximab restart failure and major complications, said Catherine Reenaers, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium), and her associates. Significant predictors of major complications included upper gastrointestinal disease at the time of infliximab withdrawal, white blood cell count of at least 5.0 x 10⁹ per L, and hemoglobin level under 12.5 g per dL. “Patients with at least two of these factors had a more than 40% risk of major complication in the 7 years following infliximab withdrawal,” the researchers reported.

Little is known about long-term outcomes after patients with Crohn’s disease withdraw from infliximab. Therefore, Dr. Reenaers and her associates retrospectively studied 102 patients with Crohn’s disease who had received infliximab and an antimetabolite (azathioprine, mercaptopurine, or methotrexate) for at least 12 months, had been in steroid-free clinical remission for at least 6 months, and then withdrew from infliximab. Patients were recruited from 19 centers in Belgium and France and were originally part of a prospective cohort study of infliximab withdrawal in Crohn’s disease (Gastroenterology. 2012;142[1]:63-70.e5).

About half of patients relapsed and restarted infliximab within 12 months, which is in line with other studies, the researchers noted. Over a median follow-up of 83 months (interquartile range, 71-93 months), 21% (95% confidence interval, 13.1%-30.3%) of patients had no complications, did not restart infliximab, and started no other biologics. In all, 70.2% of patients (95% CI, 60.2%-80.1%) had no major complications and did not fail to respond after restarting infliximab.

Eighteen patients (19%; 95% CI, 10%-27%) developed major complications: 14 who required surgery and 4 who developed new complex perianal lesions. In a multivariable model, the strongest independent predictor of major complications was leukocytosis (hazard ratio, 10.5; 95% CI, 1.3-83; P less than .002), followed by upper gastrointestinal disease (HR, 5.8; 95% CI, 1.5-22) and low hemoglobin level (HR, 4.1; 95% CI, 1.5-21.8; P less than .01). The 13 patients who lacked these risk factors had no major complications of infliximab withdrawal. Among 72 patients who had at least one risk factor, 16.3% (95% CI, 7%-25%) developed major complications over 7 years. Strikingly, among 17 with at least two risk factors, 43% (95% CI, 17%-69%) developed major complications over 7 years, the researchers noted.

Complications emerged a median of 50 months (interquartile range, 41-73 months) after patients received their last infliximab infusion, highlighting the need for close long-term monitoring even if patients show no signs of early clinical relapse after infliximab withdrawal, the investigators said. “One strength of this cohort was the homogeneity of the population,” they stressed. “Most studies of anti–tumor necrosis factor withdrawal after clinical remission were limited by heterogeneous populations, variable lengths of infliximab treatment before discontinuation, and variable use of immunomodulators and corticosteroids. In [our] cohort, the population was homogenous, infliximab withdrawal was standardized, and the disease characteristics at the time of stopping were collected prospectively.” Although follow-up times varied, less than 5% of patients were followed for less than 3 years, they noted.

The researchers did not acknowledge external funding sources. Dr. Reenaers disclosed ties to AbbVie, Takeda, MSD, Mundipharma, Hospira, and Ferring.
 

SOURCE: Reenaers C et al. Clin Gastro Hepatol 2018 February (in press).